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AMERICAN SOCIETY OF CLINICAL ONCOLOGY

2012 EDUCATIONAL BOOK


48th Annual Meeting | June 1-5, 2012 | Chicago, Illinois

American Society of Clinical Oncology


Educational Book
The American Society of Clinical Oncology Educational Book (ISSN 1548-8748) is published by the American Society of
Clinical Oncology.
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The American Society of Clinical Oncology assumes no responsibility for errors or omissions in this publication. The reader
is advised to check the appropriate medical literature and the product information currently provided by the manufacturer
of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is
the responsibility of the treating physician or other health care professional, relying on the independent experience and
knowledge of the patient, to determine drug dosages and the best treatment for the patient.

American Society of Clinical


Oncology
Educational Book

Editor: Ramaswamy Govindan, MD


Associate Editor: Natasha Leighl, MD
Managing Editor: Christine Smith
Editorial Coordinator: Lauren Burke
Production Manager: Donna Dottellis
Executive Editor: Lisa Greaves

2012 American Society of Clinical Oncology


Alexandria, VA

ASCO gratefully acknowledges Amgen


for their support of the 48th Annual Meeting Educational Book.

American Society of Clinical


Oncology
Educational Book
TABLE OF CONTENTS
ASCO Annual Meeting Disclosure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii
20112012 Cancer Education Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiv
2012 Annual Meeting Faculty List . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv
2012 Educational Book Expert Panel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xx
2012 Annual Meeting Supporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxii
Letter from the Editor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

The 2012 ASCO Educational Book is published online at asco.org/edbook. Articles can also be accessed
from the Attendee Resource Center at chicago2012.asco.org/attendee. Articles that are included in this
print edition include a page number reference in the table of contents below.

Breast Cancer
Controversies in the Adjuvant Treatment of Breast Cancer
Adjuvant Therapy for Older Women with Early-Stage Breast Cancer: Treatment Selection in a Complex Population
Cynthia Owusu, Arti Hurria, and Hyman Muss. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Management of Small T1a/b N0 Breast Cancers
Anthony D. Elias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Controversies in Adjuvant Endocrine Therapy for Breast Cancer
Stephen R. Johnston. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
A Dickens Tale of the Treatment of Advanced Breast Cancer: The Past, the Present, and the Future
A Dickens Tale of the Treatment of Advanced Breast Cancer: The Past, the Present, and the Future
George W. Sledge Jr., Fatima Cardoso, Eric P. Winer, and Martine J. Piccart. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
A Fresh Look at Ductal Carcinoma In Situ: Basic Science to Clinical Management
Ductal Carcinoma In Situ: Challenges, Opportunities, and Uncharted Water
Abigail W. Hoffman, Catherine Ibarra-Drendall, Virginia Espina, Lance Liotta, and Victoria Seewaldt . . . . . . . . . . . . . . . . 40
Ductal Carcinoma In Situ, and the Influence of the Mode of Detection, Population Characteristics, and Other Risk
Factors
Beth A. Virnig, Shi-Yi Wang, and Todd M. Tuttle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Key Questions in the Loco-regional Treatment of Breast Cancer
Postmastectomy Radiation and Partial Breast Irradiation
Richard C. Zellars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
The Appropriate Extent of Surgery for Early-Stage Breast Cancer
Monica Morrow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

How Does Biology Affect Local Therapy Decisions?


Thomas A. Buchholz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
The Many Options for Breast Imaging: What to Use When
Clinical and Imaging Surveillance Following Breast Cancer Diagnosis
Chris I. Flowers, Blaise P. Mooney, and Jennifer S. Drukteinis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Advanced Imaging Techniques for the Detection of Breast Cancer
Maxine Jochelson. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Update of the Oxford Overview: New Insights and Perspectives in the Era of Personalized Medicine
Update of the Oxford Overview: New Insight and Perspectives in the Era of Personalized Medicine
Kathleen I. Pritchard, Jonas Bergh, and Harold J. Burstein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Cancer Genetics
Gene Patenting: Effects on Biotechnology and Oncology
Gene Patents and Personalized Medicine
Roger D. Klein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Cancer Prevention/Epidemiology
Breast Cancer Chemoprevention: If Not Now, When?
Chemoprevention for Breast Cancer: Overcoming Barriers to Treatment
Abenaa M. Brewster, Nancy E. Davidson, and Worta McCaskill-Stevens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Controversies in Prostate Cancer: PSA Screening, Chemoprevention, and Treatment of Early Disease
The Case for Prostate Cancer Risk Reduction by 5-Alpha Reductase Inhibitors
Youssef S. Tanagho and Gerald L. Andriole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Screening for Prostate Cancer with Prostate-Specific Antigen: Whats the Evidence?
Pamela M. Marcus and Barnett S. Kramer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Central Nervous System Tumors
Glioblastoma: Taking the Standard of Care to the Cutting Edge
Glioblastoma: Biology, Genetics, and Behavior
Daniel J. Brat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Future Directions in Glioblastoma Therapy
Howard Colman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Establishing the Standard of Care for Patients with Newly Diagnosed and Recurrent Glioblastoma
Mark R. Gilbert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Imaging in Neuro-oncology: Practical Primer for the Practicing Physician
Current Concepts in Brain Tumor Imaging
Andrew D. Norden, Whitney B. Pope, and Susan M. Chang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Perspectives on Headline-Making News in Neuro-oncology
Noninvasive Application of Alternating Electric Fields in Glioblastoma: A Fourth Cancer
Treatment Modality
Philip H. Gutin and Eric T. Wong . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Clinical Trials
Adaptive Clinical Trial Designs: What Are They and Should They Be Used?
Limitations of Adaptive Clinical Trials
Marc Buyse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Endpoints for Cancer Trials in 2012: Statistical, Regulatory, and Clinical Perspectives (eQ&A)
Capturing the Patient Perspective: Patient-Reported Outcomes as Clinical Trial Endpoints
Deborah Watkins Bruner, Benjamin Movsas, and Ethan Basch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

New Looks and Challenges for Cooperative Groups


The New National Cancer Institute National Clinical Trials Network
Stephen S. Grubbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Successful Integration of Cooperative Groups: The Origin of the Childrens Oncology Group
Gregory H. Reaman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Overcoming Disparities in Clinical Trial Accrual among African Americans
A Critical Review of the Enrollment of Black Patients in Cancer Clinical Trials
Deliya R. Banda, Diane St. Germain, Worta McCaskill-Stevens, Jean G. Ford, and Sandra M. Swain . . . . . . . . . . . . . . . . 153
Developmental Therapeutics
Antibody Conjugates: Targeted Therapy Meets Chemotherapy in One Drug
Trastuzumab Emtansine (T-DM1): Hitching a Ride on a Therapeutic Antibody
Howard A. Burris III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Targeting CD30 in Hodgkin Lymphoma: Antibody-Drug Conjugates Make a Difference
Catherine S. M. Diefenbach and John P. Leonard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Early Drug Development: Casting a Wide Net versus Preselecting a Narrow Audience
Approval of New Agents after Phase II Trials
Bruce Chabner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Drug Development in the Era of Personalized Oncology: From Population-Based Trials to Enrichment and
Prescreening Strategies
Rodrigo Dienstmann, Jordi Rodon, and Josep Tabernero. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Immunotherapy with the T-cell Checkpoint Antibodies: Implications for the Practitioner
Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein Antibodies for
the Oncologist
Jeffrey S. Weber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Targeting Critical Molecular Aberrations Early in the Course of Solid Tumors: Is It about Time?
Treatment of Chronic Myelogenous Leukemia as a Paradigm for Solid Tumors: How Targeted Agents in Newly Diagnosed
Disease Transformed Outcomes
Jason R. Westin, Hagop Kantarjian, and Razelle Kurzrock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Targeting Molecular Aberrations in Breast Cancer: Is It about Time?
Laura Esserman, Christopher Benz, and Angela DeMichele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Ethics
Ethical Challenges of Health Care
Core Elements of the Patient Protection and Affordable Care Act and Their Relevance to the Delivery of
High-Quality Cancer Care
Beverly Moy, Amy P. Abernethy, and Jeffrey M. Peppercorn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
International Variation in Understanding Oncologists Professional Duties toward Patients, Families, and Themselves
A Balanced Approach to Physician Responsibilities: Oncologists Duties toward Themselves
Amy P. Abernethy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Are Oncologists Accountable Only to Patients or Also to Their Families? An International Perspective
Antonella Surbone and Lea Baider . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
The Oncologists Duty to Provide Hope: Fact or Fiction?
Simon Wein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Medical Errors in Cancer Care: Prevention, Disclosure, and Patient and Family Member Responses
Oncologists Difficulties in Facing and Disclosing Medical Errors: Suggestions for the Clinic
Antonella Surbone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Preventing Errors in Oncology: Perspective of a Physician Who Is Also a Cancer Patient
Itzhak Brook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle

Gastrointestinal (Colorectal) Cancer


Personalized Oncology for Colorectal Cancer: Ready for Prime Time or Stop the Train?
Is There Currently an Established Role for the Use of Predictive or Prognostic Molecular Markers in the Management
of Colorectal Cancer? A Point/Counterpoint
Alan P. Venook, Johanna C. Bendell, and Robert S. Warren . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Curative-Intent Treatment of Colorectal Cancer Metastases
The Interventional Radiologist Role in Treating Liver Metastases for Colorectal Cancer
Stephen B. Solomon and Constantinos T. Sofocleous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Curative-Intent Treatment for Colorectal Liver Metastases: A Medical Oncologists Perspective
Leonard B. Saltz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Surgical Treatment of Colorectal Cancer Liver Metastases
Steven A. Curley . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Rectal Cancer: New Paradigms beyond Standard Chemotherapy and Radiation
Minimally Invasive Surgery of Rectal Cancer: Current Evidence and Options
Atthaphorn Trakarnsanga and Martin R. Weiser. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Radiation in Rectal Cancer: What Are the Options and If/When Can It Be Avoided?
Karyn A. Goodman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Stage III Colon Cancer: What Works, What Doesnt and Why, and Whats Next (eQ&A)
Stage III Colon Cancer: What Works, What Doesnt and Why, and Whats Next
Thierry Andre, Bert H. ONeil, and Jeffrey A. Meyerhardt. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Gastrointestinal (Noncolorectal) Cancer
Evolving Paradigms in the Management of Unresectable Pancreatic Cancer
A New Direction for Pancreatic Cancer Treatment: FOLFIRINOX in Context
Hedy Lee Kindler. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
A Matter of Timing: Is There a Role for Radiation in Locally Advanced Pancreatic Cancer, and If So, When?
Theodore S. Hong, Jennifer Y. Wo, and Eunice L. Kwak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
A Myriad of Symptoms: New Approaches to Optimizing Palliative Care of Patients with Advanced Pancreatic Cancer
Lauren A. Wiebe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Global Perspective of Locally Advanced Gastric Cancer: Different Treatment Paradigms and Their Rationale
Varying Lymphadenectomies for Gastric Adenocarcinoma in the East Compared with the West: Effect on Outcomes
Benjamin Schmidt and Sam S. Yoon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Will Disease Heterogeneity Help Define Treatment Paradigms for Gastroesophageal Adenocarcinoma? A Global
Perspective
Manish A. Shah . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Adjuvant Treatments for Localized Advanced Gastric Cancer: Differences among Geographic Regions
Yoon-Koo Kang and Changhoon Yoo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Liver-Directed Therapeutic Options for Hepatocellular Carcinoma: Patient Selection and Clinical Outcomes
Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma
Laura A. Dawson, Sameh Hashem, and Alexis Bujold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Patient Selection, Resection, and Outcomes for Hepatocellular Carcinoma
Claudius Conrad and Kenneth K. Tanabe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
The Management of Less Common but Complex Upper Gastrointestinal Malignancies: Hepatocellular Carcinoma,
Pancreatic Neuroendocrine Tumors, and Biliary Tract Tumors
A Renaissance in Therapeutic Options for Pancreatic Neuroendocrine Tumors
Pamela L. Kunz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
A Review of the Management of Hepatocellular Carcinoma: Standard Therapy and a Look to New Targets
Andrew X. Zhu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Advanced Biliary Tract Cancers
Laura Williams Goff and Jordan D. Berlin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Genitourinary Cancer
Best Use of Imaging Techniques, Old and New, for Genitourinary Cancers in Clinical Practice
Optimal Use of Imaging to Guide Treatment Decisions for Kidney Cancer
Walter M. Stadler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
Castration-Resistant Prostate Cancer: New Insights into Biology and Treatment (eQ&A)
State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012
Oliver Sartor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Prognostic, Predictive, and Surrogate Factors for Individualizing Treatment for Men with Castration-Resistant Prostate
Cancer
Rhonda L. Bitting and Andrew J. Armstrong . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
Kidney Cancer Biology and Therapeutics: VEGFR, mTOR, and Beyond
The Evolving Landscape of Metastatic Renal Cell Carcinoma
Daniel Y. C. Heng and Toni K. Choueiri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Recent Innovations in the Management of Genitourinary Cancers (eQ&A)
New Developments in Urothelial Cancer
Matthew D. Galsky . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
New Developments in Prostate Cancer Therapy
Madhuri Bajaj and Elisabeth I. Heath . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Geriatric Oncology
Adjuvant Therapy for Older Patients
Adjuvant Treatment of Older Patients with Lung Cancer
Jeffrey Crawford . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
Treatment of Older Patients with Advanced Cancer: Balancing Efficacy with Toxicity (eQ&A)
Considerations and Controversies in the Management of Older Patients with Advanced Cancer
Supriya Gupta Mohile, Heidi D. Klepin, and Arati V. Rao. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Gynecologic Cancer
Recent Clinical Highlights in Gynecologic Oncology
International Perspective on the Global Advances in Gynecologic Oncology
Lynette Denny . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
The European Society of Gynaecological Oncology: Update on Objectives and Educational and Research Activities
Renata Brantnerova, Ranjit Manchanda, and Nicoletta Colombo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Upfront Treatment of Ovarian Cancer: International Consensus and Variation
Biologicals in the Upfront Treatment of Ovarian Cancer: Focus on Bevacizumab and Poly (ADP-Ribose) Polymerase
Inhibitors
Rene Roux, Martin Zweifel, and Gordon J. S. Rustin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Intraperitoneal Treatment in Ovarian Cancer: The Gynecologic Oncology Group Perspective in 2012
Deborah K. Armstrong, Keiichi Fujiwara, and Danijela Jelovac . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Dose-Dense Chemotherapy and Neoadjuvant Chemotherapy for Ovarian Cancer
Keiichi Fujiwara, Noriyuki Katsumata, and Takashi Onda. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Uterine Sarcoma: Challenging Cases for the Interdisciplinary Team
Uterine Sarcomas: Histology and Its Implications on Therapy
Martee L. Hensley . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Surgical Options for Recurrent Uterine Sarcomas
Sharmilee B. Korets and John P. Curtin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

Head and Neck Cancer


Patients with HPV-Positive Oropharynx Tumors: Communicating Diagnosis to Family and Treatment Options
Management of Human Papillomavirus-Induced Oropharynx Cancer
David Brizel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Translating Biologic Discoveries into Clinical Trials
Important Early Advances in Squamous Cell Carcinoma of the Head and Neck
Eric Bissada, Irene Brana, and Lillian L. Siu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Application of Genomic and Proteomic Technologies in Biomarker Discovery
Elana J. Fertig, Robbert Slebos, and Christine H. Chung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Treatment of Thyroid Cancers: New Information for Medical Oncologists
Evaluation of Patients with Disseminated or Locoregionally Advanced Thyroid Cancer: A Primer for
Medical Oncologists
A. Dimitrios Colevas and Manisha H. Shah . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384
Systemic Therapeutic Approaches to Advanced Thyroid Cancers
Michael E. Menefee, Robert C. Smallridge, and Keith C. Bible, and the Mayo Clinic Endocrine Malignancies
Disease-Oriented Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Health Services Research
Avoiding Overdiagnosis and Overtreatment of Common Cancers
Overdiagnosis and Overtreatment of Prostate Cancer
Ian M. Thompson Jr. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Overdiagnosis and Overtreatment of Breast Cancer
Michael Alvarado, Elissa Ozanne, and Laura Esserman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Costs of Cancer Care: Affordability, Access, and Policy
Reducing the Cost of Cancer Care: How to Bend the Curve Downward
Thomas J. Smith, Bruce E. Hillner, and Ronan J. Kelly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
New Diagnostics and Devices in the Era of Comparative Effectiveness
Why Hasnt Genomic Testing Changed the Landscape in Clinical Oncology?
Daniel F. Hayes, Muin J. Khoury, and David Ransohoff. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Leukemia, Myelodysplasia, and Transplantation
Management of Chronic Lymphocytic Leukemia
Predicting Clinical Outcome in B-Chronic Lymphocytic Leukemia
Neil E. Kay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Transplant in Chronic Lymphocytic Leukemia: To Do It or Not and If So, When and How?
John G. Gribben . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
New Developments in Myeloproliferative Neoplasms
Therapeutic Advances in Myeloproliferative Neoplasms: The Role of New-Small Molecule Inhibitors
Srdan Verstovsek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Insights into the Molecular Genetics of Myeloproliferative Neoplasms
Huong (Marie) Nguyen and Jason Gotlib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Classification of Myeloproliferative Neoplasms and Prognostic Factors
Francesco Passamonti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Lung Cancer
Around the World in Almost 80 Minutes: Lung Cancer Care and Research
Lung Cancer in Brazil
Gilberto Schwartsmann . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
Research and Standard Care: Lung Cancer in China
Tony S. Mok, Qing Zhou, and Yi-Long Wu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

Research and Standard of Care: Lung Cancer in Romania


Tudor E. Ciuleanu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Leveraging Virtual Patient Communities for Optimal Clinical Care and Research
A New Model: Physician-Patient Collaboration in Online Communities and the Clinical Practice of Oncology
Howard J. West, Dave deBronkart, and George D. Demetri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
Lung Cancer Screening 101
Lung Cancer Screening: Promise and Pitfalls
Christine D. Berg, Denise R. Aberle, and Douglas E. Wood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Personalized Medicine in Lung Cancer in 2012
Molecular Testing of NonSmall Cell Lung Carcinoma Biopsy and Cytology Specimens
Ignacio I. Wistuba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Thymoma and Thymic Carcinoma: Update on Management
Multidisciplinary Management of Thymic Carcinoma
Gregory J. Riely, James Huang, and Andreas Rimner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
The Creation of the International Thymic Malignancies Interest Group as a Model for Rare Diseases
Frank C. Detterbeck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Thymoma: From Chemotherapy to Targeted Therapy
Nicolas Girard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Lymphoma and Plasma Cell Disorders
Controversies in Indolent Lymphoma
What Is the Best Strategy for Incorporating New Agents into the Current Treatment of Follicular Lymphoma?
Sonali M. Smith . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
What Is the Best First-Line Treatment Strategy for Patients with Indolent Lymphomas?
Gilles Salles, Herve Ghesquie`res, and Emmanuel Bachy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
What Is the Role of Transplantation for Indolent Lymphoma?
Ryan D. Cassaday and Ajay K. Gopal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Controversies in Myeloma: Induction, Transplant, and Maintenance
Stem Cell Transplantation for Multiple Myeloma: Who, When, and What Type?
Amrita Krishnan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
Upfront Therapy for Myeloma: Tailoring Therapy across the Disease Spectrum
S. Vincent Rajkumar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508
Maintenance Therapy for Myeloma: How Much, How Long, and at What Cost?
Michel Attal and Murielle Roussel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515
Melanoma/Skin Cancers
New Options, New Questions: How to Select and Sequence Therapies for Metastatic Melanoma
New Options and New Questions: How to Select and Sequence Therapies for Patients with Metastatic Melanoma
Keith T. Flaherty, Jeff A. Sosman, and Michael B. Atkins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
Patient and Survivor Care
Antiemetics: Current Standards, Emerging Approaches, and Persistent Gaps
Antiemetic Use in Oncology: Updated Guideline Recommendations from ASCO
Ethan Basch, Ann Alexis Prestrud, Paul J. Hesketh, Mark G. Kris, Mark R. Somerfield, and Gary H. Lyman . . . . . . . . . . 532
Chemotherapy-Induced Nausea and Vomiting Incidence and Prevalence
Steven M. Grunberg. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Mucosal Injury in Patients with Cancer: Targeting the Biology
New Frontiers in Mucositis
Douglas E. Peterson, Dorothy M. Keefe, and Stephen T. Sonis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545

Short- and Long-term Cardiovascular Complications of Cancer Treatment: Overview for the Practicing Oncologist
Short- and Long-term Cardiovascular Complications of Cancer Treatment: Overview for the Practicing Oncologist
Chetan Shenoy and Gretchen Kimmick . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553
Recent Advances in Cardiotoxicity of Anticancer Therapies
Marianne Ryberg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555
When Cancer Becomes Personal: The Physicians View of Patient Care
The Oncologist as the Patient with Cancer or Relative
Teresa Gilewski, Martin Raber, and George W. Sledge Jr. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Pediatric Oncology
Advances in Infection Management in Pediatric Oncology
Prolonged Febrile Neutropenia in the Pediatric Patient with Cancer
Andrew Y. Koh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
Initial Management of Low-Risk Pediatric Fever and Neutropenia: Efficacy and Safety, Costs, Quality-of-Life
Considerations, and Preferences
Lillian Sung . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
Genetic Counseling of the Patient with Pediatric Cancer
Identification, Management, and Evaluation of Children with Cancer-Predisposition Syndromes
Sara Knapke, Kristin Zelley, Kim E. Nichols, Wendy Kohlmann, and Joshua D. Schiffman . . . . . . . . . . . . . . . . . . . . . . . . . 576
How to Manage Very Rare Pediatric Cancers
Treating Rare Cancer in Children: The Importance of Evidence
Alberto S. Pappo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
Genetic Alterations in Childhood Melanoma
Fariba Navid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Desmoid-Type Fibromatosis in Children: A Step Forward in the Cooperative Group Setting
Natalie Pounds and Stephen X. Skapek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Molecular Pathways for the Practicing Pediatric Oncologist
Targeting the Insulin-Like Growth Factor (IGF) System Is Not as Simple as Just Targeting the Type 1 IGF Receptor
Katia Scotlandi and Antonino Belfiore . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Hedgehog Pathway in Pediatric Cancers: Theyre Not Just for Brain Tumors Anymore
Tobey J. MacDonald . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Pediatric Oncology Educational Session in Honor of Dr. James Nachman
Development and Refinement of Augmented Treatment Regimens for Pediatric High-Risk Acute Lymphoblastic Leukemia
Stephen P. Hunger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
Refining the Role of Radiation Therapy in Pediatric Hodgkin Lymphoma
Melissa M. Hudson and Louis S. Constine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
Role of Doxorubicin in Rhabdomyosarcoma: Is the Answer Knowable?
Carola A. S. Arndt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Pontine Gliomas in Children: To Biopsy or Not to Biopsy
Identification of Novel Biologic Targets in the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Glioma
Nathan J. Robison and Mark W. Kieran . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?
Stephanie Puget, Thomas Blauwblomme, and Jacques Grill. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Ethics of Biopsy in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma
Nicholas K. Foreman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
Transition and Decision Making for Palliative Care of Patients with Pediatric Cancer
Communication and Decision Support for Children with Advanced Cancer and Their Families
Jennifer W. Mack, Chris Feudtner, and Pamela S. Hinds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637

Practice Management and Information Technology


Addressing the Imbalance of Supply and Demand: Integrating Advanced Practice Providers into Survivorship Care
Planning for the Future: The Role of Nurse Practitioners and Physician Assistants in Survivorship Care
Mary S. McCabe and Todd Alan Pickard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Doing It Right, and for Less: Implementing Practice Changes to Manage the Growing Complexities, Inefficiencies,
and Costs of Cancer Care
Driving Evidence-Based Standardization of Care within a Framework of Personalized Medicine
Adam Brufsky, Kathleen Lokay, and Melissa McDonald . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Patient Portals in Oncology
The Future of Oncology Care with Personal Health Records
Henry Feldman and Elizabeth S. Rodriguez . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
The ASCO Quality Oncology Practice Initiative (QOPI) and Beyond
Measuring and Improving Value of Care in Oncology Practices: ASCO Programs from Quality Oncology Practice
Initiative to the Rapid Learning System
Joseph O. Jacobson, Michael N. Neuss, and Robert Hauser . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Professional Development
Physician Wellness: Coping with Repetitive Loss and Work-Related Stress
Buoyancy: A Model for Self-Reflection about Stress and Burnout in Oncology Providers
Michael J. Fisch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Encountering Grief in Patient Care
Teresa Gilewski. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Talking in Sync with Patients across Cultural Barriers
New Insights in Cross-Cultural Communication
Lidia Schapira. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
The Oncologist, the Patient, and the Media
Patients with Cancer, Internet Information, and the Clinical Encounter: A Taxonomy of Patient Users
Paul R. Helft . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle
Sarcoma
Global Variations in Access to New Therapies for Sarcomas and Gastrointestinal Stromal Tumor
How to Decide Whether to Offer and Use Nonstandard Therapies in Patients with Advanced Sarcomas and
Gastrointestinal Stromal Tumors: Global Variations in Clinical Practice, Assessment, and Access to Therapies in
Diseases with Limited Incidence and Data
Stefan Sleijfer, Ian Judson, and George D. Demetri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645
Targeted Therapies in Targeted or Untargeted Sarcomas
Targeted Therapy in Sarcoma: Should We Be Lumpers or Splitters?
Richard F. Riedel, Robert G. Maki, and Andrew J. Wagner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
What the Busy Oncologist Needs to Know about Gastrointestinal Stromal Tumor
Adjuvant Treatment of Gastrointestinal Stromal Tumor: The Proof, the Pro, and the Practice
Jaap Verweij . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Management of Tyrosine Kinase InhibitorResistant Gastrointestinal Stromal Tumors
Christine M. Barnett and Michael C. Heinrich . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
Tumor Biology
Biologic Principles of Targeted Combination Therapy
Opportunities and Pitfalls of Targeted Therapeutic Combinations in Solid Tumors
Joaquin Mateo, Michael Ong, Timothy A. Yap, and Johann S. de Bono . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670

Combination Therapies Building on the Efficacy of CTLA4 and BRAF Inhibitors for Metastatic Melanoma
Antoni Ribas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
Mechanisms of Resistance to Targeted Anticancer Agents
Mechanisms of Resistance to Mitogen-Activated Protein Kinase Pathway Inhibition in BRAF-Mutant Melanoma
Eva M. Goetz and Levi A. Garraway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
Mechanisms of Resistance to Targeted Therapies in Acute Myeloid Leukemia and Chronic Myeloid Leukemia
Catherine C. Smith and Neil P. Shah . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Toward Successful Targeting of the PI3 Kinase Pathway in Cancer
Translating PI3K-Delta Inhibitors to the Clinic in Chronic Lymphocytic Leukemia: The Story of CAL-101 (GS1101)
John C. Byrd, Jennifer A. Woyach, and Amy J. Johnson . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
PI3 Kinase in Cancer: From Biology to Clinic
Paul Workman and Paul Clarke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . eArticle

2012 ASCO Annual Meeting Disclosure


In compliance with the ASCO Conflict of Interest Policy and the Accreditation Council for Continuing Medical
Education (ACCME) Standards for Commercial Support, authors and faculty who participate in any ASCOsponsored meeting must disclose financial interests and other relationships with entities that have an
investment, licensing, or other commercial interest in the subject matter under consideration in their paper
or presentation. Author and faculty disclosures may be published in ASCO publications where appropriate.
Definition of notations: L Leadership Position; I Immediate Family Member; B Myself and immediate
Family Member; U Uncompensated.
Authors and faculty will be asked to disclose financial interests and other relationships in the following
categories:

Employment or Leadership Positions


Any full- or part-time employment or service as an officer or board member for an entity having an investment,
licensing, or other commercial interest in the subject matter under consideration must be disclosed.

Advisory Role
Consultant or advisory arrangements with an entity having an investment, licensing, or other commercial
interest in the subject matter under consideration must be disclosed if consultation was performed or payments
made for such consultation within 2 years of the activity or subject matter in question.

Stock Ownership
Any ownership interest (except when invested in a diversified fund not controlled by the covered individual) in
a start-up company, the stock of which is not publicly traded, or in any publicly traded company must be disclosed
if the company is an entity having an investment, licensing, or other commercial interest in the subject matter
under consideration.

Honoraria
Honoraria are reasonable payments for specific speeches, seminar presentations, or appearances. Disclosure of
honoraria is required when paid directly to the covered individual by an entity having an investment, licensing,
or other commercial interest in the subject matter under consideration and when provided within 2 years of the
activity or subject matter in question.

Research Funding
All payments associated with the conduct of the clinical research project in question must be disclosed if provided
by the trial sponsor or agents employed by the sponsor.

Expert Testimony
Provision of expert testimony must be disclosed when the testimony relates to the subject matter under
consideration.

Other Remuneration
The value of trips, travel, gifts, or other in-kind payments not directly related to research activities must be
disclosed if received from an entity having an investment, licensing, or other commercial interest in the subject
matter under consideration and when received within 2 years of the activity or subject matter in question. These
payments exclude research-related costs and travel.

Continuing Medical Education Information


This activity has been approved for AMA PRA Category 1 Credit. For information detailing the
Continuing Medical Education components of the 48th ASCO Annual Meeting, please visit
chicago2012.asco.org.

20112012 Cancer Education Committee


Harold J. Burstein MD, PhD, Chair
Antoinette R. Tan, MD, Chair-Elect
Charles Blanke, MD, Immediate Past
Chair
Gary I. Cohen, MD, Board Liaison
Breast Cancer
Anna Maria Storniolo, MD (Track
Leader)
Angelo Di Leo, MD, PhD
Stephen R. Grobmyer, MD
Erica L. Mayer, MD, MPH
Karen A. Gelmon, MD
Jonas Bergh, MD, PhD
Barbara A. Parker, MD
Richard C. Zellars, MD
Cancer Genetics
Sancy Ann Leachman, MD (Track
Leader)
James M. Ford, MD
Kenneth Offit, MD, MPH
Michael J. Hall, MD
Zsofia Kinga Stadler, MD
Cancer Prevention/Epidemiology
Pamela Jean Goodwin, MD (Track
Leader)
Christopher S. Lathan, MD, MS, MPH
Abenaa M. Brewster, MD, MHS
James Roger Marshall, PhD
Melanie R. Palomares, MD
Central Nervous System Tumors
Joon H. Uhm, MD (Track Leader)
Jay Steven Loeffler, MD
Timothy Francis Cloughesy, MD
Clinical Trials
David M. Dilts, PhD, MBA (Track
Leader)
Donna S. Neuberg, ScD
Tatiana Michelle Prowell, MD
Philip Jordan Gold, MD
Mary W. Redman, PhD
Tim Eisen, PhD
Developmental Therapeutics
Keith T. Flaherty, MD (Track Leader)
Howard A. Burris III, MD
Razelle Kurzrock, MD
Timothy W. Synold, PharmD
Ethics
Antonella Surbone, MD, PhD (Track
Leader)
Amy Pickar Abernethy, MD
Eileen P. Smith, MD
Rudolph M. Navari, MD, PhD

Gastrointestinal (Colorectal) Cancer


Jeffrey A. Meyerhardt, MD, MPH
(Track Leader)
Johanna C. Bendell, MD
Alan Paul Venook, MD
David P. Ryan, MD
Gastrointestinal (Noncolorectal)
Cancer
Jordan Berlin, MD (Track Leader)
Hedy Lee Kindler, MD
Matthew Kulke, MD
Pamela L. Kunz, MD
Manish A. Shah, MD
Cliff P. Connery, MD
Genitourinary Cancer
Kim N. Chi, MD (Track Leader)
Toni K. Choueiri, MD
Johann Sebastian De Bono, MD, PhD,
MSc
Matt D. Galsky, MD
Primo Lara Jr., MD
Andrew J. Stephenson, MD
Geriatric Oncology
Supriya Gupta Mohile, MD, MS (Track
Leader)
Arti Hurria, MD
Arati Rao, MD
Homayoon Sanati, MD
Gynecologic Cancer
Don S. Dizon, MD (Track Leader)
Gini F. Fleming, MD
David E. Cohn, MD
Head and Neck Cancer
David Sidransky, MD (Track Leader)
Ezra E.W. Cohen, MD
Vassiliki Papadimitrakopoulou, MD
Health Services Research
Jennifer J. Griggs, MD, MPH (Track
Leader)
Dawn L. Hershman, MD
Jennifer Malin, MD
Rinaa S. Punglia, MD
Steven J. Katz, MD
Leukemia, Myelodysplasia, and
Transplantation
Martin S. Tallman, MD (Track Leader)
Daniel J. DeAngelo, MD, PhD
Koen Van Besien, MD
Lung Cancer
Renato Martins, MD, MPH (Track
Leader)
David E. Gerber, MD
Pasi A. Janne, MD, PhD
Jyoti D. Patel, MD
Charles Andrew Butts, MD
Natasha B. Leighl, MD

Lymphoma and Plasma Cell


Disorders
Amrita Y. Krishnan, MD (Track Leader)
Ranjana Advani, MD
Nancy Bartlett, MD
Steven M. Horwitz, MD
Jeremy S. Abramson, MD, MSc
Melanoma/Skin Cancers
Leslie Anne Fecher, MD (Track Leader)
F. Stephen Hodi, MD
Vernon K. Sondak, MD
Denise L. Johnson Miller, MD
Hensin Tsao, MD
Patient and Survivor Care
Julia Howe Rowland, PhD (Track
Leader)
Sydney Morss Dy, MD
Teresa Gilewski, MD
Gretchen Genevieve Kimmick, MD
Pediatric Oncology
Stephen L. Lessnick, MD, PhD (Track
Leader)
Mark W. Kieran MD, PhD
Stephen Skapek, MD
Judith K. Sato, MD
Practice Management and
Information Technology
Craig A. Bunnell, MD (Track Leader)
Robert Stephen Miller, MD
William Charles Penley, MD
Alan M. Keller, MD
David R. Artz, MD
Professional Development
Michael Anthony Carducci, MD (Track
Leader)
Emily K. Bergsland, MD
Christine Marie Lovly, MD, PhD
Vikki A. Canfield, MD
Katherine Elizabeth Reeder-Hayes, MD
Robert A. Wolff, MD
Sarcoma
George D. Demetri, MD (Track Leader)
Richard F. Riedel, MD
Warren Allen Chow, MD
Jayesh Desai, MD
R. Lor Randall, MD
Tumor Biology
Levi Garraway, MD, PhD (Track
Leader)
Ross L. Levine, MD
Lee M. Ellis, MD
Josep Tabernero, MD

2012 Annual Meeting Faculty List


Matti S. Aapro, MD
Clinique De Genolier
Denise R. Aberle, MD
University of California, Los
Angeles
Amy Pickar Abernethy, MD
Duke University Medical Center
Thierry Andre,
Pitie-Salpetriere Hospital
Gerald L. Andriole, MD
Washington University School of
Medicine
Andrew J. Armstrong, MD, ScM
Duke Cancer Institute
Deborah Kay Armstrong, MD
Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
University
Carola A. S. Arndt, MD
Mayo Clinic
Carlos L. Arteaga, MD
Vanderbilt University
Michael B. Atkins, MD
Beth Israel Deaconess Medical
Center
Michel Attal, MD
CHU Purpan
Peter Bach, MD
Memorial Sloan-Kettering Cancer
Center
Deliya Banda, PhD, MPH
Washington Hospital Center
Alberto Bardelli, PhD
Istituto Ricerca Cura Cancro and
FIRC
Ethan M. Basch, MD, MSc
Memorial Sloan-Kettering Cancer
Center
Johanna C. Bendell, MD
The Sarah Cannon Research
Institute
Christine D. Berg, MD
National Cancer Institute
Carl Bergh, MD
Karolinska Institutet
Jordan Berlin, MD
Vanderbilt-Ingram Cancer Center
Donald A. Berry, PhD
University of Texas M. D.
Anderson Cancer Center
Keith C. Bible, MD, PhD
Mayo Clinic
Douglas W. Blayney, MD
Stanford University
Diane Blum, MSW
Lymphoma Research Foundation
Daniel Brat, MD, PhD
Emory University

Abenaa M. Brewster, MD, MHS


University of Texas M. D.
Anderson Cancer Center
David M. Brizel, MD
Duke University Medical Center
Itzhak Brook, MD, MSc
Georgetown University
Adam Brufsky, MD, PhD
University of Pittsburgh School
of Medicine
Deborah Watkins Bruner, PhD, RN
Abramson Cancer Center,
University of Pennsylvania
Thomas A. Buchholz, MD
University of Texas M. D.
Anderson Cancer Center
Howard A. Burris, MD
The Sarah Cannon Research
Institute
Harold J. Burstein, MD, PhD
Dana-Farber Cancer Institute
Marc E. Buyse, ScD
International Drug Development
Institute
John C. Byrd, MD
The Ohio State University
Comprehensive Cancer Center
D. Ross Camidge, MD, PhD
University of Colorado Cancer
Center
Fatima Cardoso, MD
Breast Unit, Champalimaud
Cancer Center
Bruce Allan Chabner, MD
Massachusetts General Hospital
Susan Marina Chang, MD
University of California, San
Francisco
E. Antonio Chiocca, MD, PhD
The Ohio State University
Medical Center
Toni K. Choueiri, MD
Dana-Farber Cancer Institute/
Harvard Medical School
Christine H. Chung, MD
Johns Hopkins University
Tudor-Eliade Ciuleanu, MD
Institute Ion Chiricuta
Rebecca Anne Clark-Snow, RN
University of Kansas Cancer
Center
Timothy Francis Cloughesy, MD
University of California, Los
Angeles
Kenneth J. Cohen, MD, MBA
Johns Hopkins School of
Medicine
A. Dimitrios Colevas, MD
Stanford University School of
Medicine

Howard Colman, MD, PhD


University of Utah
Nicoletta Colombo, MD
University of Milan-Bicocca
Robert Leo Comis, MD
Coalition of Cancer Cooperative
Groups
Carolyn C. Compton, MD, PhD
National Institutes of Health
Fergus J. Couch, PhD
Mayo Clinic
Jeffrey Crawford, MD
Duke University Medical Center
Steven A. Curley, MD
University of Texas M. D.
Anderson Cancer Center
John Patrick Curtin, MD
New York University School of
Medicine
Nancy E. Davidson, MD
University of Pittsburgh Cancer
Institute
Laura A. Dawson, MD
Princess Margaret Hospital
Johann Sebastian De Bono, MB,
ChB, MSc, PhD
Royal Marsden Hospital
Dave Debronkart
Boston, Massachusetts
John F. Deeken, MD
Lombardi Comprehensive
Cancer Center, Georgetown
University
George D. Demetri, MD
Dana-Farber Cancer Institute/
Harvard Medical School
Lynette Denny, MD, PhD
University of Cape Town
Frank C. Detterbeck, MD
Yale School of Medicine
Craig Earle, MD
Institute for Clinical Evaluative
Sciences
Anthony D. Elias, MD
University of Colorado Cancer
Center
Lee M. Ellis, MD
University of Texas M. D.
Anderson Cancer Center
William F. Elmquist, PhD,
PharmD
University of Minnesota
Laura Esserman, MD, MBA
University of California, San
Francisco Helen Diller Family
Comprehensive Cancer Center
Ruth D. Etzioni, PhD
University of Washington

Ann T. Farrell, MD
U. S. Food and Drug
Administration
Henry Feldman, MD
Division of Clinical Informatics
Chris Feudtner, MD, PhD, MPH
Childrens Hospital of
Philadelphia
Michael Fisch, MD, MPH
University of Texas M. D.
Anderson Cancer Center
Keith T. Flaherty, MD
Massachusetts General Hospital
Chris Flowers, MD
H. Lee Moffitt Cancer Center &
Research Institute
Jean G. Ford, MD
Johns Hopkins School of
Medicine
Nicholas K. Foreman, MD
The Childrens Hospital
Josef J. Fox, MD
Memorial Sloan-Kettering Cancer
Center
Keiichi Fujiwara, MD, PhD
Saitama Medical University
International Medical Center
Gwendolyn A. Fyfe, MD
San Francisco, California
Matt D. Galsky, MD
The Tisch Cancer Institute,
Mount Sinai School of Medicine
Patricia A. Ganz, MD
University of California, Los
Angeles Schools of Medicine and
Public Health
Levi A. Garraway, MD, PhD
Dana-Farber Cancer Institute
Karen A. Gelmon, MD
British Columbia Cancer
Agency
Mark R. Gilbert, MD
University of Texas M. D.
Anderson Cancer Center
Teresa Gilewski, MD
Memorial Sloan-Kettering Cancer
Center
Maura L. Gillison, MD, PhD
The Ohio State University
Nicolas Girard, MD, MSc
Hopital Louis Pradel
Michael Goldstein, MD
Beth Israel Deaconess Medical
Center and Harvard Medical
School
Paul J. Goodfellow, PhD
Washington University School of
Medicine
Karyn A. Goodman, MD
Memorial Sloan-Kettering Cancer
Center

Ajay K. Gopal, MD
University of Washington
Jason R. Gotlib, MD
Stanford University School of
Medicine
Bernardo Haddock Lobo Goulart,
MD
Fred Hutchinson Cancer
Research Center
John G. Gribben, DSc, MD
St. Bartholomews Hospital
Stephen S. Grubbs, MD
Helen F. Graham Cancer Center
at Christiana Care
Stephen B. Gruber, MD, PhD,
MPH
University of Michigan
Steven M. Grunberg, MD
Fletcher Allen Health Care
Eva Grunfeld, MD, DPhil
University of Toronto
Philip H. Gutin, MD
Memorial Sloan-Kettering Cancer
Center
Paul Han, MD, MA, MPH
Maine Medical Center Reseach
Institute
Robert Hauser, PhD, PharmD
American Society of Clinical
Oncology
Joshua Hauser, MD
Northwestern University
Daniel F. Hayes, MD
University of Michigan Medical
Center
Elisabeth I. Heath, MD
Karmanos Cancer Institute
Michael C. Heinrich, MD
Oregon Health & Science
University Knight Cancer
Institute
Paul R. Helft, MD
Indiana University Simon Cancer
Center
Daniel Yick Chin Heng, MD,
MPH
Tom Baker Cancer Centre,
University of Calgary
Martee Leigh Hensley, MD, MSc
Memorial Sloan-Kettering Cancer
Center
Dawn L. Hershman, MD, MS
Columbia University Medical
Center
William J. Hicks, MD
The Ohio State University
Peter Hillmen, PhD
Leeds General Infirmary
Bruce E. Hillner, MD
Virginia Commonwealth
University

Pamela S. Hinds, PhD, RN


Childrens National Medical
Center
F. Stephen Hodi, MD
Dana-Farber Cancer Institute
Theodore S. Hong, MD
Massachusetts General Hospital
Melissa M. Hudson, MD
St. Jude Childrens Research
Hospital
Stephen Hunger, MD
University of Colorado Denver
School of Medicine
Arti Hurria, MD
City of Hope
Eun-Sil Shelley Hwang, MD,
MPH
Duke Unversity Medical Center
Nadine Jackson McCleary, MD
Dana-Farber Cancer Institute
Joseph O. Jacobson, MD
North Shore Medical Center
Pasi A. Janne, MD, PhD
Dana-Farber Cancer Institute
Anuja Jhingran, MD
University of Texas M. D.
Anderson Cancer Center
Maxine S. Jochelson, MD
Memorial Sloan-Kettering Cancer
Center
Stephen R. D. Johnston, MA, MD,
PhD
Royal Marsden Hospital
Ian Robert Judson, MD
Royal Marsden Hospital and
NHS Foundation Trust
William G. Kaelin, MD
Dana-Farber Cancer Institute
Yoon-Koo Kang, MD, PhD
Asan Medical Center
Hagop Kantarjian, MD
University of Texas M. D.
Anderson Cancer Center
Neil E. Kay, MD
Mayo Clinic
Dorothy Mary Kate Keefe, MD,
MBBS
Royal Adelaide Hospital
Karla Kerlikowske, MD
University of California, San
Francisco
Muin Khoury, MD, PhD
Office of Public Health
Genomics, Centers for Disease
Control and Prevention
Mark W. Kieran, MD, PhD
Dana-Farber Cancer Institute
Gretchen Genevieve Kimmick,
MD, MS
Duke University Medical Center

Hedy Lee Kindler, MD


The University of Chicago
Medical Center
Roger David Klein, MD, JD
Bloodcenter of Wisconsin
Heidi D. Klepin, MD, MS
Wake Forest University School of
Medicine
Sara Knapke, MS
Cincinnati Childrens Hospital
Medical Center
Andrew Y. Koh, MD
University of Texas Southwestern
Medical Center
Barnett S. Kramer, MD, MPH
National Cancer Institute
Amrita Y. Krishnan, MD
City of Hope National Medical
Center
Pamela L. Kunz, MD
Stanford University Medical
Center
Razelle Kurzrock, MD
University of Texas M. D.
Anderson Cancer Center
Sancy Ann Leachman, MD
University of Utah Hospitals and
Clinics
J. Jack Lee, PhD, DDS
University of Texas M. D.
Anderson Cancer Center
Fred T. Lee, MD
University of Wisconsin
Natasha B. Leighl, MD
Princess Margaret Hospital
John Leonard, MD
Weill Cornell Medical College
Stephen L. Lessnick, MD, PhD
Huntsman Cancer Institute at the
University of Utah
Douglas A. Levine, MD
Memorial Sloan-Kettering Cancer
Center
Lisa F. Licitra, MD
Fondazione IRCCS Istituto
Nazionale dei Tumori
Patricia LoRusso, DO
Karmanos Cancer Institute
Tobey MacDonald, MD
Emory University
Jennifer W. Mack, MD
Dana-Farber Cancer Institute
Michael L. Maitland, MD, PhD
The University of Chicago
Robert G. Maki, MD, PhD
Mount Sinai School of Medicine
Jeremy Manier
The University of Chicago
Elizabeth Mansfield, PhD
U. S. Food and Drug
Administration

John M. Maris, MD
Childrens Hospital of
Philadelphia
James D. Marks, MD, PhD
University of California, San
Francisco
Mary S. McCabe, RN, MA
Memorial Sloan-Kettering Cancer
Center
Worta J. McCaskill-Stevens, MD
Division of Cancer Prevention,
National Cancer Institute
D. Scott McMeekin, MD
University of Oklahoma Health
Sciences Center
Jerry Menikoff, MD, JD
U.S. Department of Health and
Human Services
Jeffrey A. Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Robert Stephen Miller, MD
Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Tetsuya Mitsudomi, MD, PhD
Aichi Cancer Center Hospital
Supriya Gupta Mohile, MD, MS
University of Rochester Medical
Center
Tony Mok, MD
Prince of Wales Hospital
Monica Morrow, MD
Memorial Sloan-Kettering Cancer
Center
Robert John Motzer, MD
Memorial Sloan-Kettering Cancer
Center
Beverly Moy, MD
Massachusetts General Hospital
Therese M. Mulvey, MD
Southcoast Hospitals Group
Hyman Bernard Muss, MD
University of North Carolina
Lineberger Comprehensive
Cancer Center
Fariba Navid, MD
St. Jude Childrens Research
Hospital
Michael N. Neuss, MD
Vanderbilt-Ingram Cancer
Center
Kim Nichols, MD
Childrens Hospital of
Philadelphia
Andrew David Norden, MD, MPH
Dana-Farber Cancer Institute
Kenneth Offit, MD, MPH
Memorial Sloan-Kettering Cancer
Center
Bert H. ONeil, MD
University of North Carolina at
Chapel Hill

Henry Orlando Otero, MD


Virginia Mason Medical Center
Cynthia Owusu, MD, MS
Case Western Reserve
University
William Pao, MD, PhD
Vanderbilt-Ingram Cancer
Center
Alberto S. Pappo, MD
St. Jude Childrens Research
Hospital
Donald W. Parsons, MD, PhD
Texas Childrens Hospital
Francesco Passamonti, MD
Fondazione IRCCS Policlinico
San Matteo
Jeffrey M. Peppercorn, MD, MPH
Duke University Medical
Center
Douglas E. Peterson, DMD, PhD
University of Connecticut Health
Center
Martine J. Piccart-Gebhart, MD,
PhD
Jules Bordet Institute
Todd Alan Pickard, PA-C
University of Texas M. D.
Anderson Cancer Center
Whitney Pope, MD, PhD
University of California, Los
Angeles
Kathleen I. Pritchard, MD
Sunnybrook Health Sciences
Centre
Stephanie Puget, MD, PhD
Necker Hospital, Universite
Paris-Descartes
Martin N. Raber, MD
University of Texas M. D.
Anderson Cancer Center
Derek Raghavan, MD, PhD
Carolinas Medical Center
S. Vincent Rajkumar, MD
Mayo Clinic
David Ransohoff, MD
University of North Carolina at
Chapel Hill
Arati Rao, MD
Duke University Medical
Center
Gregory H. Reaman, MD
Childrens National Medical
Center
Mary Weber Redman, PhD
Fred Hutchinson Cancer
Research Center
Robert Evan Reiter, MD
University of California, Los
Angeles
Antoni Ribas, MD
University of California, Los
Angeles

Richard F. Riedel, MD
Duke Cancer Institute, Duke
University Medical Center
Gregory J. Riely, MD, PhD
Memorial Sloan-Kettering Cancer
Center
Elizabeth Schmidt Rodriguez, RN
Memorial Sloan-Kettering Cancer
Center
Lee S. Rosen, MD
University of California, Los
Angeles Division of HematologyOncology
Michael Rowe, PhD
Yale School of Medicine
Gordon J. S. Rustin, MD, MBBS
Mount Vernon Cancer Centre
David P. Ryan, MD
Massachusetts General Hospital
Cancer Center
Charles J. Ryan, MD
University of California, San
Francisco
Marianne Ryberg, MD
Herlev University Hospital
Gilles A. Salles, MD, PhD
Hospices Civils de Lyon and
Universite de Lyon
Leonard Saltz, MD
Memorial Sloan-Kettering Cancer
Center
Daniel J. Sargent, PhD
Mayo Clinic
Oliver Sartor, MD
Tulane Cancer Center
Hans Sauer, PhD, JD
Biotechnology Industry
Organization
Doug Sawyer, MD, PhD
Vanderbilt University
Lidia Schapira, MD
Massachusetts General Hospital
Joshua David Schiffman, MD
University of Utah
Lowell E. Schnipper, MD
Beth Israel Deaconess Medical
Center
Gilberto Schwartsmann, MD, PhD
Federal University of Rio Grande
do Sul
Katia Scotlandi, PhD
Istituto Ortopedico Rizzoli
Victoria Louise Seewaldt, MD
Duke University Medical
Center
Lecia V. Sequist, MD, MPH
Massachusetts General Hospital
Manish A. Shah, MD
Weill Cornell Medical College
Manisha H. Shah, MD
The Ohio State University
Comprehensive Cancer Center

Neil P. Shah, MD, PhD


University of California, San
Francisco
Geoffrey Shapiro, MD, PhD
Dana-Farber Cancer Institute
Alice Tsang Shaw, MD, PhD
Massachusetts General Hospital
Cancer Center
Lillian L. Siu, MD
Princess Margaret Hospital
Stephen Skapek, MD
The University of Chicago
Martha L. Slattery, PhD
University of Utah
George W. Sledge, MD
Indiana University Simon Cancer
Center
Stefan Sleijfer, MD, PhD
Erasmus University Medical
Center, Daniel den Hoed Cancer
Center
Sonali M. Smith, MD
The University of Chicago
Thomas J. Smith, MD
Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Stephen Barnett Solomon, MD
Memorial Sloan-Kettering Cancer
Center
Stephen T. Sonis, DMSc, DDS
Biomodels
Jeffrey Alan Sosman, MD
Vanderbilt Medical Center
Paul Spellman, PhD
Oregon Health & Science
University
Margaret R. Spitz, MD
University of Texas M. D.
Anderson Cancer Center
Zsofia Kinga Stadler, MD
Memorial Sloan-Kettering Cancer
Center
Walter Michael Stadler, MD
The University of Chicago
Richard Sullivan, PhD, MBBS
Kings Health Partners Integrated
Cancer Centre
Lillian Sung, MD, PhD
The Hospital for Sick Children
Antonella Surbone, MD, PhD
New York University
Sandra M. Swain, MD
Washington Hospital Center
Mario Sznol, MD
Yale Cancer Center
Josep Tabernero, MD
Vall dHebron University
Hospital
Kenneth Tanabe, MD
Massachusetts General Hospital
Cancer Center

William D. Tap, MD
University of California, Los
Angeles
Ian Murchie Thompson, MD
University of Texas Health
Science Center at San Antonio
Michael A. Thompson, MD, PhD
ProHealth Regional Cancer
Center
Anthony W. Tolcher, MD
South Texas Accelerated
Research Therapeutics (START)
Sean R. Tunis, MD, MSc
Center for Medical Technology
Policy
Alan Paul Venook, MD
University of California, San
Francisco
Srdan Verstovsek, MD, PhD
University of Texas M. D.
Anderson Cancer Center
Jaap Verweij, MD, PhD
Erasmus University Medical
Center
Louise Villejo, MPH
University of Texas M. D.
Anderson Cancer Center
Beth A. Virnig, PhD
University of Minnesota, School
of Public Health
Andrew J. Wagner, MD, PhD
Dana-Farber Cancer Institute
James Ross Waisman, MD
Breastlink Medical Group Inc
Robert S. Warren, MD
University of California, San
Francisco
Jeffrey S. Weber, MD, PhD
H. Lee Moffitt Cancer Center &
Research Institute
Simon Wein, MD
Davidoff Cancer Center, Rabin
Medical Center
Martin R. Weiser, MD
Memorial Sloan-Kettering Cancer
Center
Howard Jack West, MD
Swedish Cancer Institute
William H. Westra, MD
Johns Hopkins School of
Medicine
Lauren Allison Wiebe, MD
Medical College of Wisconsin
Timothy J. Wilt, MD, MPH
United States Department of
Veterans Affairs
Eric P. Winer, MD
Dana-Farber Cancer Institute
Ignacio I. Wistuba, MD
University of Texas M. D.
Anderson Cancer Center

Douglas E. Wood, MD
University of Washington
Paul Workman, BSc, PhD, DSc
The Institute of Cancer Research
Michael Xing, MD, PhD
Johns Hopkins University
Sam S. Yoon, MD
Massachusetts General Hospital

Anas Younes, MD
University of Texas M. D.
Anderson Cancer Center
Theoklis Zaoutis, MD
Childrens Hospital of
Philadelphia

Richard C. Zellars, MD
Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins
Andrew X. Zhu, MD, PhD
Massachusetts General Hospital

2012 Educational Book Expert Panel


The Expert Panel is a group of well-recognized physicians and researchers in oncology
and related fields who have served as peer reviewers on the Educational Book articles.

David Adelstein, MD
Cleveland Clinic
Alex Adjei, MD
University of Texas M. D.
Anderson Cancer Center
Doug Adkins, MD
Washington University School of
Medicine
Stefan Anker, MD
Charite, Universitatsmedizin
Berlin
Robert Arceci, MD, PhD
Sidney Kimmel Cancer Center
Voichita Bar-Ad, MD
Thomas Jefferson University
Hospital
Helen Barraclough, MS
Eli Lilly
Leif Bergsagel, MD
Mayo Clinic
Jan Beumer, PharmD, PhD
University of Pittsburgh
George Blumenschein, MD
University of Texas M. D.
Anderson Cancer Center
Louise Bordeleau, MD, MSc
McMaster University
Alan Bryce, MD
Mayo Clinic
Kevin Camphausen, MD
National Cancer Institute
James Cassidy, MD
Roche
Nelson Chao, MD
Duke University
Carien Creutzberg, MD
Leiden University Medical
Center
Brian Czito, MD
Duke University
Adam Dicker, MD
Thomas Jefferson University
Brenda Diergaarde, PhD
University of Pittsburgh
Benjamin Djulbegovic, MD
University of South Florida
Laura Dominici, MD
Brigham and Womens Hospital
Fritz Eilber, MD
University of California,
Los Angeles
Rebecca Elstrom, MD
Weill Cornell Medical College

Edward Garon, MD
University of California,
Los Angeles
Julia Glade, MD
Columbia University
Stewart Goldman, MD
Childrens Memorial Hospital
Mary Gospodarowicz, MD
Princess Margaret Hospital
Victor Grann, MD
Columbia University
Parameswaran Hari, MD
Medical College of Wisconsin
Michael Hassett, MD
Dana-Farber Cancer Institute
Michael Isakoff, MD
Conneticut Childrens Medical
Center
Michael Kelly, MD, PhD
Medical College of Wisconsin
Scott Kopetz, MD
University of Texas M. D.
Anderson Cancer Center
Mario Lacouture, MD
Northwestern University
Edward Levine, MD
Wake Forest University
Gerry Linette, MD, PhD
Washington University School of
Medicine
Steven Lipshultz, MD
University of Miami
Christophe Louvet, MD
lInstitut Mutualiste Montsouris
Bo Lu, MD, PhD
Vanderbilt University
Mario Malogolowkin, MD
Medical College of Wisconsin
Guido Marcucci, MD
The Ohio State University
Medical Center
Erica Mayer, MD
Dana-Farber Cancer Institute
Minesh Mehta, MD
University of Wisconsin
Vicki Morrison, MD
University of Minnesota
Joanne Mortimer, MD
City of Hope
Craig Moskowitz, MD
Memorial Sloan-Kettering Cancer
Center
Timothy Moynihan, MD
Mayo Clinic

Barbara Murphy, MD
Vanderbilt University
P.B. Ottevanger, MD
Radboud University Nijmegen
Medical Centre
Rebecca Pentz, PhD
Emory University
James Pingpank, MD
University of Pittsburgh
Katherine Pisters, MD
University of Texas M. D.
Anderson Cancer Center
Dennis Priebat, MD
Washington Hospital Center
Rinaa Punglia, MD
Dana-Farber Cancer Institute
David Quinn, MD
University of Southern California
Nithya Ramnath, MD
University of Michigan
Paul Gerard Guy Richardson, MD
Dana-Farber Cancer Institute
Jonathan Rosenberg, MD
Dana-Farber Cancer Institute
David Rosenthal, MD
Harvard University
Anna Roshal, MD
Washington University School of
Medicine
John Ruckdeschel, MD
Karmanos Cancer Institute
Hope Rugo, MD
University of California, San
Francisco
Rachel Sanborn, MD
Providence Portland Medical
Center
Alan Sandler, MD
Oregon Health & Science
University
Rafael Santana-Davilla, MD
Medical College of Wisconsin
Takami Sato, MD, PhD
Jefferson Medical College
Lee Schwartzberg, MD
The West Clinic
Sunil Sharma, MD
University of Utah
Wenyin Shi, MD
Thomas Jefferson University
Hospital
Timothy Showalter, MD
Thomas Jefferson University
Hospital

Mary Lou Smith, JD, MBA


Research Advocacy Network,
Chicago
Andrew Stephenson, MD
Cleveland Clinic
Timothy Synold, PharmD
City of Hope
Ben Tan, MD
Washington University School of
Medicine
Meaghan Tenney, MD
University of Chicago
Brian Van Tine, MD, PhD
Washington University School of
Medicine
Gauri Varadhachary, MD
University of Texas M. D.
Anderson Cancer Center

Ravi Vij, MD
Washington University School of
Medicine
Nina Wagner-Johnston, MD
Washington University School of
Medicine
Heather Wakelee, MD
Stanford University
Ellen Warner, MD
Odette Cancer Center
Theresa Werner, MD
University of Utah
Mier Wetzler, MD
Roswell Park Cancer Institute
William Wierda, MD
University of Texas M. D.
Anderson Cancer Center
Dennis Wigle, MD, PhD
Mayo Clinic

Tanya Wildes, MD
Washington University School of
Medicine
Els Witteveen, MD
University Medical Center
Utrecht
Sandra Wong, MD
University of Michigan Health
Systems
Seiko Yamada, MD
University of Chicago
Darrell Yamashiro, MD, PhD
Columbia University
Jonathan Zager, MD
H. Lee Moffitt Cancer Center
Robin Zon, MD
Michiana Hematology-Oncology

2012 Annual Meeting Supporters*


CONQUER CANCER FOUNDATION MISSION ENDOWMENT FOUNDING DONORS
Genentech BioOncologyTM
GlaxoSmithKline Oncology

Novartis Oncology
Sanofi Oncology

CONQUER CANCER FOUNDATION MISSION ENDOWMENT SUSTAINING DONORS


Abbott Oncology
Amgen
Celgene Corporation

Lilly USA, LLC


Millennium: The Takeda Oncology Company
Sanofi Oncology

EDUCATIONAL SUPPORT

Merck Oncology
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Amgen
Educational Book
Astellas
AVEO Pharmaceuticals, Inc.
Medivation
Genitourinary Cancer Track
Bristol-Myers Squibb
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Celgene Corporation
Best of ASCO Meetings
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Leukemia, Myelodysplasia, and Transplantation Track
Lung Cancer Track
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Daiichi Sankyo, Inc.
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Best of ASCO Meetings
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Clinical Trials Track
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* This list reflects commitments as of April 16, 2012

Millennium: The Takeda Oncology Company


Genitourinary Cancer Track
Professional Development Track
Myriad Genetics Laboratories, Inc.
Breast Cancer Track
Cancer Genetics Track
Novartis Oncology
Breast Cancer Track
Gastrointestinal (Noncolorectal) Cancer Track
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Breast Cancer Track
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Genitourinary Cancer Track
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Lung Cancer Track
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Sanofi Oncology
Genitourinary Cancer Track
Sanofi Oncology and Regeneron Pharmaceuticals
Best of ASCO Meetings
Gastrointestinal (Colorectal) Cancer Track
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GENERAL SUPPORT
Abbott Oncology
Young Investigator Award
American Cancer Society
ASCO-American Cancer Society Award and Lecture
Amgen
Career Development Award
International Development and Education Awards
Long-term International Fellowship (LIFe)
Merit Awards
Young Investigator Award

ASCO and Conquer Cancer Foundation Boards of


Directors
Jane C. Wright, MD, Young Investigator Award

Doris Duke Charitable Foundation


Medical Student Rotation for Underrepresented
Populations

ASCO Cancer Research Committee


Young Investigator Award

Eisai Inc.
Charging Stations
Interactive Locator Maps
International Development and Education Awards
Internet Stations
Patient Advocate Scholarship Program
Laptop Stations (Wi-Fi Zones)
Young Investigator Award (2)

ASCO Clinical Practice Committee


Young Investigator Award
Astellas
Young Investigator Award
Avon Foundation for Women
International Development and Education Awards in
Breast Cancer
Bayer Healthcare Pharmaceuticals Inc.
International Development and Education Awards
Boehringer Ingelheim Pharmaceuticals, Inc.
iMeetings Mobile Application
Virtual Meetings
Bradley Stuart Beller Endowed Fund
Bradley Stuart Beller Special Merit Award
The Breast Cancer Research Foundation
Advanced Clinical Research Award in Breast Cancer
Career Development Award in Breast Cancer
Comparative Effectiveness Research Professorship in
Breast Cancer
Long-term International Award (LIFe) in Breast or
Related Cancers
Young Investigator Award in Breast Cancer
Young Investigator Award in Breast Cancer in honor of
Susan Hirschhorn and in memory of her mother
Bristol-Myers Squibb
Annual Meeting Program
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Young Investigator Award
Celgene Corporation
Career Development Award
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Young Investigator Award
Celltrion Healthcare Co., Ltd.
Annual Meeting Program Mobile Application (iPlanner)
Coalition of Cancer Cooperative Groups
Clinical Trials Participation Awards
Daiichi Sankyo, Inc.
Annual Meeting Program Mobile Application (iPlanner)
Young Investigator Award
Dendreon Corporation
Annual Meeting ASCO TV
Internet Stations
Laptop Stations (Wi-Fi Zones)
Don Shula Foundation, Inc.
Young Investigator Award in Breast Cancer

Estate of Sandra Syms


Young Investigator Award in Kidney Cancer Research
Genentech BioOncology
Advanced Clinical Research Award in Colorectal Cancer
Advanced Clinical Research Award in Glioma
Advanced Clinical Research Award in Hematologic
Malignancies
Career Development Award (5)
Program Announcement
Registration and Housing Announcement
Translational Research Professorship
Young Investigator Award (5)
GlaxoSmithKline Oncology
Gianni Bonadonna Breast Cancer Award and Fellowship
Translational Research Professorship
Incyte Corporation
Annual Meeting ASCO TV
Charging Stations
Interactive Locator Maps
Internet Stations
Jackson Simpson
Merit Awards in Lung Cancer and Lymphoma
James B. Nachman Pediatric Oncology Fund
James B. Nachman ASCO Junior Faculty Award in
Pediatric Oncology
Journal of Clinical Oncology
Young Investigator Award
Kidney Cancer Association
Young Investigator Award in Renal Cell Carcinoma
Lilly USA, LLC
Career Development Award
Merit Awards
Patient Advocate Scholarship Program
Young Investigator Award
Merck Oncology
Young Investigator Award
Millennium: The Takeda Oncology Company
International Development and Education Awards
Merit Awards
Oncology Trainee Travel Awards
Patient Advocate Scholarship Program
Young Investigator Award (2)

National Cancer Institute


International Development and Education Awards in
Palliative Care
Novartis Oncology
Career Development Award
Young Investigator Award (2)
Open Society Foundations
International Development and Education Awards in
Palliative Care
Palo Alto Medical Foundation
Leaders in PracticeSilver Supporter
Pepper Hamilton LLC
Pro Bono Legal Services: Diversity in Oncology Initiative
Pfizer Oncology
Virtual Meetings
Young Investigator Award
Raj Mantena, RPh
Leaders in PracticePrimary Supporter
Roche
Career Development Award (2)
Annual Meeting Program Mobile Application (iPlanner)
Laptop Stations (Wi-Fi Zones)
Young Investigator Award (5)
Sanofi Oncology
Career Development Award
Drug Development Research Professorship
Sarcoma Foundation of America
Career Development Award in Sarcoma Research
Young Investigator Award in Sarcoma Research
Seattle Genetics
iMeetings Mobile Application
Internet Stations
Patient Advocate Scholarship Program
Young Investigator Award

Strike 3 Foundation
Young Investigator Award in Pediatric Oncology
Susan G. Komen for the Cure
The Susan G. Komen for the Cure/Conquer Cancer
Foundation Research Initiative
Conquer Cancer Foundation of ASCO Improving
Cancer Care Grant, funded by Susan G. Komen for the
Cure
The Susan G. Komen for the Cure/ASCO Quality of Care
Initiative
The ASCO Breast Cancer Registry Pilot Program,
funded by Susan G. Komen for the Cure
The ASCO Diversity in Oncology Initiative, funded by
Susan G. Komen for the Cure
The ASCO Study of Collaborative Practice
Arrangements, funded by Susan G. Komen for the
Cure
The ASCO Study of Geographic Access to Oncology
Care, funded by Susan G. Komen for the Cure
Assessing and Monitoring Demand for Cancer Care
Services, with funding from Susan G. Komen for the
Cure
William D. Piety Living Trust
Young Investigator Award in Cholangiocarcinoma
Research
WWWW Foundation, Inc. (QuadW) and The Sarcoma
Fund of the QuadW Foundation
Young Investigator Award in Sarcoma in memory of Willie
Tichenor

Letter from the Editor

he theme of the 2012 American Society of Clinical


Oncology Annual Meeting is Collaborating to Conquer
Cancer, and the sessions being presented at this years
meeting certainly look toward this theme with the goal of
advancing the education of oncologists so that they can
improve the care provided to their patients.
The ASCO Educational Book is meant to serve as an
enduring record of the information presented at these sessions. This year, 92 educational sessions are represented by
the articles published in this book, written by some of the
most recognized clinicians and investigators in their field. In
order to ensure the utmost accuracy and clarity, each article
is reviewed by our editorial team, as well as by peer
reviewers from our extensive expert panel. In addition,
Natasha Leighl, MD, an expert in lung cancer and cost-ofcare issues and the Associate Editor of the Educational
Book, has provided valuable insights to the review process.
We are grateful to the authors who, despite their demanding schedules, took the time to write and, in some cases,
revise their articles according to the peer reviewers comments. We appreciate the efforts of our peer reviewers for
their careful, thorough reviews that undoubtedly contributed to the high quality of this book.
Please visit asco.org/edbook for access to all of the 2012
Educational Book articles. The following are examples for
citing both print and electronic articles:

Girard N. Thymoma: From Chemotherapy to Targeted


Therapy. In: Govindan R, ed. 2012 ASCO Educational Book.
Alexandria, VA: American Society of Clinical Oncology;
2012;475-479.
Surbone A, Baider L. Are Oncologists Accountable Only to
Patients or Also to Their Families? An International Perspective. In: Govindan R, ed. 2012 ASCO Educational Book.
Alexandria, VA: American Society of Clinical Oncology;
2012;e15-e19.
The ASCO Educational Book would not exist today but for
the remarkable staff at ASCO. I want to specifically thank
Christine Smith and Lauren Burke, who have worked very
hard year-round to make this publication possible. Dr.
Leighl and I welcome your feedback and suggestions on how
we can improve the content, so please feel free to email me
with your comments at EdBook@asco.org.

Ramaswamy Govindan, MD
Editor

CONTROVERSIES IN THE ADJUVANT TREATMENT


OF BREAST CANCER
CHAIR
Stephen R. Johnston, MA, PhD
Royal Marsden Hospital
London, United Kingdom
SPEAKERS
Anthony D. Elias, MD
University of Colorado Cancer Center
Aurora, CO
Hyman Muss, MD
University of North Carolina Lineberger
Comprehensive Cancer Center
Chapel Hill, NC

Adjuvant Therapy for Older Women with


Early-Stage Breast Cancer: Treatment
Selection in a Complex Population
By Cynthia Owusu, MD, MS, Arti Hurria, MD, and Hyman Muss, MD

Overview: Breast cancer is a disease of aging. However,


older women with breast cancer are less likely to participate in
clinical trials or to receive recommended treatment. This
undertreatment has contributed to a lag in breast cancer
survival outcomes for older women compared with that for
their younger counterparts. The principles that govern recommendations for adjuvant treatment of breast cancer are the
same for younger and older women. Systemic adjuvant treatment recommendations should be offered on the basis of
tumor characteristics that divide patients into three distinct
subgroups. These include (1) older women with hormone
receptor (HR)-positive and human epidermal growth factor 2
(HER2)-negative breast cancer who should be offered endocrine therapy; (2) older women with HR-negative and HER2negative breast cancer who should be offered adjuvant

REAST CANCER is the most common cancer in American women and the second leading cause of cancerrelated deaths among women. In 2011, approximately
230,480 new cases were diagnosed in the United States,
with an expected 39,520 deaths.1,2 The most important risk
factor for breast cancer is age. The estimated lifetime risk of
a new breast cancer is 1 in 15, 1 in 29, 1 in 27 and 1 in 207
for women 70 years or older, 60 to 69, 40 to 59, and 39 or
younger, respectively.1 The median age at the time of breast
cancer diagnosis is currently 61 years and an estimated 45%
of women are 65 or older at the time of initial diagnosis.2,3
Recent gains in life expectancy, coupled with aging as a risk
factor for breast cancer, makes breast cancer primarily a
disease of older women, with increasing public health importance. In 1980, persons 65 and older represented 11.3%
of the total population, but by 2030 this proportion is
expected to increase to 20%.3 In addition, by 2030, persons
older than 75 will be expected to account for just under 50%
of the total cohort older than 65.4 Given the nonlinear
age-risk relationship and increasing life expectancy, a substantial proportion of older women are expected to be affected by breast cancer.
Age-Related Cancer Health Disparities

Evaluation of the biology of breast cancer by patient age


has shown that hormone receptor-positive, low S-phase, low
tumor grade and HER2-negative tumors are more common
among older than younger women,5 although these differences are relatively modest. Despite the favorable tumor
profile of breast cancer in older women, this has not translated into any major survival advantage for older women
with breast cancer in comparison with their younger counterparts. In a study that drew data from National Vital
Statistics Reports and the Surveillance Epidemiology and
End Results database of the National Cancer Institute,
Smith and colleagues6 found that although the rate of breast
cancer death in the general population and the adjusted risk
of death among women with newly diagnosed disease are
declining among all age groups, the least decline has been
among older women. Relative to 1990, the rate of breast

chemotherapy; and (3) older women with HER2-positive disease who should be offered chemotherapy with trastuzumab.
Exceptions to these guidelines may be made for older women
with small node-negative tumors or frail older women with
limited life expectancy, where close surveillance may be a
reasonable alternative. Addressing the current age-related
disparities in breast cancer survival will require that older
women are offered the same state-of-the-art-treatment as
their younger counterparts, with a careful weighing of the
risks and benefits of each treatment in the context of the
individuals preferences. In addition, older women should be
encouraged to participate in breast cancer clinical trials to
generate additional chemotherapy efficacy, toxicity, and quality of life data.

cancer death in the general population decreased 2.5% per


year for women age 20 to 49, 2.1% per year for those age 50
to 64, 2% per year for those age 65 to 74, but 1.1% per year
for those age 75 years and older. Moreover, among women
with newly diagnosed breast cancer between 1980 and 1997,
the adjusted risk of death decreased by 3.6% per year among
women younger than age 75 compared with 1.3% per year
among those age 75 and older (p 0.01). These differences
were even greater for older black women. The age-related
disparity in survival outcomes was hypothesized to be related to the undertreatment of older women with breast
cancer. In an analysis of 9,766 patients enrolled in the
TEAM (Tamoxifen Exemestane Adjuvant Multinational)
randomized controlled trial conducted with postmenopausal
women with hormone receptor-positive breast cancer, increasing age was associated with a higher disease-specific
mortality.7 Treatments received and tumor characteristics
did not completely explain the age-related differences in
survival outcomes but older patients in this trial were much
less likely to receive chemotherapy. Together, these data
clearly underscore the fact that breast cancer is an important disease of older women who bear a disproportionate
burden of the morbidity and mortality associated with the
disease and who should be offered proven treatments that
improve survival outcomes. Given that treatment differences do not completely explain the age-related disparities
in survival outcomes, additional population and translational studies are needed to provide further insight into the
reasons for these disparities.

From the Case Western Reserve University School of Medicine, Cleveland, OH; City of
Hope Medical Center and Beckman Research Institute, Duarte, CA; and, Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Cynthia Owusu, MD, MS, Case Western Reserve University
School of Medicine, Division of Hematology/Oncology and Case Comprehensive Cancer
Center-BHC 5055, 11100 Euclid Avenue, Cleveland, OH 44106; e-mail: cynthia.owusu@
case.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

OWUSU, HURRIA, AND MUSS


Adjuvant Systemic Therapy

Adjuvant systemic therapy refers to the administration of


anticancer therapy after primary breast surgery for early
stage breast cancer with the goal of eradicating occult
micrometastatic disease thought to be responsible for distant recurrence. Systemic treatment modalities include
endocrine therapy and chemotherapy with or without trastuzumab. Treatment decision making regarding adjuvant
systemic therapy for older women should involve consideration of such factors as the risk of morbidity and mortality
from breast cancer, life expectancy and treatment tolerance,
and patient preference. A geriatric assessment that includes
evaluation of functional, cognitive, nutritional, and psychosocial status, and review of comorbidities and concomitant
medications is particularly helpful in estimating the health
status and life expectancy of older adults. Each of the
components of a geriatric assessment can identify older
adults at increased risk for morbidity and mortality. This
assessment can also identify areas of vulnerability that may
affect the patients ability to participate in a treatment plan
(for example, ability to take medications on ones own).
Items in a geriatric assessment are able to identify older
adults at risk of chemotherapy toxicity.8,9 In a multisite
study of 500 older adults with cancer, conducted by the
Cancer and Aging Research Group, five geriatric assessment
questions were independent predictors of the risk of chemotherapy toxicity, in addition to age, tumor, treatment, and
laboratory variables. The geriatric assessment questions
that were predictive of chemotherapy toxicity included hearing impairment (rated at fair or worse), difficulty in walking
one block, need for assistance with taking medications, one
or more falls in the past 6 months, and decrease in social
activities because of either physical or emotional health.8
This predictive model for chemotherapy toxicity is being
validated specifically in older adults receiving adjuvant
chemotherapy for breast cancer (clinicaltrials.gov
NCT01472094). In another study of 518 evaluable older
adults with cancer (Chemotherapy Risk Assessment Scale
for High Age Patients), predictors of chemotherapy toxicity
included measures of functional status (ability to complete

KEY POINTS

The undertreatment of older women with breast


cancer has contributed to poorer survival outcomes
for older women than for younger women.
The principles that guide breast cancer treatment
recommendations for younger and older women are
fundamentally the same.
Breast cancer treatment decision making should consider the risk of breast cancer relapse, patient health
status, life expectancy, and patient preference.
The use of systemic therapy in the adjuvant setting
should be based on tumor characteristics and include
endocrine therapy, and/or chemotherapy with or
without trastuzumab.
Omission of postoperative radiation therapy is a
reasonable strategy for older women with small
hormone-receptor positive tumors.

instrumental activities of daily living), cognition (MiniMental Status score), and nutrition (Mini-Nutritional Assessment score).9 This information can be used in the
treatment decision-making process in order to estimate life
expectancy and risk of chemotherapy side effects and to
identify areas of intervention to assist the patient during her
treatment course.
Endocrine Therapy

The majority of older patients present with hormone


receptorpositive breast cancer. Endocrine therapy is the
mainstay of adjuvant therapy for these patients and results
in proportional reductions in the risk of relapse and dying
of breast cancer that exceed any available chemotherapy
regimen. Current consensus guidelines recommend adjuvant systemic endocrine therapy for hormone receptorpositive breast cancer. The National Comprehensive Center
Network (NCCN) guidelines10 recommend the use of adjuvant endocrine therapy for women with hormone receptorpositive breast cancer regardless of age, menopausal status,
or HER2 status, with the possible exception of women
with lymph node-negative cancers 0.5 cm or less, or 0.6 to
1.0 cm in diameter with favorable prognostic features;
benefit from endocrine therapy is likely to be small for
tumors of this size. In contrast, the St. Gallen International
Consensus Panel recommends adjuvant systemic endocrine
therapy for all women with endocrine-responsive disease
with no exceptions and has defined endocrine-responsive
tumors as those with as few as 1% of cells staining positive
for hormone receptor proteins.11 The Society of International Geriatric-Oncology (SIOG) breast cancer task force
recommended that older women with endocrine-responsive
breast cancer be offered systemic endocrine therapy. However, for women with minimal risk disease, the decision to
offer endocrine therapy should be based on a risk-benefit
analysis.12
Tamoxifen is the most firmly established adjuvant endocrine therapy for both premenopausal and postmenopausal
women. Supporting these recommendations are results
from the Early Breast Cancer Trialists Collaborative
Group (EBCTCG) overview analysis, which demonstrated
that over a 15-year period, use of adjuvant tamoxifen
therapy for women with known estrogen receptor-positive
disease, compared with no tamoxifen, decreased the 15-year
risk of recurrence and death by 39% and 31%, respectively,
regardless of age.13 It is clear from these data that
tamoxifen is of benefit for older women. In addition to
decreasing the risk of disease relapse and death, there are
also potential nonbreast cancer benefits of tamoxifen therapy in postmenopausal women. Tamoxifen may prevent
osteoporosis14 and reduce the risk of cardiovascular disease.15 Adjuvant tamoxifen therapy is, however, underutilized in older women. Women 80 years or older are half as
likely to report having had a discussion about tamoxifen
with their doctor compared with women 65 to 79 years, and
women age 85 to 92 years are 25% less likely to receive a
tamoxifen prescription than those 80 to 84 years.16 Additionally, older women are more likely to self-discontinue and
to be nonadherent to tamoxifen before the recommended
treatment period of 5 years,17,18 undercutting the treatment
benefit from tamoxifen. Oncologists should always ask their
patients if they are taking their prescribed medications and

TREATMENT FOR OLDER WOMEN WITH BREAST CANCER

should reinforce the importance of adherence to maximize


treatment benefit.
The adjuvant use of aromatase inhibitors (anastrozole,
letrozole, exemestane) for postmenopausal women with
early breast cancer has been evaluated in several studies.
These studies have involved the use of aromatase inhibitors
either as initial adjuvant therapy,19 as sequential therapy
after 2 to 3 years of tamoxifen,20 or as extended therapy
after 4.5 to 6 years of tamoxifen.21 The findings of these
studies are consistent in demonstrating that the use of a
third-generation aromatase inhibitor for postmenopausal
women with hormone receptorpositive breast cancer, regardless of patient age, is superior in decreasing the risk of
disease recurrence, including ipsilateral and contralateral
breast cancer, and distant metastatic disease compared with
tamoxifen. Additionally, sequential use of aromatase inhibitors20 or extended therapy21 has been shown to provide an
overall survival advantage compared with tamoxifen use for
5 years. No survival advantage has been demonstrated with
the upfront use of aromatase inhibitors for 5 years compared
with tamoxifen.
There are differences in the toxicity profiles of aromatase
inhibitors and tamoxifen. The incidence of venous thromboembolic disease, cerebrovascular events, endometrial cancer, vaginal bleeding, and hot flashes are less likely to be
associated with aromatase inhibitors than tamoxifen,
whereas the incidence of musculoskeletal pain, osteoporosis,
and bone fractures have been found to be higher with
aromatase inhibitors.19 Emerging data also suggest that
aromatase inhibitors may be associated with a small but
higher risk of cardiovascular events compared with tamoxifen,22,23 but not compared with placebo.24 In a metaanalysis of seven trials in which aromatase inhibitors were
compared with tamoxifen, longer duration of aromatase
inhibitor use or aromatase inhibitor use alone for 5 years
was associated with a higher likelihood of cardiovascular
events compared with tamoxifen alone (odds ratio [OR]
1.26, 95% CI 1.10 1.43).25 Because studies of aromatase
inhibitors have not included extensive follow-up, the full
effect of aromatase inhibitors on cardiovascular disease and
coronary heart risk remains to be determined.
Although there is little evidence of age-related differences
in the benefits of aromatase inhibitors for postmenopausal
women, results of studies designed to examine age-related
differences in the pattern of toxicity have been mixed. In
general, the incidence of grade 35 nonfracture-related adverse events is higher among women 75 and older than
among women less than 75 years.26 However, a comparison
of the quality of life and the side effect profile for women who
participated in MA-17, a study in which 5 years of letrozole
was compared with placebo, showed no age-related differences in side effects.24 The long-term consequences and
implications of these side effects and any-age-related differences remain to be well characterized.
Based on the results from recent studies that favor aromatase inhibitors over tamoxifen, current guidelines recommend that aromatase inhibitors should be offered to all
postmenopausal women with hormone receptor-positive
early stage breast cancer, either alone, as sequential therapy after 23 years of tamoxifen. Given the lack of overall
survival advantage associated with aromatase inhibitor use
for 5 years, for women with pre-existing heart disease or
bone loss, use of tamoxifen for 5 years or a switching

strategy is a reasonable approach. For women with low


grade, node-negative tumors 1 cm or smaller, endocrine
therapy may be optional and observation acceptable, although the risks and benefits should be discussed with the
patient.
Adjuvant Chemotherapy

Cytotoxic chemotherapy can be considered for older


women with either node-positive or high-risk node-negative
disease, particularly, triple-negative breast cancer. An
abundance of literature has demonstrated the benefit of
adjuvant chemotherapy for younger women, with benefit
decreasing as age increases. The EBCTCG overview analysis,13 which has 15 years of follow-up data, demonstrated
that adjuvant chemotherapy reduced the annual risk of
recurrence by 37% and 19%, for women younger than 50 and
50 to 69, respectively. The annual risk of death was reduced
by 30% and 12%, for women younger than 50 and 50 to 69,
respectively. The benefit of adjuvant chemotherapy for
women with early stage breast cancer over age 70 was
difficult to assess in the EBCTCG overview analysis
because of the paucity of randomized trials that incorporated this age group. Of 29,000 women included in 60
adjuvant polychemotherapy trials, 4% were 70 and older.
This paucity of data has prevented definitive estimates
regarding the magnitude of benefit of chemotherapy for
women age 70 and older. In addition, with advancing age,
organ function and performance status decline, and comorbidities increase, making the risks associated with chemotherapy even greater. Moreover, the risk reductions for
chemotherapy are lower for postmenopausal women than for
premenopausal women, although the reasons are unclear.
Coupled with the apparent decline in the efficacy of chemotherapy with age is the increased risk of death from competing illnesses (comorbidity), leading to additional decline in
the benefit from chemotherapy. As a result of all these
factors, older women with early stage breast cancer receive
adjuvant chemotherapy considerably less frequently than do
younger women.
However, a growing body of evidence suggests that adjuvant chemotherapy leads to improved survival outcomes
for older women with breast cancer, particularly older
women with hormone receptor-negative and node-positive
breast cancer. A retrospective analysis of four Cancer and
Leukemia Group B (CALGB) randomized clinical trials
showed superior disease-free and overall survival benefits
with the use of more aggressive chemotherapy (compared
with less aggressive chemotherapy), among 6,487 women
with node-positive breast cancer in all age groups, including
70 and older.27 This benefit, however, came at the cost of
increased risk of toxicity in older women, with older women
more likely to discontinue treatment and to have an increased risk of treatment-related mortality. Additionally,
data from large population studies have demonstrated a
survival benefit from adjuvant chemotherapy for older
women with hormone-negative or node-positive early stage
breast cancer.28,29
Results from randomized controlled clinical trials that
have specifically focused on older women with breast cancer,
though scant, have helped to fill the gap on chemotherapy
benefit for older women with early stage breast cancer.
In the largest study in this population to date, a CALGB and
Breast Cancer Intergroup study, 33 patients 65 and older

OWUSU, HURRIA, AND MUSS

with early-stage breast cancer were randomly assigned to


either standard treatment (doxorubicin and cyclophosphamide [AC] for four cycles or cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] for six cycles) or to an
experimental arm of single-agent capecitabine for six cycles.30 At a median follow-up of 2.4 years, the relapse-free
survival for patients receiving single-agent capecitabine was
inferior to that for women receiving standard therapy (hazard ratio [HR] 2.09 (1.38 3.17) p 0 0.0001), as was
overall survival (HR 1.85 (1.113.08) p 0.02). An
unplanned subset analysis demonstrated that standard
combination chemotherapy was particularly effective in
patients with hormone receptor-negative disease. Overall,
these results demonstrate that standard combination chemotherapy in the adjuvant setting, provides an overall
survival benefit for older women with breast cancer, particularly those with hormone-receptor negative disease.
The optimum chemotherapy regimen for treating breast
cancer in the adjuvant setting remains debatable. Regardless, anthracycline-based regimens have become the norm,
particularly for high-risk disease. However, the long-term
complications associated with anthracycline use include,
but are not limited to, dose-dependent cardiomyopathy. Age
is a risk factor for cardiac disease, including anthracyclinerelated cardiomyopathy. Often, this precludes the use of
anthracycline-based regimens in older women with breast
cancer. Jones and colleagues,31 in a US Oncology trial,
compared an anthracycline-based regimen (AC for four cycles) with a nonanthracycline taxane-based regimen docetaxel and cyclophosphamide (TC) for four cycles in 1,016
women with node-negative and node-positive disease. At a
median follow-up of 7 years, TC use was associated with
superior disease-free survival (HR 0.74, 95% CI (0.56
0.98) p 0 0.03) and overall survival (HR 0.69, 95%
(0.50 0.97) p 0 0.03) compared with AC. Sixteen percent
of the study population were 65 and older. Unplanned
subgroup analysis showed that TC was associated with
superior disease-free and overall survival in all age groups,
including older ages. TC therefore is a reasonable treatment
regimen in the adjuvant setting for older women, particularly those with pre-existing heart disease and other contraindications to anthracycline-based regimens. A recent study
has shown that this regimen is well tolerated in older
women.32 In another EBCTCG overview analysis in which
different polychemotherapy regimens for early stage breast
cancer were compared, adding a taxane to an anthracyclinebased chemotherapy regimen or a higher cumulative-dosage
anthracycline-based regimen reduced breast cancer mortality, on average, by one-third. This benefit was irrespective
of node status, tumor size, tumor grade, or age (70).33
No definitive conclusion could be drawn regarding women
70 and older because few women in that age group were
included in the meta-analyses.
For older women with node-negative, hormone-positive
breast cancer, gene-expression profiling analysis can be used
to identify women with high-risk disease who are likely to
benefit from chemotherapy. The most widely used assay for
this purpose is the 21-gene assay, which quantifies the
likelihood of breast cancer recurrence in women with nodenegative, estrogen receptor-positive breast cancer and predicts the magnitude of endocrine therapy and chemotherapy
benefit.34 To the extent that the 21-gene assay allows for

individualization of cancer treatment, it is indeed a useful


tool for the management of older patients with breast
cancer, who were well represented in the validation cohorts
(NSABP-14 and NSABP-20) for the assay. Moreover, the
predictive ability of the 21-gene assay has been found to be
independent of age.34 Older patients with low scores are not
likely to derive substantial benefit from chemotherapy,
whereas those with high scores may derive great benefit.
The benefit of adjuvant chemotherapy among patients with
intermediate scores on the assay is being evaluated in the
Tailor Rx study.
Adjuvant! Online is another tool that can assist in decision
making regarding the benefits of adjuvant endocrine therapy and chemotherapy for an individual patient. This online
tool (available at www.adjuvantonline.com) summarizes the
absolute benefit of chemotherapy and endocrine therapy,
taking into account the patients age, brief assessment of
comorbid medical illnesses, and tumor characteristics.35 To
further inform this discussion, the risks associated with
chemotherapy can be calculated with the predictive models
for chemotherapy toxicity8,9 as described earlier (See Adjuvant Systemic Therapy).
Adjuvant Trastuzumab for HER2-Positive
Breast Cancer

Amplification or overexpression of HER2 is seen in approximately 10% to 15% of invasive breast cancers in older
women,5 and it is associated with an unfavorable prognosis.
A substantial body of literature from phase III trials in
the adjuvant setting has demonstrated considerable benefit
in disease-free and overall survival when trastuzumab is
used either concurrently or sequential to chemotherapy
compared with chemotherapy alone.36-38 The main adverse
effect associated with trastuzumab use is cardiotoxicity. In
five phase III trials of adjuvant trastuzumab, the incidence
of severe heart failure (New York Heart Association class III
or IV), ranged from 0 to 3.9% among patients receiving
trastuzumab, compared with 0 to 1.3% among patients who
did not receive trastuzumab.39 In the Breast Cancer International Research Group (BCIRG) 006 study,38 two
trastuzumab-containing regimens (AC plus docetaxel and
trastuzumab and a nonanthracycline regimen of docetaxel,
carboplatin, and trastuzumab [TCH]) were compared with
standard chemotherapy alone. This study demonstrated
disease-free and overall survival benefits with the use of
trastuzumab plus chemotherapy compared with chemotherapy alone. There was no substantial difference between the
two trastuzumab-containing arms. Moreover, the incidence
of cardiotoxicity associated with the nonanthracycline-based
trastuzumab regimen was lower than that associated with
the anthracycline-based trastuzumab regimen.
Consistent with the under-representation of older women
in breast cancer clinical trials of chemotherapy, older women
have also been under-represented in clinical trials of trastuzumab therapy. With the notable exception of cardiac
dysfunction, which was found to be associated with increasing age (older than 50), limitations in data collection precluded a determination of whether the toxicity profile of
trastuzumab in older patients was different from that in
younger patients. The reported clinical experience was also
not adequate to determine whether the efficacy improvements (overall and disease-free survival) associated with
trastuzumab in older patients was different from that in

TREATMENT FOR OLDER WOMEN WITH BREAST CANCER


Table 1. Summary of Recommendations for Adjuvant Systemic Therapy in Early Stage Breast Cancer in Older Women
Node-negative,
Tumor size 1 cm

Node-negative,
Tumor size 1 cm

Node-positive

Endocrine-positive,
HER2-negative

No adjuvant therapy or
Consider hormonal therapy if tumor size 0.6 cm,
grade 2, or other high risk features

Hormonal therapy
Consider chemotherapy based on geneexpression profiling results

Hormonal therapy
Chemotherapy

Endocrine-negative,
HER2-negative

No adjuvant therapy or
Consider chemotherapy if tumor size 0.6 cm plus
other high risk features

Chemotherapy alone

Chemotherapy alone

HER2-positive

No adjuvant therapy or
Consider chemotherapy with trastuzumab if tumor
size 0.6 cm plus high risk features

Chemotherapy with trastuzumab


Add hormonal therapy if hormone
positive

Chemotherapy with trastuzumab


Add hormonal therapy
if hormone positive

patients younger than 65. Regardless, in the absence of


contraindications, trastuzumab is currently recommended
for the adjuvant treatment of HER2-positive breast cancer,
even for older women. In older women, a nonanthracycline,
trastuzumab-containing regimen of TCH is often used because of the increased risk of cardiotoxicity associated with
the anthracycline and trastuzumab regimen.
In summary, the principles that govern recommendations
for systemic adjuvant treatment of breast cancer are the
same for younger and older women. Older women should
be offered guideline-recommended therapies (Table 1).
Broadly, these recommendations should be offered along
three clinically distinct subgroups based on tumor characteristics. (1) Older women with hormone receptor-positive
and HER2-negative breast cancer who should be offered
endocrine therapy regardless of node status. Gene expression profiling assay may be used to determine the added
benefit of chemotherapy for those with node-negative
disease; (2) older women with hormone receptornegative
and HER2-negative breast cancer (triple-negative breast
cancer) who should be offered adjuvant chemotherapy; and
(3) older women with HER2-positive disease who should
be offered chemotherapy with trastuzumab. In the last
group, women with hormone receptor-positive tumors
should also be offered endocrine therapy. Exceptions to
these guidelines may be made for older women in any of the
three subgroups who have node-negative disease and a
tumor less than 1 cm or for frail older women with limited
life expectancy, where close surveillance may be a reasonable alternative.
Adjuvant Radiation Therapy

Until recently, the guideline recommendation, regardless


of age, was for all women to receive radiation therapy
after breast-conserving surgery and for postmastectomy
radiation to be offered to women with a high probability of
local recurrence. A recent meta-analysis of the EBCTCG
supports these recommendations, showing that radiation
therapy decreased the 10-year risk of any first recurrence
from 35% to 19% and the 15-year risk of breast cancer death
from 25% to 21% among women treated with breastconserving surgery.40 Although the proportional reductions
in relapse were similar among all women, the absolute
benefits varied substantially by age, grade, estrogen receptor status, tamoxifen use, and extent of surgery. The authors
concluded that radiation therapy after breast-conserving
surgery halves the rate at which the disease recurs and
reduces the breast cancer death rate by about a sixth.
However, older women with small tumors can be spared

radiation therapy. In a landmark randomized controlled


study by Hughes and colleagues41,42 636 women 70 or older
who had undergone lumpectomy for stage I hormone
receptor-positive breast cancer were randomly assigned to
receive either radiation therapy and adjuvant tamoxifen
for 5 years or to adjuvant tamoxifen for 5 years alone. The
results demonstrated no substantial differences between
the two groups with regard to mastectomy rates for local
recurrence, distant metastases, or overall survival (median
follow-up of 12 years). Of the 49% of patients who died
during follow-up, 3% died of breast cancer. The only statistically significant difference was found in the rate of local
or regional recurrence at 5 years, (2% among women who
had radiation therapy compared with 9% who did not).
Based on results from this study, one may reasonably
consider lumpectomy (with surgically clear margins)
without radiation therapy for women 70 and older with
clinically negative lymph nodes, a tumor 2 cm or smaller,
and hormone receptor-positive breast cancer who agree
to take endocrine therapy. This strategy is limited by the
high rate of nonadherence and early discontinuation of
adjuvant systemic endocrine therapy among older
women.43,44 Omission of postoperative radiation therapy,
coupled with nonadherence to adjuvant systemic endocrine
therapy, may result in earlier recurrences and, ultimately,
poorer survival outcomes for older women. A favorable
outcome from this approach can be achieved only when
older women are adherent to prescribed oral endocrine
therapies. Adherence to prescribed endocrine therapy
should therefore be discussed and encouraged at follow-up
visits.
Conclusion

Breast cancer is a disease of aging. With minor differences, existing data support similar recommendations for
both younger and older women. However, there are agerelated differences in treatment patterns, with older women
less likely than younger women to receive standard therapies. Furthermore, survival outcomes lag behind that of
younger women. Closing the current gap in age-related
disparities in breast cancer survival will require that
older women are offered the same state-of-the-art treatment
as younger women, with a careful weighing of the risks
and benefits of each treatment in the context of the individuals preferences. Newer tools that estimate life
expectancy and toxicity as well as the potential benefits of
therapy should make it easier for oncologists to make better
treatment decisions with older patients. In addition, older
women should be encouraged to participate in breast cancer

OWUSU, HURRIA, AND MUSS

clinical trials to generate additional efficacy and toxicity


data. Such information will provide further knowledge so

that oncologists can offer older women the best treatment


options.

Authors Disclosures of Potential Conflicts of Interest

Author
Cynthia Owusu*
Arti Hurria

Hyman Muss

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Amgen;
Genentech; GTx

Research
Funding

Expert
Testimony

Other
Remuneration

Abraxis
BioScience;
Celgene;
GlaxoSmithKline

Boehringer
Ingelheim; Eisai;
Pfizer; Sandoz

*No relevant relationships to disclose.

REFERENCES
1. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of
eliminating socioeconomic and racial disparities on premature cancer deaths.
CA Cancer J Clin. 2011;61:212-236.
2. DeSantis C, Siegel R, Bandi P, et al. Breast cancer statistics, 2011. CA
Cancer J Clin. 2011;61:409-418.
3. SEER stat fact sheets. http://seer.cancer.gov/csr/1975_2008/results_
single/sect_01_table.11_2pgs.pdf. Accessed March 8, 2012.
4. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in U.S. breast
cancer incidence, survival, and mortality rates. J Natl Cancer Inst. 1996;88:
1571-1579.
5. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical
outcome of elderly women with breast cancer. J Natl Cancer Inst. 2000;92:
550-556.
6. Smith BD, Jiang J, McLaughlin SS, et al. Improvement in breast cancer
outcomes over time: are older women missing out? J Clin Oncol. 2011;29:
4647-4653.
7. van de Water W, Markopoulos C, van de Velde CJ, et al. Association
between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA. 2012;
307:590-597.
8. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity
in older adults with cancer: a prospective multicenter study. J Clin Oncol.
2011;29:3457-3465.
9. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for
High-Age Patients (CRASH) score. Cancer. Epub 2011 Nov 9. doi: 10.1002/
cncr.26646
10. National Comprehensive Cancer Network. Clinical Practice Guidelines
in Breast Cancer. Version 1. 2012. www.nccn.org. Accessed February 28,
2012.
11. Goldhirsch A, Wood WC, Gelber RD, et al. Meeting highlights: updated
international expert consensus on the primary therapy of early breast cancer.
J Clin Oncol. 2003;21:3357-3365.
12. Wildiers H, Kunkler I, Biganzoli L, et al. Management of breast cancer
in elderly individuals: recommendations of the International Society of
Geriatric Oncology. Lancet Oncol. 2007;8:1101-1115.
13. Effects of chemotherapy and hormonal therapy for early breast cancer
on recurrence and 15-year survival: an overview of the randomised trials.
Lancet. 2005;365:1687-1717.
14. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone
mineral density in postmenopausal women with breast cancer. N Engl J Med.
1992;326:852-856.
15. Love RR, Wiebe DA, Feyzi JM, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women after 5 years of treatment. J Natl
Cancer Inst. 1994;86:1534-1539.
16. Blackman SB, Lash TL, Fink AK, et al. Advanced age and adjuvant
tamoxifen prescription in early-stage breast carcinoma patients. Cancer.
2002;95:2465-2472.
17. Partridge AH, Wang PS, Winer EP, et al. Nonadherence to adjuvant
tamoxifen therapy in women with primary breast cancer. J Clin Oncol.
2003;21:602 606.
18. Owusu C, Buist DS, Field T, et al. Tamoxifen discontinuance among
older women with estrogen-receptor-positive breast cancer. J Clin Oncol.
2006;24: (suppl; abstr 648).
19. Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex,

Tamoxifen, Alone or in Combination) trial after completion of 5 years


adjuvant treatment for breast cancer. Lancet. 2005;365:60-62.
20. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women
with primary breast cancer. N Engl J Med. 2004;350:1081-1092.
21. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in
postmenopausal women after five years of tamoxifen therapy for early-stage
breast cancer. N Engl J Med. 2003;349:1793-1802.
22. Mouridsen H, Keshaviah A, Coates AS, et al. Cardiovascular adverse
events during adjuvant endocrine therapy for early breast cancer using
letrozole or tamoxifen: safety analysis of BIG 1-98 trial. J Clin Oncol.
2007;25:5715-5722.
23. Buzdar A, Howell A, et al. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer:
long-term safety analysis of the ATAC trial. Lancet Oncol. 2006;7:633-643.
24. Muss HB, Tu D, Ingle JN, et al. Efficacy, toxicity, and quality of life in
older women with early-stage breast cancer treated with letrozole or placebo
after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol.
2008;26:1956-1964.
25. Amir E, Seruga B, Niraula S, et al. Toxicity of adjuvant endocrine
therapy in postmenopausal breast cancer patients: a systematic review and
meta-analysis. J Natl Cancer Inst. 2011;103:1299-1309.
26. Crivellari D, Sun Z, Coates AS, et al. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the
BIG 1-98 trial. J Clin Oncol. 2008;26:1972-1979.
27. Muss HB, Woolf S, Berry D, et al. Adjuvant chemotherapy in older and
younger women with lymph node-positive breast cancer. JAMA. 2005;293:
1073-1081.
28. Du XL, Jones DV, Zhang D. Effectiveness of adjuvant chemotherapy for
node-positive operable breast cancer in older women. J Gerontol A Biol Sci
Med Sci. 2005;60:1137-1144.
29. Elkin EB, Hurria A, Mitra N, et al. Adjuvant chemotherapy and
survival in older women with hormone receptor-negative breast cancer:
assessing outcome in a population-based, observational cohort. J Clin Oncol.
2006;24:2757-2764.
30. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in
older women with early-stage breast cancer. N Engl J Med. 2009;360:20552065.
31. Jones S, Holmes FA, OShaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology Research
Trial 9735. J Clin Oncol. 2009;27:1177-1183.
32. Freyer G, Campone M, Peron J, et al. Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: results of an observational
study. Crit Rev Oncol Hematol. 2011;80:466-473. Epub 2011 May 11.
33. Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term
outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379:
432-444.
34. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence
of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:
2817-2826.
35. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist
in making decisions about adjuvant therapy for women with early breast
cancer. J Clin Oncol. 2001;19:980-991.
36. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab

TREATMENT FOR OLDER WOMEN WITH BREAST CANCER


after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med.
2005;353:1659-1672.
37. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353:1673-1684.
38. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in
HER2-positive breast cancer. N Engl J Med. 2011;365:1273-1283.
39. Ewer SM, Ewer MS. Cardiotoxicity profile of trastuzumab. Drug Saf.
2008;31:459-467.
40. Darby S, McGale P, et al. Effect of radiotherapy after breast-conserving
surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis
of individual patient data for 10,801 women in 17 randomised trials. Lancet.
2011;378:1707-1716.

41. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen
with or without irradiation in women 70 years of age or older with early
breast cancer. N Engl J Med. 2004;351:971-977.
42. Hughes KS, Schnaper LA, Cirrincione C, et al. Lumpectomy plus
tamoxifen with or without irradiation in women age 70 or older with early
breast cancer. J Clin Oncol. 2010;28:15s (suppl; abstr 507).
43. Owusu C, Buist DS, Field TS, et al. Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer.
J Clin Oncol. 2008;26:549-555.
44. Partridge AH, LaFountain A, Mayer E, et al. Adherence to initial
adjuvant anastrozole therapy among women with early-stage breast cancer.
J Clin Oncol. 2008;26:556-562.

Management of Small T1a/b N0


Breast Cancers
By Anthony D. Elias, MD

Overview: T1ab N0 breast cancer generally has excellent


prognosis. Adverse prognostic factors include HER2 disease, ER-negative disease, high-grade histology, T1b, and
young age of patient. These patients are largely excluded from
most trials, and to date, no prospective studies for this group

HE INCIDENCE of small ( 1 cm) node-negative breast


cancers (BC) is increasing in mammography-screened
populations.1 About two-thirds of all breast cancers (BCs) in
the Surveillance, Epidemiology, and End Results (SEER)
registry are T1; approximately 72% and 28% are T1b and
T1a, respectively.1
Approximately 50% to 60% of T1abN0 human epidermal
growth factor receptor 2 (HER2)-positive tumors are estrogen receptor (ER) positive.2-4 Approximately 10% to 15% of
patients with T1abN0 have HER2-positive disease.2-9 Several studies have reported that T1mic and T1a are more
likely to be ER negative and HER2 positive compared with
T1b, although an early study of OncotypeDx suggested that
among the ER-positive tumors, a greater percentage of the
T1b had low recurrence score (RS).4,10,11 In the Kwon report,
HER2 was positive in 46%, 23%, and 13%, and ER positive
in 42%, 66%, and 78% of T1mic, T1a, and T1b, respectively.4
Small node-negative BC are generally associated with
excellent outcomes, with disease-free (DFS) and relapse-free
survivals (RFS) in excess of 90%, and with survivals exceeding 95% at 5 to 10 years. Older studies have shown 10-year
RFS between 83% and 91%.12-14 However, these tumors are
quite heterogeneous, and some subsets of tumors have a far
higher risk of relapse. Because these patients are generally
not included in clinical trials, outcomes are poorly characterized, management is uncertain, and treatment varies
considerably from one oncologist to another.
This article will review the outcomes literature for T1ab
N0M0 BCs, focusing on articles presented in the last decade,
at a time where molecular testing of ER, progesterone
receptor (PR), and HER2 have become routine. For more
details of earlier literature, refer to the excellent review by
Hanrahan et al.15 Because of a recent spike in interest in the
oncology community, the majority of articles on this topic
have been published in manuscript or abstract form in 2010
and 2011.
T1a tumors are 0.5 cm or smaller, while T1b are larger
than 0.5 to 1 cm or smaller. Typical definitions include RFS:
date of diagnosis or initial surgery to date of recurrence
(distant or local), death from any cause, or last follow-up.
DFS includes contralateral new BCs as events. Distant DFS
only includes metastatic events.

yet reported. Treatment guidelines are vague and treatment


inconsistent. As yet, in the HER2 population, little experience with targeted therapy has been reported. Prospective
trials are needed.

were chemotherapy naive with ER-negative BC, the 8-year


RFS was only 79% with an overall survival (OS) of 93%. A
90% 8-year RFS was achieved when chemotherapy was
given. For the 264 patients with ER-positive BC, an 8-year
RFS of 86% and an OS of 90% were achieved with surgery
alone. For those treated with tamoxifen, a 93% 8-year RFS
was noted.
Wood et al studied the outcomes of 282 consecutive women
with T1abN0 BCs at Emory.17 The mean follow-up was 7
years. Tamoxifen and chemotherapy was administered to 93
and 20 patients, respectively. One patient had local recurrence and two suffered metastatic spread despite tamoxifen
for an estimated 10-year distant DFS (DDFS) of 98.7%.
Joensuu described a cohort of 852 Finnish patients with
T1N0 BC, of whom 12% had HER2-positive disease and 75%
had ER-positive disease.18 Median follow-up was 114
months. Three hundred and thirteen patients had T1ab
disease with a 9-year DFS of 93%; for T1a 100%. Nine-year
DDFS was much better for HER2-negative compared with
HER2-positive BCs (89% vs. 73%, p 0.0003). In the T1b
group, this difference was greater (95% vs. 67%). Thirty
patients had TN BC, of whom nine received chemotherapy.
No relapses were observed. Adverse prognostic factors included T size (in mm), HER2 positivity, Ki67 greater than
20%, and possibly grade 2 to 3 disease.
Fisher et al reported on the outcomes of the patients with
T1abN0 disease from the NSABP B21 study who were
randomly selected to receive lumpectomy plus tamoxifen,
lumpectomy plus radiation therapy, or all three.19 Median
follow-up was 87 months. HER2 status was unknown. Twothirds received endocrine therapy, and the remainder received observation. Radiation therapy reduced ipsilateral
breast tumor recurrence (IBTR; hazard ratio [HR] 0.19) as
did tamoxifen (HR 0.37). Eight-year DFS for the best arm
(preoperative cetuximab and radiation [XRT] plus tamoxifen) was 84.4%. An update was provided in 2007 with
14-year follow-up.20 Adverse prognostic factors were grade
3, nontubular histology, and, for survival, lymphovascular
invasion (LVI).
Chia et al reported the outcomes of 2,026 patients in
British Columbia with N0 BC treated in 1986 to 1992.21
Seventy percent had no adjuvant therapy. Ten-year RFS
was 76% (and only 66% in the HER2 population [10% of

Literature Review
Studies in Which 10% of Patients Received Adjuvant Chemotherapy
and No Trastuzumab

Fisher et al presented the National Surgical Adjuvant


Breast and Bowel Project (NSABP) experience with T1abN0
BC in the B-06, B-13, B-14, B-19, and B-20 studies (Table
1).16 Median follow-up was 8 years. For the 61 patients who

10

From the University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Anthony D. Elias, MD, University of Colorado Cancer Center,
Anschutz Medical Campus, MS 8117, Research Tower South, 12801 East 17th Avenue,
Room 8111, Aurora, CO 80045; email: anthony.elias@ucdenver.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

MANAGEMENT OF T1 BREAST CANCERS

the group]). Of the 307 T1abN0 HER2-negative BCs, 10-year


RFS was approximately 94%. Of the 21 T1abN0 HER2positive BCs, the 10-year RFS was approximately 85%. T1b
fared a bit worse than T1a.
Gonzalez-Angulo et al analyzed a University of Texas
M. D. Anderson Cancer Center (MDACC) dataset (later
reported by Theriault et al9) plus a confirmatory dataset
from the Institutes Bordet and Leoben.22 Nine hundred and
sixty five patients from MDACC and 350 patients from the
other two institutions with T1abN0 were included. Endocrine therapy was given to 55% of the MDACC patients;
treatment details were sparse from the other group. Overall
5-year RFS was 92% and 96% for the two groups but only
77% and 87% for the HER2-positive subset. Adverse prognostic factors included HER2-positivity, ER-negativity, age
younger than 50, and grade 3 tumor. Tumor size was not a
factor. The TN group had a 5-year RFS of 83% at MDACC,
but it was substantially better (95%) at the other institutions. It is uncertain whether this was a result of differences
in treatment.
Theriault et al summarized the MDACC experience for
1,012 patients with T1abN0 BC in 1990 to 2002.9 Median
follow-up was roughly 60 months. Patients who had received
chemotherapy or trastuzumab were excluded from this article. Of the 771 patients with ER-positive BC, 61% received
endocrine therapy. Of the 98 and 143 patients with HER2positive and TN BC, endocrine therapy was given to 46%
and 21%, respectively. Five-year DDFS was 97.5%, 86.9%,
and 96.3% for the patients with HR-positive, HER2-positive,
and TN disease, respectively. Five-year RFS was 94.5%,
77.2%, and 84.9%, respectively. Adverse prognostic factors
included age younger than 35, HER2 positivity, and less so
TN BC.
Cancello et al reported on the European Institute of
Oncology experience for patients with T1mic/a/bN0 BC
treated in 1997 to 2005.8 It is not clear how these patients
overlap with a prior report from Curigliano et al.23 Median
follow-up was 76 months for the 1,691 patients. Overall
treatment consisted of endocrine therapy in 35% (93% of all
ER) and chemotherapy in 10% (54% and 71% of HER2
and TN BC). No trastuzumab was administered. Using
cutoffs of 1% for ER/PR and 14% for Ki67, patients were
categorized by IHC to have BCs that were luminal A (881,
52%), luminal B (532, 31%), luminal B HER2 positive (101,
6%), HER2 positive/ER negative (82, 5%), and TN (95, 6%).
Five-year BC-specific survival was approximately 98%, 97%,
95%, 91%, and 91%, respectively. Adverse prognostic factors
included age younger than 35, HER2 positivity, TN, and
LVI.
KEY POINTS

T1ab N0 breast cancer generally has excellent prognosis.


Adverse prognostic factors include HER2 disease,
ER disease, high-grade histology, T1b, and younger
age.
Vague treatment guidelines exist.
No prospective trials have yet been reported.
For the HER2 population, there is almost no trastuzumab experience in the absence of chemotherapy.

Rouanet et al reported the outcomes of 703 French patients with T1abN0 BC treated in 1999 to 2004.10 Only 6%
had HER2-positive disease. Of these, 50% had dual positive
disease. Treatment consisted of endocrine therapy in 41%,
chemotherapy in 10%, and observation in 55%, which
achieved a 5-year DFS of only 74%. For the 661 patients
with HER2-negative disease, 10% had TN disease and 90%
ER-positive disease. Treatment for this group was endocrine
for 80%, chemotherapy for 5%, and observation for 17%,
which achieved a 5-year DFS of 95%. Adverse prognostic
factors included HER2-positivity, ER-negativity, age
younger than 50, no adjuvant therapy, and grade 3 disease.
Five-year DFS for the TN cohort was 91%.
Livi et al presented 704 Florentines with T1abN0 BC
treated in 2002 to 2008.2,24 Median follow-up was 59
months. No chemotherapy or trastuzumab was given; endocrine therapy was given in 64%. Five hundred and fifty-nine
had ER-positive/HER2-negative disease, 75 had HER2positive disease of whom 55% had ER-positive disease
and 70 had TN BC.24 Five-year DDFS was 97.8%, 92%, and
91.8%, respectively. Overall 5-year DFS was 96.5%. Adverse
prognostic factors included age 50 or younger and ERnegative and HER2-positive disease.
Studies in Which >10% Patients Received Adjuvant Chemotherapy,
but No Trastuzumab

Colleoni et al reported on a cohort of patients with T1mic/


a/b N0 disease from the European Institute of Oncology
treated in 1997 to 2001.14 Median follow-up was only 43
months. Of the 425 patients, 358 had ER-positive BC (11%
HER2), and 60 had ER-negative BC (40% HER2, 60%
TN). Most received adjuvant therapy. Of the patients who
were ER positive, only six relapsed following treatment
(endocrine 88%, chemotherapy 12%, observation 11%). Of
the patients who were ER negative, only three relapsed
following treatment (chemotherapy 60%, observation 40%).
Adverse prognostic factors included Ki67 greater than 20%,
age younger than 35, and PR-negative disease.
Hanrahan et al analyzed the outcomes of patients with
T1abN0 disease in the SEER registry from 1988 to 2001.26
Treatment details are not available. By 10 years, only
approximately 4% died of BC, whereas an additional 20%
died of other causes, mostly cardiovascular. For OS, prognostic factors included black race, T1b, and PR-negative
disease. For each mm tumor size, the HR for OS was 1.02.
Prognostic factors for BC-specific mortality were age
younger than 50, grade 3, ER negativity, PR negativity, and
fewer than six lymph nodes in the axillary lymph node
dissection (ALND).
Curigliano et al reviewed 2,130 patients with T1abN0 BC
treated at the European Institute of Oncology in 1999 to
2006.23 The extent of overlap with Cancellos presentation is
not clear. Median follow-up was 55 months. A subset had
immunohistochemical (IHC) testing: 79 with HER2-positive/
ER-positive disease and 71 with HER2-positive/ER-negative
disease; 158 patients with ER-positive/HER2-negative BC
were matched by HR status, age, and year of surgery.
Treatment for the ER-positive/HER2-negative group was
endocrine in 93%, chemotherapy in 1% and observation in
6% resulting in a 5-year DFS of 99%. Treatment for the dual
positive group was endocrine in 66% and chemotherapy in
25%, resulting in a 5-year DFS of 92%. Treatment for the
HER2-positive/ER-negative group was endocrine in 3%, che-

11

ANTHONY D. ELIAS
Table 1. T1ab N0 Breast Cancer Literature Review (Papers Published 20022011)

Author

F/U
(mos)

Types of Treatment

Institution

Fisher

16

NSABP B21

2002 19891998

Wood
Joensuu

17
18

Emory
Finland

2002
?
84 mean T1abN0
2003 19911992
114
T1N0
T1ab
TN
HRHER2-

Fisher

Chia

GonzalezAngulo

19,20 NSABP
Subset of
1009
in B21
21

9,22

Year

Pt Accrual
Yrs

Ref(s)

2007 19891998

British
Columbia

2008 19861992

MDACC

2009 19902002

87

134

Stage
T1abN0

T1abN0

N0
T1ab HER2T1ab HER2
74

T1abN0

Bordet
Leoben

Theriault

Cancello

Rouanet

Livi

10

2,24

MDACC

2011 19902002

Florence

2011 19992004

60

76

77

2011 20022008

59

Colleoni

16

Eur Inst
2004 19972001
Oncology

43

Hanrahan

26

SEER

2007 19882001

64

Curigliano

23

Eur Inst Onc 2009 19992006

55

12

T1abN0
ER
HER2
TN
T1m/a/bN0
Luminal A
Luminal B
Luminal B HER2
HER2
TN
T1abN0
T1a
T1b

T1a/bN0
T1a/b H
T1a/b TN
T1mic/a/b N0
ER
ERT1abN0

T1abN0
ER/HER2
matched ER/HER-/HER2
Matched ER-/H-

%ER

1009
57% (30% unk)
332
57
334
54
334
59
282
NR
852
75
313
30
396*
*#s dont add up
638
n/a
204
228
206
2026
307
21
965

350

Eur Inst Onc 2011 19972005

ONCO

# Pts

1012
771
98
143
1691
881
532
101
82
95
703*
131
572
424 others*
661
42
704
75
70
425
358
60
51,246

2130
79
158
71
71

%HER2
nd

nd
12

%OBS

70
93
nd

%ET %Chemo %anti HER2

33
67
XRT only
0
XRT
100
no XRT
100
NR
33
95

32
68
XRT only
0
XRT
100
no XRT
100

10

70
82
76

77
86
61
48

10

45

55

76

10
39
54
79
NR

61
46
21
35

73% any T
39% any T

11

100
100
100
0
0
93
77
97

0
0
100
100
0
6
14
4
unk
0
100

58% (30% unk)

30
0

10

20

92
94
94
1
3
83

1
7
7
54
71
6

17
55
36

80
36
64

5
5
0

0
0
0

16
11
40
NR

66
88
0
NR

16
12
60
NR

0
0
0
0

10
6
54
31

89
94
4
3

25
1
43
66

0
0
0
0
0

90

90
50
84
55
0
84

13

nd

MANAGEMENT OF T1 BREAST CANCERS


Table 1. T1ab N0 Breast Cancer Literature Review (Papers Published 20022011) (Contd)
Measure of Efficacy
Time

%DFS

%RFS

%DDFS

%OS

%IBTR

Adverse Factors

81.6
84.4
77.8

96.7
98.5
96.8
98.7

7y
4.2 y

94
93.4
94

90.7
97.8
83.5
size, HER2, Ki67
20%, G 1

93
100

5y

5 y BCS

66 versus
76 HER2
94
85
92

71 versus
82 HER2

94
77 (HR 2.7)
HR 3.9
96

97
86 (HR 5.3)
HR 2.8

T1b a bit worse


96

97
87
91.5
96.3
94.5
97.5
77.2 (HR 4.98) 86.9 (HR 4.7)
84.9 (HR 2.71) 96.3 (HR 2.1)

5y

49 T1a 100% DFS

HER2 Test
HER2 unk

HER2 unk
IHC 3 10%
or CISH

DFS: high nuclear


IBTR: nuclear grade, HER2 unk
grade, non-tubular
DCIS present
82.1
89.2
OS: LVI
77.8
89.8
82.2
80.5

60.6
56
61.5
10 y

Comments
71% T1b
IBTR: HR 0.19 for XRT;
HR 0.37 for Tam

8y

IHC 3 10%
or FISH
HER2HER2
TN
5y RFS TN 95% (n 125);
IHC 3 10%
no diff T1a versus T1b
or FISH
HER2HER2
Age 35, HER2 worse Fig 1
IHC 3 10%
than TN
excluded CT and trastuzumab
or FISH
more T1a

94.6

HER2, ER-, age


50, high grade

ER-5y RFS 83.3%

Age 35, HER2 then


TN, LVI

ER/PR at 1% threshold;
Ki67 14%
Fig 1

IHC 3 10%
or FISH
SP3 Ab

98
97
95
91
91

IHC 3 10%

Tmic overrepresented (27%)

5y

97

HER2, ER-, 50 y,
no adj therapy, G3

T1a more HER2, ER50% HER also ER


TN 5 y DFS 91%

IHC 3 or DISH

age 50; ER-, HER2

HR 3.66 for HER2 DFS


63% T1b

IHC 10% 3
or FISH

Ki67 20% HR 12.9;


35, PR-

76% T1b; more G3 in


T1mic, no events in T1mic

IHC 3 10%

BCSM: 50, G3,


ER-, PR-, 6LN in
ALND; OS: 50,
AA, T1b, PR-

4% died of BC;
24% all-cause

HER2 unk

95
74
5y

96.5
92
91.8

93.7
90.3

1
1
1

4y
6 events
3 events
10 y

5y

HR 1.02 for
1 mm T size

HR 2.4
92 (HR 5.2)
99
91
92

HR 5.1 for HER2


T1b, multifocal

T1a
T1a
T1a
T1a

DFS 88%; T1b 95%


97%; T1b 99%
93%; T1b 85%
87%; T1b 94%

IHC 3 10%
or FISH

13

ANTHONY D. ELIAS
Table 1. T1ab N0 Breast Cancer Literature Review (Papers Published 20022011) (Contd)

Author
Kwon

Park

Lai

Tanaka

Ref(s)
4

27

28

Institution
Seoul

Seoul

Taiwan

Japan

Year

Pt Accrual
Yrs

2010 20002006

F/U
(mos)
61

2010 19942004

61

2011 19952006

289
54
31
33
48

2011 20012007

46

Fehrenbacher

29

KPNC

2010 20002006

70

Amar

30

Mayo

2010 20012005

34

Horio

Wong

McArthur

Nagoya

3
Singapore
subset
subset
subset
6

MSKCC

2011 20032007

2011 19892009

2011 20022008
20022004

52

57

Shao

14

T1ab
N0 or Nx
TN
non-TN
T1N0
T1N0 HT1N0 H
T1a/b H
T1abN0 HER2
T1a
T1b
T1abN0
ER
HER2
TN
T1a/b
HT1a
T1b
H
T1a
T1b
TN
T1N0
T1N0 HER2
T1c
T1a/b HT1a/b H
T1N0 HER2

Beth Israel NYC

2011 19952008

42

%ER

%HER2

375
120
93
162
31
65
56
370
57(13%)

67
42
66
78

26
46
23
13

HR/HER2 any
ER/HER2
HER2/ERTN
377
323
47 of 311
454
376
78
28
237
116
121
421
364
28
29

%OBS %ET
26

62

%Chemo

%anti HER2

16

34% of ER82

9 (not dual )

NR

74

36

94

25

65
64
65

29
36
18
17

0
0
0

NR
NR

77
44

14
45

100

NR

NR

NR

44
48
36
4

25
12.9
36.3
6
3
39
28

37
36

55
62

9
4

41
48
32

24
17
32

43
35
53

12
9
16

NR

78
47

8
24

0
9
0

60

59

63

61

66
42
100
100
49

59
52
65
87
50

T1a/b H
T1abN0 HER2
HR
HR-

59
100
0

100
100
100

T1abN0
HR
HER2
TN

658
494
109
55

75
100
27
0

17
0
100
0

36
41

# Pts

267
225
42
183
42
23
19
10
519
89
315
170
34
261
106
45
155
54
205
121
84

T1a/b H

20052008
subset
31
AERIO/Unicancer 2011 20002010

32

T1mic/a/bN0
T1mic
T1a
T1b
HER2HR
HER2HRTN
T1abN0
T1abN1

78

subset

Peron

Types of Treatment
Stage

86

16

36

8.4
6.8
9.9
1
18

17
18

NR

54
90

NR
NR
NR
55

NR
NR
NR
NR

10
31
42

100
100
45

0
0
17

MANAGEMENT OF T1 BREAST CANCERS


Table 1. T1ab N0 Breast Cancer Literature Review (Papers Published 20022011) (Contd)
Measure of Efficacy
Time

%DFS

5y

%RFS

%DDFS

%OS

%IBTR

Adverse Factors
age 35, TN

97.2

Comments
48% MRM

HER2 Test
IHC 3 (10%?)

96.8
98.5
92.6
5y

HER2, TN
for N1, multi,
HER2, TN

HR 7.2
HR 5.5
5y

98
92
90 (HR 5.7)
90 (HR 6)

T1b TN DDFS 84%,


HER2 87%
N1, HER2, TN

85.6
95.5 (HR 2.01)
97.4

3 M1, 54 N1 (15%)

IHC 3 30%
or FISH

HR 4.16 HER2, HR 3.37 TN

5y

HER2, ER-, grade 3,


premenopausal, LVI

97.2
88
5y

IHC 3 10%
or FISH

94.2
97.4
91.1

96.5
99.1
94

2.9

ER- 15%
ER- 51%
1 cm tumors have 12.5% 5 y
distant recurrence risk

3y

DAKO 3
or FISH

IHC 3 10%
or FISH
IHC 3 10%
or FISH

99
89
83
5y

IHC 3 or FISH
97.7

90.5

5 y,
10 y OS

T1b 79%

92.3

95.7

98.6

83.7
95.7
85.1

89.9

83.3
100
99.2

HER2 (HR 4.1 for DFS);


size for DDFS

5 y DFS HER2 83.7%


ER- 39%

3.5
14.9

HER2 (but not OS)

3y

More LVI, T1c in T-treated group


82
78
97
95

95
97
100
100

5y

IHC 3 or FISH

97
98
99
98

96 if treated w/chemo/
trastuzumab
86 if not treated

5y

DAKO 3
or FISH

25% T1a; 3 pts trastuzumab alone

TN

Chemo given for ER-, G2-3,


high mitoses
35% T1a

97.9
95.6 (HR 1.64)
93.5 (HR 3.13)
Abbreviations: Pt, patient; yrs, years; F/U, follow-up; mos, months; ER, estrogen receptor; HER, human epidermal growth factor receptor; OBS, observation; ET,
endocrine therapy; DFS, disease-free survival; RFS, recurrence-free survival; DDFS, distant disease-free survival; OS, overall survival; IBTR, ipsilateral breast tumor
recurrence; NSABP, National Surgical Breast and Bowel Project; unk, unknown; nd, not done; XRT, radiation therapy; HR, hazard ratio; Tam, tamoxifen; NR, not
reported; IHC, immunohistochemical; CISH, chromagen in situ hybridization; PR, progesterone receptor; LVI, lymphovascular invasion; SEER, Surveillance,
Epidemiology, and End Results; BCSM, breast cancer-specific mortality; LN, lymph node; ALND, axillary lymph node dissection; AA, African American; BC, breast
cancer; FISH, fluorescence in situ hybridization; T, tumor; SP3 Ab, SP3 antibody; MDACC, M. D. Anderson Cancer Center; TN, triple-negative; MRM, modified radical
mastectomy; BCS, breast cancer survival; CT, computed tomography; DAKO, DAKO, Inc.; MSKCC, Memorial Sloan-Kettering Cancer Center; KPNC, Kaiser Permanente
Northern California; ONCO, ONCO Languedoc-Roussillon Network.

15

ANTHONY D. ELIAS

motherapy in 43%, and observation in 54%, resulting in a


5-year DFS of 91%. Adverse prognostic factors included T1b
compared with T1a and multifocal BC in the HER2-positive
group.
Kwon et al treated 375 Koreans with T1mic/a/bN0 BC in
2000 to 2006.4 Median follow-up was 61 months. Treatment
consisted of observation in 26%, chemotherapy in 16%, and
endocrine therapy in 62%. No trastuzumab was given.
Five-year RFS was 97.2%. Adverse prognostic factors included age younger than 35, and TN disease. Five-year RFS
was 96.8%, 98.5%, and 92.5% for the HER2-positive/ERpositive, HER2-positive/ER-negative, and TN groups.
Park et al reported on 370 Korean patients with T1abN0
BC treated in 1994 to 2004.27 Median follow-up was 61
months. Treatment consisted of endocrine therapy in 74%
and chemotherapy in 36%. No trastuzumab was given.
Five-year DDFS was approximately 98%, 92%, 90%, and
90% for HR-positive, HER2-positive/ER-positive, HER2positive/ER-negative, and TN disease. Adverse prognostic
factors included T1b compared with T1a, TN, and HER2positive disease. The 5-year DDFS for the T1b TN and
HER2-positive groups was 84% and 87%, respectively.
Lai et al reported on 377 Taiwanese patients with T1ab
BC treated in 1995 to 2006.28 Fifty-four patients had node
involvement and three had metastatic disease. The overall
five-year DFS was 85.6% and the prognostic factors were N1,
HER2-positive, and TN disease.
Tanaka et al reported on 454 Japanese patients with
T1N0 BC treated from 2001 to 2007.5 Median follow-up was
46 months. Treatment followed St. Gallen guidelines, thus
only 14% of the T1N0 HER2-negative group and 45% of the
HER2-positive group received chemotherapy. No trastuzumab was given. Five-year RFS was 97.2% and 88% for the
HER2-negative and HER2-positive groups. By univariate
analysis, HER2-positivity, ER-negativity, grade 3 histology,
premenopausal status, and LVI were adverse prognostic
factors. By multivariate analysis, HER2-positivity and LVI
retained significance. Only 28 patients had T1abN0 HER2positive disease.
Fehrenbach et al reported the outcomes of 237 patients
with T1abN0 HER2-positive disease treated at Kaiser Permanente Northern California (KPNC) in 2000 to 2006.29
Median follow-up was 70 months. T1a disease was present
in 49% of patients and ER-positive disease in 59%. Chemotherapy was given to 17% (29% in T1b, 4% in T1a) and
trastuzumab to 8% (generally with chemotherapy). Fiveyear DDFS was excellent (99.1 in T1a and 94% in T1b).
Studies Including the Use of Trastuzumab

Amar et al reviewed the experience of the Mayo Clinic


with patients with T1abN0 in 2001 to 2005.30 Median
follow-up was 34 months. Of 421 patients, 87% had ERpositive, 7% HER2-positive, and 7% TN disease. Treatment
consisted of hormone therapy in 44%, chemotherapy in 7%,
and trastuzumab in 1%. Of the 28 patients with HER2positive disease, four had trastuzumab plus chemotherapy
and seven had chemotherapy alone. Endocrine therapy was
given to 48% of ER-positive BC and 36% of HER2-positive
BC. Chemotherapy was given to 28% of patients with TN
disease. Three-year RFS was 99% in ER-positive BC but
only 89% and 83% in patients with HER2-positive and TN
disease.
Horio et al reported on 267 patients from Nagoya with

16

T1abN0 BC treated in 2003 to 2007. Median follow-up was


52 months. Overall treatment was observation in 27%,
chemotherapy in 9%, and endocrine therapy in 55%. Of the
42 patients with HER2-positive BC, 12% received trastuzumab together with chemotherapy. Five-year RFS was
97.7% and 90.5% in the ER-positive/HER2-negative and
HER2-positive groups, respectively. There were no obvious
differences in relapse in the T1a group compared with the
T1b group. Only 10 patients had TN BC.
Wong et al published their institutional outcomes for 519
patients with T1N0 BC treated in Singapore from 1989 to
2009.3 Treatment details were not provided, although endocrine therapy was given to most patients with ER-positive
disease, chemotherapy to approximately 10%, and chemotherapy plus trastuzumab to three patients. Median
follow-up was 57 months. Five-year DFS, DDFS, and OS
were 92.3%, 95.7%, and 98.6%, respectively. Major prognostic factors were the presence of HER2 (HR 4.1 for DFS)
and tumor size (for DDFS). The 17% who had HER2-positive
disease had a 5-year DFS of only 83.7% and an OS of 83.3%.
Two hundred and four patients had T1abN0 disease, of
whom 34 had tumors positive for HER2. The patients with
T1ab HER2-negative disease did well with a 5-year DFS of
95.7%, OS of 100%, and an IBTR of only 3.5%. However, the
patients with T1ab HER2-positive disease fared less well
with a 5-year DFS of 85.1%, OS of 99.2%, and an IBTR of
14.9%.
McArthur et al summarized the MSKCC experience with
the T1N0 HER2-positive BCs in the pre-trastuzumab era of
2002 to 2004 and the post-trastuzumab era of 2005 to 2008.6
Median follow-up was 78 and 36 months for the two groups.
In the pre-trastuzumab era, 66% of the cohort received
chemotherapy (42% in the T1ab subset), and 59% (essentially all of those ER) received endocrine therapy. Threeyear DFS was only 82% (78% for the T1ab group), although
3-year DDFS was 95% to 97%. A high rate of local recurrence
was observed. In the post-trastuzumab era, all patients
received chemotherapy plus trastuzumab and 61% (essentially all of those ER) received endocrine therapy. The
3-year DFS was 97% (95% in the T1ab subset) and the DDFS
was 100%. This trial certainly suggests that aggressive
treatment, including anti-HER2 treatment, can reduce relapses but at the risk of overtreatment in a large proportion.
Peron et al updated the outcomes of 205 patients with
T1abN0 HER2-positive BC treated in 2000 to 2010.31 Median follow-up was 41 months. Adjuvant therapy consisted
of endocrine therapy in 54% (90% of the HER2/ER group)
and chemotherapy with trastuzumab in 44%, chemotherapy
in 5%, and trastuzumab alone in three patients. Five-year
RFS was 96% if treated with chemotherapy plus trastuzumab and only 86% if not treated. Chemotherapy was
selectively given for ER-negative disease, grade 2 to 3
disease, and high mitotic count.
Shao et al presented a cohort of 658 patients with T1abN0
BC from Beth Israel Deaconess Medical Center treated in
1995 to 2008.32 Median follow-up was 42 months. Four
hundred and ninety-four patients had ER-positive BC, of
whom 10% received chemotherapy, and endocrine therapy
was not reported. One hundred and nine patients had
HER2-positive BC (27% ER as well), of whom 14% received
chemotherapy, and 17% received chemotherapy plus trastuzumab. Fifty-five patients had TN BC, of whom 42% received chemotherapy. Five-year DFS was 97.9%, 95.6%, and

MANAGEMENT OF T1 BREAST CANCERS

93.5%, respectively. Adverse prognostic factors included TN


disease. Hazard function did not reach statistical significance for HER2-positive disease.
Local-Regional Management

A major trend in BC therapy is the lessening extent of


axillary surgery. ALN dissection is completed for patients
with clinically node-positive disease but not for patients
with sentinel node (SN)-negative disease and is controversial even for the patients with clinically negative, SNpositive disease. SN sampling is occasionally omitted for the
elderly. Since ALN involvement is less common for small
primary tumors, there is a great temptation to avoid this
surgery. In various series of small primary tumors, the
likelihood of ALN involvement is between 3% and 37%.33 In
this series of 888 T1ab tumors with a 12% ALN involvement
rate, factors associated with ALN involvement in these
small tumors included LVI (HR 12.63), perineural invasion (HR 5.47), grade 3 tumor (HR 3.07), and ERnegative disease (HR 1.84).33
Rivadeneira et al found that 18% of 919 patients (199 T1a)
had ALN metastases following a standard ALND.34 Although tumor size was predictive, even the T1a group had a
16% rate of ALN involvement. Other factors included grade
3, LVI, and age younger than 50. These risk factors are
consistently observed in other series.35 HER2 status was not
tested. In the very best group of older patients with welldifferentiated T1a tumors without LVI, 13% still had metastases.34 The authors recommend routine use of SLN biopsy.
Literature Conclusions

T1abN0 BC generally has an excellent prognosis. Consistent adverse prognostic factors include HER2-positive disease, ER-negative disease, high grade, T1b, and age younger
than 50 years. Because most of the articles treated these
patients variably, these prognostic factors actually are
mixed prognostic/predictive factors demonstrating benefit of
specific therapies. Grade is problematic because of poor
concordance between expert pathologists in its determination. Ki67prognostic in many articleslacks standardization between pathology laboratories. Age is a complex
variable: low comorbidity rates and high life expectancy
allow extended time for BC events; premenopausal status
with different hormonal milieu; different genetic drivers to
develop BC in the young; a different mix of molecular
subtypes; and independent of subtypes, a more aggressive
metastasis pattern in the young, perhaps related to the
immunologic and inflammatory signals generated by pregnancy and weaning.36
In addition to these factors, which ultimately reflect
molecular subtype, size, and premenopausal status, the fact
remains that most events in these patients with good prognosis are unrelated to BC. Comorbiditiesparticularly cardiovascular healthas competing risks may represent up to
80% of all events, particularly in the elderly.22 Thus, the
best endpoints to help us make decisions may not be OS,
DFS, or RFS but the balancing of DDFS (or BCSS) and the
risks of treatment.
Most adjuvant trials find a strong correlation between an
intervention and the relative risk reduction independent of
stage. Thus, we expect approximately 25% risk reduction
with older polychemotherapy, approximately 40% risk re-

duction with docetaxel plus cyclophosphamide (TC), a reduction of approximately 41% with tamoxifen, approximately
50% with aromatase inhibitors, and approximately 50%
reduction with the addition of trastuzumab to chemotherapy. Thus, one can estimate the magnitude of absolute risk
reduction with these interventions by estimating the absolute risk if untreated.
Guidelines

Both major guidelines (National Comprehensive Cancer


Network [NCCN] and St. Gallens Expert Panel) require the
oncologist to consider much, but detailed instructions are
nebulous, as paraphrased below.
NCCN 2009. If T1a/T1mic N0, or if T1b and G1, no
adjuvant therapy is recommended, although endocrine therapy can be considered. If T1b N0 and grade 2 to 3, then
adjuvant endocrine therapy is recommended if ER positive.
If younger than age 60, adjuvant chemotherapy could be
considered. If T1b HER2 positive, endocrine therapy with or
without chemotherapy with or without trastuzumab could
be considered, but no further guidance is provided.
St. Gallen 2011. For luminal T1N0 ER-positive BC, antiestrogen therapies are recommended but not chemotherapy.
For the HER2-positive subtype, the panel of experts was
willing to extrapolate the chemotherapy/trastuzumab studies to T1bN0 BCs but would not recommend any adjuvant
therapy for T1a tumors. For the TN subtype, chemotherapy
is considered; no specific recommendation was made based
on tumor size. Trastuzumab with or without endocrine
therapy alone without chemotherapy was not considered to
be an acceptable adjuvant treatment for small HER2positive BC by 78% of the experts unless a contraindication
to chemotherapy existed.37 Chemotherapy would be more
strongly considered for large tumor size, involved nodes, or
bad biology (HER2 or TN, grade 3).
In My Opinion

ER-positive/HER2-negative BC. Adjuvant endocrine therapy should be considered for all, particularly for the T1b
group, subject to the patient tolerance of the endocrine
therapy. DFS/RFS is uniformly greater than 90% and typically approaches 97%. OncotypeRx is considered valid for
the T1bN0 ER-positive subset but has not been tested in the
T1mic or T1a groups. This test would be potentially useful in
T1b tumors that have adverse features such as higher grade,
low ER positivity, PR negativity, and possibly high Ki67
scores. Size and grade remain weak prognostic factors despite RS, and a new integrated RS is anticipated to account
for size.11 Chemotherapy could be considered for T1b disease
with high RS.
HER-positive/ER-positive BC. Treatment for this group is
highly controversial.38 HER2 amplification increases recurrence risk. Observation with or without endocrine therapy
alone has resulted in series with 5-year DFS of 85% to 92%,
particularly for the T1b group. Combination chemotherapy
plus trastuzumab with or without endocrine therapy has
resulted in extremely few recurrences; however, most patients are therefore over-treated. This treatment commits
the patient to myelosuppression, acute chemotherapy toxicities, increased cardiac morbidity, peripheral neuropathy
that can affect balance (particularly in the elderly), and
possible leukemia. Moreover, intravenous therapy is for a
year. Alternative approaches are beginning to be studied. A

17

ANTHONY D. ELIAS

phase II clinical trial, conducted by the Dana-Farber Cancer


Institute, collaborators, and Genentech, administered
single-agent paclitaxel with or without trastuzumab and
recently completed accrual but is not yet reported. The
Japanese RESPECT study is comparing trastuzumab with
or without chemotherapy in older patients with early-stage
HER2-positive BC.
There is no reported experience with anti-HER2 therapy
alone with or without endocrine therapy, although targeted
therapy alone is an attractive option that should be studied
prospectively. A legitimate concern would be some, but low,
cardiac risk. Another more concerning one would be the
observation that single-agent trastuzumab may not be as
effective in the absence of synergy with chemotherapy. For
example, sequential trastuzumab reduced relative relapse
risk by 0%, 14%, and 40% in adjuvant trials compared with
concurrent chemotherapy plus trastuzumab with risk reductions consistently above 50%.39-42 More recently, there is
strong data to suggest that dual anti-HER2 therapy in the
absence of chemotherapy can be highly effective.43,44 Thus,
combinations of trastuzumab/lapatinib, trastuzumab/pertuzumab, and T-DM1 with or without pertuzumab would
make sense. A phase III study in this population would
require an international effort.45
TN BC. At present, TN BC is defined by the absence of
predictive markers for all but chemotherapy, given its high
proliferative thrust. Thus, chemotherapy, particularly for
the T1b group older than age 50, could be considered. I
would use a regimen such as TC for four cycles, without
anthracyclines. Once predictive biomarkers for specific targeted treatments are established in the TN subgroup, the
discussion may read just like the previous paragraph, and

these patients (especially the T1b subset) should be included


in the definitive trials.
The prognosis of T1a and T1mic is also variable. Some
articles, but not all, find that size matters. Because T1mic
and T1a tumors frequently represent small areas of invasion
within a sea of DCIS, careful histologic sampling is required
to avoid missing areas of greater invasion. The very young,
especially younger than 35, could be considered for adjuvant
chemotherapy.
Local-regional control is clearly affected by tumor biology.
IBR is higher in the HER2-positive and TN cancers, thus
local-regional treatment recommendations would be the
same as for T1cN0 tumors.3,6 Sentinel node sampling is still
indicated in these small tumors. The incidence of axillary
node involvement, while lower in smaller primary tumors, is
still 5% to 15%. In the future, once the RxSPONDER trial is
reportedwhich is testing the utility of chemotherapy in
node-positive, low to intermediate RS ER-positive BCs
perhaps nodal stage will become less important. Currently,
nodal involvement still affects absolute risk of distant metastasis, and much of the decision making has to do with the
absolute benefit of given interventions relative to their risks.
Conclusion

Small BCs are increasing in frequency. Although their


risk of disseminated disease is low following local-regional
treatment, certain subtypes are at greater risk. These patients have generally not been included in prospective clinical trials; a fact reflected by the heterogeneous approaches
to systemic adjuvant therapy in the community of clinical
oncologists. Optimal management remains controversial
and will not be clarified until dedicated clinical trials are
conducted.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Anthony D. Elias*
*No relevant relationships to disclose.

REFERENCES
1. Kennedy T, Stewart AK, Bilimoria KY, et al. Treatment trends and
factors associated with survival in T1aN0 and T1bN0 breast cancer patients.
Ann Surg Oncol. 2007;14:2918-2927.
2. Livi L, Meattini I, Saieva C, et al. Prognostic value of positive human
epidermal growth factor receptor 2 status and negative hormone status in
patients with T1a/T1b, lymph node-negative breast cancer. Cancer. Epub
2011 October 25.
3. Wong FY, Yip CSP, Chua ET. Implications of HER2 amplification in
small, node-negative breast cancers: Do Asians differ? World J Surg. Epub
2011 November 22.
4. Kwon JH, Kim YJ, Lee K-W, et al. Triple negativity and young age as
prognostic factors in lymph node-negative invasive ductal carcinoma of 1 cm
or less. BMC Cancer. 2010;10:557.
5. Tanaka K, Kawaguchi H, Nakamura Y, et al. Effect of HER2 status on
risk of recurrence in women with small, node-negative breast tumours. Br J
Surg. 2011;98:1561-1565.
6. McArthur HL, Mahoney KM, Morris PG, et al. Adjuvant trastuzumab
with chemotherapy is effective in women with small, node-negative, HER2positive breast cancer. Cancer. 2011;117:5461-5468.
7. Horio A, Fujita T, Hayashi H, et al. High recurrence risk and use of
adjuvant trastuzumab in patients with small, HER2-positive, node-negative
breast cancers. Int J Clin Oncol. Epub 2011 June 18.
8. Cancello G, Maisonneuve P, Rotmensz N, et al. Prognosis in women with

18

small (T1mic, T1a, T1b) node-negative operable breast cancer by immunohistochemically selected subtypes. Breast Cancer Res Treat. 2011;127:713-720.
9. Theriault RL, Litton JK, Mittendorf EA, et al. Age and survival estimates in patients who have node-negative T1ab breast cancer by breast
cancer subtype. Clin Breast Cancer. 2011;11:325-331.
10. Rouanet P, Roger P, Daures JP, et al. HER2 expression is the major
risk factor for recurrence in pT1a-b, N0 breast cancer: Clinical implications
from a French regional population-based study of 703 patients. Proc SABCS.
2011;P2:12-16.
11. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor
gene expression and risk of breast cancer death among lymph node-negative
patients. Breast Cancer Res. Epub 2006 May 31.
12. Rosen PP, Groshen S, Saigo PE, et al. A long-term follow-up study of
survival in stage I T1N0M0) and stage II (T1N1M0) breast carcinoma. J Clin
Oncol. 1989;7:355-366.
13. Moon TE, Jones SE, Bonadonna G, et al. Development and use of a
natural history data base of breast cancer studies. Am J Clin Oncol.
1987;10:396-403.
14. Stierer M, Rosen HR, Weber R, et al. Long term analysis of factors
influencing the outcome in carcinoma of the breast smaller than one centimeter. Surg Gynecol Obstet. 1992;175:151-160.
15. Hanrahan EO, Valero V, Gonzalez-Angulo AM, et al. Prognosis and
management of patients with node-negative invasive breast carcinoma that is

MANAGEMENT OF T1 BREAST CANCERS


1 cm or smaller in size (stage 1; T1a,bN0M0): a review of the literature. J Clin
Oncol. 2006;24:2133-2122.
16. Fisher B, Dignam J, Tan-Chiu E, et al. Prognosis and treatment of
patients with breast tumors of one centimeter or less and negative lymph
nodes. J Natl Cancer Inst. 2001;93:112-120.
17. Wood WC, Anderson M, Lyles RH, et al. Can we select which patients
with small breast cancers should receive adjuvant chemotherapy? Ann Surg.
2002;235:859-862.
18. Joensuu H, Isola J, Lundin M, et al. Amplification of erbB2 and erbB2
expression are superior to estrogen receptor status as risk factors for distant
recurrence in pT1N0M0 breast cancer: A nationwide population-based study.
Clin Cancer Res. 2003;9:923-930.
19. Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation therapy, or
both for prevention of ipsilateral breast tumor recurrence after lumpectomy in
women with invasive breast cancers of one centimeter or less. J Clin Oncol.
2002;20:4141-4149.
20. Fisher ER, Costantino JP, Leon ME, et al. Pathobiology of small
invasive breast cancers without metastases (T1a/b, N0, M0). NSABP B-21.
Cancer. 2007;110:1929-1936.
21. Chia S, Norris B, Speers C, et al. Human epidermal growth factor
receptor 2 overexpression as a prognositic factor in a large tissue microarray
series of node-negative breast cancers. J Clin Oncol. 2008;26:5697-5704.
22. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of
recurrence for patients with breast cancer who have human epidermal growth
factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol.
2009;27:5700-5706.
23. Curigliano G, Viale G, Bagnardi V, et al. Clinical relevance of Her2
overexpression/amplification in patients with small tumor size and nodenegative breast cancer. J Clin Oncol. 2009;27:5693-5699.
24. Meattini I, Livi L, Saieva C, et al. Prognostic value of HER2 positivity
and negative hormonal status in patients with small tumor (1cm) and
node-negative breast cancer. Proc SABCS. 2011;P2-12-14.
25. Colleoni M, Rotmensz N, Peruzzotti G, et al. Minimal and small size
invasive breast cancer with no axillary lymph node involvement: The need for
tailored adjuvant therapies. Ann Oncol. 2004;15:1633-1639.
26. Hanrahan EO, Gonzalez-Angulo AM, Giordano SH, et al. Overall
survival and cause-specific mortality of patients with stage T1a,bN0M0
breast carcinoma. J Clin Oncol. 2007;25:4952-4960.
27. Park YH, Kim ST, Cho EY, et al. A risk stratification by hormonal
receptors (ER, PgR) and HER2 status in small (1cm) invasive breast cancer:
Who might be possible candidates for adjuvant treatment. Breast Cancer Res
Treat. 2010;119:653-661.
28. Lai HW, Kuo SJ, Chen LS, et al. Prognostic significance of triple
negative breast cancer at tumor size 1 cm and smaller. Eur J Surg Oncol.
2011;37:18-24.
29. Fehrenbacher L, Shiraz P, Sattavat M, et al. T1abN0M0 HER2
invasive breast cancer recurrence: Population based cohort of 17,000 consecutive breast cancers 2000-2006 at Kaiser Permanente Northern California, KPNC. J Clin Oncol. 2011;29: (suppl; abstr 551).
30. Amar S, McCullough AE, Tan W, et al. Prognosis and outcome of small

(1cm), node-negative breast cancer on the basis of hormonal and Her2


status. Oncologist. 2010;15:1043-1049.
31. Peron J, Frenel JS, Vano Y, et al. Systemic adjuvant treatment of T1a
and T1b N0M0 HER2 breast carcinomas; an AERIO/UNICANCER study.
Proc SABCS. 2011;P2-18-03.
32. Shao T, Boolbol SK, Boachi-Adjei K, Klein P. Clinical significance of
HER2 and triple-negative status in patients with tumor size 1 cm and
node negative breast cancer. Proc SABCS. 2011;4-09-03.
33. Cserni G, Bianchi S, Vezzosi V, et al. Sentinel lymph node biopsy in
staging small (up to 15 mm) breast carcinomas. Results from a European
multi-institutional study. Path Oncol Res. 2007;13:5-14.
34. Rivadeneira DE, Simmons RM, Christos PJ, et al. Predictive factors
associated with axillary lymph node metastases in T1a and T1b breast
carcinomas: Analysis in more than 900 patients. J Am Coll Surg. 2000;191:
1-8.
35. Khair TA, Boolbol SK, Boachi-Adjei K, Klein P. Factors affecting the
development of axillary lymph node metastases in T1a-T1b breast cancers.
Proc SABCS. 2011;P4-09-16.
36. Lyons TR, OBrien J, Borges VF, et al. Postpartum mammary gland
involution drives progression of ductal carcinoma in situ through collagen and
COX-2. Nat Med. 2011;17:1109-1115.
37. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes
dealing with the diversity of breast cancer: Highlights of the St. Gallen
International Expert Consensus on the primary therapy of early breast
cancer 2011. Ann Oncol. 2011;22:1736-1747.
38. Kelly CM, Pritchard KI, Trudeau M, et al. Coping with uncertainty:
T1a,bN0M0 HER2-positive breast cancer, do we have a treatment threshold?
Ann Oncol. 2011;22:2387-2393.
39. Spielmann M, Roche H, Delozier T, et al. Trastuzumab for patients
with axillary-node positive breast cancer: Results of the FNCLCC-PACS04
trial. J Clin Oncol. 2009;27:6129-6134.
40. Perez EA, Romond EH, Suman VJ. Updated results of the combined
analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/
without trastuzumab in patients with HER2-positive breast cancer. J Clin
Oncol. 2007;25 (suppl 18s; abstr 512).
41. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab
after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med.
2005;353:1659-1672.
42. Untch M, Gelber RD, Jackisch C, et al. Estimating the magnitude of
trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol.
2008;19:1090-1096.
43. Blackwell KL, Burstein HJ, Stroniolo AM, et al. Randomized study of
Lapatinib alone or in combination with trastuzumab in women with ErbB2positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol.
2010;28:1124-1130.
44. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and
trastuzumab in patients with human epidermal growth factor receptor
2-positive metastatic breast cancer that progressed during prior trastuzumab
therapy. J Clin Oncol. 2010;28:1138-1144.
45. Constantinidou A, Smith I. Is there a case for anti-HER2 therapy
without chemotherapy in early breast cancer? Breast. 2011;20:S158-S161.

19

Controversies in Adjuvant Endocrine Therapy


for Breast Cancer
By Stephen R. Johnston, PhD, MA

Overview: Adjuvant endocrine therapy for early-stage breast


cancer has had the single biggest impact on improving survival from the diseasewith tamoxifen alone contributing to
saving many thousands of lives. In postmenopausal women,
additional progress has been made by the incorporation of
aromatase inhibitors into the treatment of early-stage, estrogen receptor (ER)positive breast cancer, as several large
well-conducted trials have established either up-front or
switch strategies that are now widely used. To date, both
have been shown to be beneficial when compared with tamoxifen alone, although controversy exists as to which approach
is superior. Increasingly, extended adjuvant therapy is being
considered, as longer may be better for some women who
have an ongoing risk of recurrence beyond 5 years. However,
controversy remains as to how long adjuvant endocrine therapy should be given for; in clinical practice, clinicians balance

T IS well established that for patients with early-stage


ER-positive breast cancer, adjuvant endocrine therapy
given for 5 years after primary surgery delays local and
distant relapse and prolongs overall survival.1 In addition,
adjuvant therapy substantially reduces the incidence of
contralateral breast cancer in patients with primary breast
cancer. Endocrine responsiveness, for the most part, is
dependent on the presence of a functional estrogen receptor
(ER), a protein that can be detected in approximately 70% to
80% of primary breast cancers. Hormonal manipulation is
either achieved at a cellular level by using antiestrogens
such as tamoxifen to compete for ER in the breast tumor,
or by lowering systemic estrogen levels in premenopausal
women with the use of LHRH agonists, and in postmenopausal women by the use of aromatase inhibitors that block
estrogen biosynthesis in nonovarian tissues. All of these
approaches have been extensively investigated within the
context of large-scale international trials of adjuvant endocrine therapy over the past two decades. However, several
key issues and unanswered questions remain, namely the
best choice of endocrine agents and the optimal strategies
in the postmenopausal setting, the appropriate duration
of endocrine therapy, and the true role of ovarian suppression in premenopausal women. In addition, the molecular
classification of breast cancer has now allowed us to better
estimate endocrine responsiveness in ER-positive breast
cancer, introducing another tool in addition to established
guidelines for decision making in the adjuvant setting. In
particular, this has allowed us to address the issue of
whether endocrine therapy alone is enough for many patients.

The Benefit of Tamoxifen

In early-stage breast cancer, tamoxifen has been the gold


standard of adjuvant endocrine therapy for both premenopausal and postmenopausal breast cancer for more than
three decades. In an overview of the effects of chemotherapy
and hormone therapy for early-stage breast cancer by
the Early Breast Cancer Trialists Collaborative Group
(EBCTG), a 50% reduction in the risk of relapse and a 31%
reduction in the annual breast cancer death rate was re-

20

the level of risk for individual patients versus any ongoing


toxicity concerns. For premenopausal women, with ERpositive breast cancer, tamoxifen remains the gold standard
with uncertainty in the added overall benefit of ovarian suppression. Important clinical trials have recently been completed that may help answers this question, including whether
complete estrogen deprivation using a luteinizing hormone
releasing hormone (LHRH) agonist plus aromatase inhibitors
(AIs) is of added benefit. In recent years, molecular profiling
of ER-positive breast cancer has started to distinguish those
women with a low risk of recurrence on endocrine therapy who
may not need chemotherapy. Thus, with more therapy options
and greater tumour stratification, modern, adjuvant endocrine
therapy is becoming increasingly personalised to suit each
individual patients risk.

ported for 5 years of adjuvant tamoxifen at 15 years of


follow-up.1 Although the risk of distant recurrence is greatest during the first decade, it can still continue through the
second decade,2 raising the question about the magnitude
of carry-over effect from initial therapy, or the need for
extended adjuvant therapy beyond 5 years in those women
at greater risk. In 2011, the EBCTG updated their metaanalysis of long-term outcomes in 21,457 women with earlystage breast cancer from 20 randomized trials of 5 years of
tamoxifen compared with observation or placebo.3 They
showed that 5 years of tamoxifen reduced the recurrence
rate substantially in years 0 4 during therapy (rate ratio
[RR] 0.53), and also in years 59 (RR 0.68) and throughout
the first 15 years (RR 0.70, p 0.00001). Most importantly,
the relapse curves do not converge after year 10, with a
continued annual absolute gain from the annual reduction
in breast cancer mortality through to year 15. Furthermore,
the benefit only occurs in those with ER-positive tumors,
being maximal in those with rich expression of the receptor.
As such, 5 years of tamoxifen probably cures many patients
rather than simply delays an inevitable recurrence.
These mature data from the meta-analysis regarding a
well-established treatment such as tamoxifen give both
clinicians and patients confidence in the beneficial effects
of endocrine therapy on improving overall survival from
breast cancerso how long do patients need to take tamoxifen? Studies of duration such as NSABP-14 have compared
5 to 10 years of tamoxifen and shown no advantage beyond
5 years, indeed perhaps a slight disadvantage in terms of
disease-free survival.4 However, this study only examined
node-negative patients, and in two further trials (aTTOm
and ATLAS), preliminary results have suggested a small

From the Department of Medicine, Royal Marsden NHS Foundation Trust, Chelsea,
London, United Kingdom.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Stephen R.D. Johnston, MA, PhD, Department of Medicine,
Royal Marsden NHS Foundation Trust, Fulham Road, Chelsea, London, SW3 6JJ, UK;
email: stephen.johnston@rmh.nhs.uk.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

ADJUVANT ENDOCRINE THERAPY

reduction in breast cancer recurrence for those randomized


to continue tamoxifen, although no significant difference
was observed for breast cancer specific or overall mortality.5,6 Further follow-up of these studies is required to
reliably assess the longer term effects on recurrence and
overall effects, if any, on mortality.
Although tamoxifen remains the most appropriate sole
treatment option for many premenopausal and perimenopausal women, the issue for postmenopausal women remains whether there are any better options than tamoxifen,
especially given that some women will still relapse despite
therapy, and that for others, tamoxifen has either unacceptable short-term vasomotor toxicities or increased long-term
risks such as venous thromboses and endometrial cancer.
The incorporation of AIs into the treatment of postmenopausal early-stage ER-positive breast cancer has now led
to further improvements in outcomes over tamoxifen. The
key issue is how AIs should be incorporated as adjuvant
therapy in early-stage breast cancer, and whether a role for
tamoxifen still remains in postmenopausal breast cancer.
AIs: How Should We Use Them?

In contrast to tamoxifen, which antagonizes estrogen at


the ER, the oral AIs such as anastrozole, letrozole and
exemestane all reduce serum estrogen levels in postmenopausal women by preventing the conversion of adrenal
androgens (androstenedione and testosterone) into estradiol
(E1) and estrone (E2) by the cytochrome P450 enzyme

KEY POINTS

Aromatase inhibitors are recommended to be part of


adjuvant endocrine therapy for most postmenopausal
women with estrogen receptor (ER)-positive breast
cancer, either as up-front therapy or as a switch
strategy following initial tamoxifen therapy. Both
approaches are equally effective, and both are superior to tamoxifen alone for 5 years.
The optimal duration for aromatase inhibitors given
as adjuvant therapy is 5 years based on current
safety and efficacy data.
Extended adjuvant therapy with aromatase inhibitors after 5 years of tamoxifen is an additional accepted strategy for reducing ongoing risk of
recurrence, especially for those at greater risk.
The added benefit of ovarian suppression in premenopausal women with ER-positive early-stage breast
cancer over and above tamoxifen remains unknown.
In women younger than 40 years, added benefit may
exist, but must be weighed up against both short and
long-term tolerability.
Molecular profiling of ER-positive breast cancer can
identify those subtypes at low risk of recurrence for
whom the addition of adjuvant chemotherapy over
and above endocrine therapy is not indicated. To date
biomarkers, although clearly of prognostic value, have
not been shown to identify those more likely to benefit
from aromatase inhibitors rather than tamoxifen.

Table 1. Comparative Efficacy of Up-Front 5 Years Aromatase


Inhibitors Versus 5 Years Tamoxifen in Early Breast Cancer
Study (reference)

ATAC11

BIG-19816

Number of patients
Median follow up
Disease-free survival
Five-year disease-free survival difference
Time to distant recurrence
Overall survival

6,241
100 mo
HR 0.90 p .025
2.8%
HR 0.86 p .022
HR 1.00 p .99

4,922
76 mo
HR 0.88 p .03
2.9%
HR 0.85 p .05
HR 0.87 p .08

Abbreviations: HR, hazard ratio.


p .05 significant.

aromatase.7 Although estrogens are primarily synthesized


in the ovary in premenopausal women under the control of
stimulatory effects of luteinizing hormone (LH) and follicle
stimulating hormone (FSH), following menopause, mean
plasma E2 levels fall from about 400 600 pmol/L to around
2550 pmol/L. These residual estrogens come solely from
peripheral aromatase conversion, particularly in muscle and
subcutaneous fat.
The establishment of the efficacy and tolerability of AIs in
advanced breast cancer encouraged the development of a
number of trials examining their use in the adjuvant setting.7 In general, these therapeutic studies have either
compared primary up-front AI therapy for 5 years with 5
years of tamoxifen, or a so-called switch strategy of initial
tamoxifen for 23 years followed either by an AI for 23
years of continued tamoxifen through to year 5. The absolute
benefits of these approaches have been assessed in a recent
meta-analysis of all the adjuvant trials of AIs compared with
the previous standard of care, namely, 5 years of tamoxifen.8
The key message is that AIs produce significantly lower
recurrence rates compared with tamoxifen, either as initial
monotherapy or following 23 years of tamoxifen, although
the true effect on long-term survival is less clear at this
stage. The recent 2010 American Society of Clinical Oncology (ASCO) guidelines on adjuvant endocrine therapy for
women with ER-positive breast cancer recommend incorporating AI therapy at some point during adjuvant treatment,9
while recognizing that the optimal timing and duration of
therapy remain unresolved questions. So what are the
benefits, and what has been learned from all the trials of
adjuvant AIs to date?
Up-Front AIs

Two large studies have assessed the efficacy of AIs compared with tamoxifen as up-front adjuvant endocrine
therapy in postmenopausal women with early-stage breast
cancer (Table 1).10-14 The Arimidex, Tamoxifen, Alone or
in Combination (ATAC) trial was the first large study to
investigate the role of AIs as adjuvant therapy for earlystage breast cancer. Over 4 years, 9,366 postmenopausal
women from 21 countries were enrolled. The hypotheses
tested were that anastrozole was noninferior or superior to
tamoxifen, or that the combination of anastrozole and tamoxifen was superior to tamoxifen alone. The combination
treatment was discontinued following the initial analysis
because it showed no efficacy or tolerability benefits over
tamoxifen alone.10 Following a median follow-up of 100
months,11 anastrozole compared with tamoxifen was associated with a significantly improved disease-free survival
(DFS) in hormone-receptor-positive patients (hazard ratio
[HR] 0.85, p 0.003). In the most recent 10-year analysis,

21

STEPHEN R. JOHNSTON

the absolute differences in time to recurrence (TTR) in


hormone-receptor-positive patients increased over time,
being 2.7% at 5 years and 4.3% at 10 years.12 In addition,
recurrence rates remained significantly lower on anastrozole
compared with tamoxifen after treatment completion (HR
0.81, p 0.03), although the carry-over effect was smaller
after 8 years. However, these differences in preventing/
delaying disease recurrence did not result in a difference in
overall survival between the two treatments (HR 0.95, 95%
CI 0.84 1.06).12 Differences in toxicity profile demonstrated
a higher incidence of thromboembolic and cardiovascular
events with tamoxifen, and more musculoskeletal events
and fractures with anastrozole.13 A bone sub-study of the
main trial confirmed that AI therapy was associated with
accelerated bone loss during the 5-year treatment period,
although no patients with normal bone mineral density at
baseline became osteoporotic at 5 years.14
The BIG 198 trial assessed both the efficacy of up-front
AI therapy with letrozole for 5 years compared with tamoxifen, as well as switching strategies. It recruited 8,028
women who were randomized to one of four treatment arms.
In 2005, the first analysis at a median follow-up of 25.8
months reported that 5 years of letrozole demonstrated a
significant improvement in DFS over tamoxifen (HR 0.81,
p 0.003) and distant disease-free survival (DDFS) (HR
0.73 p 0.001).15 These results led to the unblinding of
the tamoxifen alone arm, and 25.2% of patients selectively
crossed over to letrozole, which has complicated subsequent
intention to treat (ITT) analyses of the monotherapy arms.
The updated report at a median follow-up of 76 months16
included both an ITT analysis and a censored analysis at
the time of cross-over, and still demonstrated a statistically
significant improvement in DFS and DDFS in favor of
letrozole over tamoxifen, with a nonsignificant improvement
in overall survival (HR 0.87, 95% CI 0.751.02, p 0.08). In
terms of toxicity, endometrial cancer, vaginal bleeding, and
thrombo-embolism were more common with tamoxifen,
while musculoskeletal events and hypercholesterolemia
were higher with letrozole.
The meta-analysis of both of these studies showed an
absolute 5-year reduction in recurrence of 2.9% (9.6% for AI
vs 12.6% for tamoxifen, p0.00001), with an absolute 3.9%
reduction at 8 years.8 This was associated with only a 1.1%
reduction in breast cancer mortality at 5 years, which was
nonsignificant.
Switching from Tamoxifen to AIs Compared with Tamoxifen Alone

In terms of a switching strategy, several trials have


evaluated a switch to an aromatase inhibitor after 23 of
tamoxifen compared with 5 years tamoxifen alone, in an
attempt to pre-empt the development of resistance to tamoxifen, and to minimize long-term side effects of either therapy
if given alone for 5 years (Table 2).17-21 The largest of these
studies was the Intergroup Exemestane Study (IES), which
compared switching to exemestane after 23 years of tamoxifen with tamoxifen for 5 years. This demonstrated not only
a statistically significant improvement in disease-free survival (HR 0.68, p 0.001),17 but also in overall survival in
an updated analysis of those with ER-positive disease (HR
0.86, p 0.04).18 These findings were also confirmed in a
meta-analysis of three separate trials with the tamoxifenanastrozole switch compared with tamoxifen alone (the
Austrian Breast and Colorectal Cancer Study Group

22

Table 2. Comparative Efficacy of 23 Years Tamoxifen Followed


by a Switch to 23 Years Aromatase Inhibitor Versus 5 Years
Tamoxifen Alone
Study (reference)

IES18

ARNO 9519

ITA20

ABCSG 819

Number of patients
Median follow up
Disease-free survival

4,724
55.7 mo
HR 0.76
p .0001
HR 0.83*
p .05

979
30.1 mo
HR 0.66
p .49
HR 0.53
p .045

448
64 mo
HR 0.56
p .01
HR 0.56
p .1

3,714
72 mo
HR 0.79
p .038
HR 0.77
p .025

Overall survival

Abbreviations: HR, hazard ratio.


* In a subset of estrogen-receptor positive patients only p .05 significant.

(ABCSG 8), Arimidex-Nolvadex (ARNO 95) and Italian


Tamoxifen Anastrozole (ITA) studies19,20). The metaanalysis included more than 4,000 patients with a mean
follow-up of 30 months, which is shorter follow-up than in
the IES study. Despite this, the combined analysis still
showed that switching to anastrozole resulted in a significant improvement in disease-free survival (HR 0.59, p
0.0001), and was also associated with a statistically significant reduction in breast cancer mortality and death from
any cause (HR 0.71, p 0.037).21
These individual studies certainly all seem to suggest
significantly better outcomes in terms of disease-free and
overall survival by a switching strategy when compared
with tamoxfen alonein addition to less long-term toxicities
with tamoxifen, there appears to be a substantial gain in
efficacy, presumably by preventing relapses that were destined to occur during continued tamoxifen by utilizing a
noncross-resistant therapy. However, it has been questioned
by some whether early relapses on tamoxifen could be
prevented by an up-front AI strategy, and as such it has
been unclear which approach (tamoxifen switch to an AI, or
AI upfront) would yield better efficacy outcomes and which
would be better tolerated overall. Two large trials (BIG 198
and TEAM) have now given us direct data on these comparisons.
Switching Tamoxifen to AIs Compared with AI Upfront

The Breast International Group (BIG) 198 study was the


first clinical trial to report a direct comparison between the
use of an upfront AI and a switching strategy.16 At a median
follow-up of 76 months, there was no significant difference
in disease-free recurrence, overall survival or time to distant
recurrence between the switching (tamoxifen to letrozole)
and the letrozole monotherapy arms. However, there were
fewer early relapses among women who were assigned to
letrozole alone compared with the switch of tamoxifen followed by letrozolethis trend was greatest in node-positive
patients with a 1.4% difference in breast cancer recurrence
in node-negative patients (3.5% vs. 4.9%), and a 2.3% absolute difference in node-positive patients (12.4% vs. 14.7%) at
5 years. Interestingly, there was no significant difference
in breast cancer recurrence between the letrozole followed
by a reverse-switch to tamoxifen and the letrozole monotherapy arm. The clinical significance of this is that patients
who commence an AI but experience side effects or toxicity
may be safely switched over to tamoxifen to complete their
adjuvant endocrine therapy, without compromising on the
efficacy provided by the AIs.
The second study to provide a direct comparison was the
Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial,

ADJUVANT ENDOCRINE THERAPY

which randomized 9,779 postmenopausal women with ERpositive early-stage breast cancer to either exemestane for
5 years, or tamoxifen for 2.53 years followed by exemestane.22 At median follow-up of 5.1 years, there was no
difference in either disease-free or overall survival, a result
very similar to that observed in the BIG 198 study.
Who Benefits from Which StrategyUp-Front or Switch?

So what are we to conclude from these large, wellconducted studies as to which strategy is the best? From the
meta-analysis of all these studies the addition of an AI in
either strategy (up-front or switch) clearly improves diseasefree survival compared with 5 years of tamoxifen, although
delaying relapse does not appear to translate into a substantial survival advantage, apart a modest benefit that was
seen in the analysis of all the switching studies, which
yielded an absolute gain in overall survival of 1.7% at 8
years.8 Biomarker studies in many of these trials have
attempted to see whether conventional indicators of hormone responsiveness, such as absolute ER and PgR
levels,23-25 coexpression of HER2,23 proliferation as assessed
by Ki-67 labeling index,26 or the 21-gene recurrence score,27
can identify those who benefit more from an AI than tamoxifen. Although confirming the prognostic role of all these
different biomarkers in each individual study, none have
been shown to identify patients with a differential response
between tamoxifen and AI therapy. At the present time, the
two direct comparisons between up-front AI or switch strategy (BIG 198 and TEAM) have shown no significant differences between these approaches; although in the letrozole
study, for higher-risk node-positive patients, fewer recurrences were seen with AI up-front compared with switching.16 As such, tumor burden in addition to other inherent
risk factors related to the biology of the disease (higher
grade or proliferation score, lower levels of ER or PgR,
coexpression of HER2) might be reasonable factors to use in
clinical practice to favor an up-front use of AIs as opposed to
a switch strategy.
In addition, patient-related factors and toxicity concerns
should always be considered when making a decision with a
patient between either up-front AI use or a switch strategy.
In general, the third generation AIs are well tolerated, and
in the clinical trial setting, the different side effect profiles of
tamoxifen and aromatase inhibitors do not appear to affect
patients quality of life.28 Assessing an individuals risk or
history of venous thrombosis may influence whether tamoxifen is indicated, and assessing joint arthropathies or the
risk of osteoporosis may determine the optimal timing of
starting an AI. Current ASCO guidelines recommend that
postmenopausal women who receive an AI should have their
bone mineral density evaluated, with calcium and vitamin D
supplementation or bisphosphonate use dependent on the
result.29 As such, clinicians and patients have a choice on
when and how to use an AI, dependent on the level of risk
for the cancer and the general health issues for each individual womanwith often only marginal differences in efficacy outcomes (in particular survival), consideration of all
these issues is important.
Which AI Is Best?

The only reported comparison to date is the MA.17 study,


where 5 years of adjuvant exemestane yielded similar results to 5 years of adjuvant anastrozole.30 A trial compar-

Table 3. Comparative Efficacy of Extended Adjuvant Therapy of


5 Years Tamoxifen Followed by 35 Years Aromatase Inhibitor
Versus 5 Years Tamoxifen Alone
Study (reference)

MA-1732

NSABP B-3336

ABCSG-6a35

Number of patients
Median follow up
Disease-free survival

5,170
64 mo
HR 0.68
p .0001
HR 0.98
p .853

1,562
30 mo
HR 0.68
p .07
NR

852
62 mo
HR 0.62
p .031
HR 0.89
p .57

Overall survival

Abbreviations: HR, hazard ratio; NR, not recorded.

ing the two nonsteroidal aromatase inhibitors letrozole and


anastrozole (FACE) has completed recruitment, and results
are awaited. Tolerability profiles between the different AIs
are very similar, so, to date, there is no evidence to suggest
that one agent is substantially better than another.
Adjuvant Endocrine TherapyIs There an
Optimal Duration?

ER-positive breast cancer has a chronic relapsing nature,


with the risk of recurrence continuing indefinitely. In the
tamoxifen overview, approximately half of all recurrences
occurred between 5 and 15 years after surgery despite 5
years of adjuvant tamoxifen treatment.1,3 There is, therefore, a clear rationale for considering extended adjuvant
endocrine therapy beyond 5 years in an attempt to reduce
long-term risk of recurrence further. The MA.27 study31 was
a double-blind, placebo-controlled trial designed to test
whether 5 years of letrozole therapy in more than 5,000
postmenopausal women who had completed 5 years of adjuvant tamoxifen could lead to a further improvement in
disease-free survival between years 5 and 10 from diagnosis.
The trial demonstrated a significant improvement in
disease-free survival in all patients who continued onto
letrozole after completion of 5 years of tamoxifen, with a
4-year disease-free survival rate (i.e., year 9 since initial
diagnosis) of 93% compared with 87%.31 Furthermore, after
a median follow-up of 30 months among higher risk lymph
node-positive patients, overall survival was statistically significantly improved with letrozole (HR 0.61, 95% CI,
0.38 0.98; p 0.04).32 Subsequent analyses of this trial
have suggested that this benefit was greatest in those with
ER-positive PgR-positive tumors,33 and that benefit may
also have occurred if the switch to extended adjuvant letrozole occurred late following a period of a few years since
completion of tamoxifen.34 Two additional, smaller separate
studies with either anastrozole35 or exemestane36 as extended adjuvant therapy after completion of 5 years of
tamoxifen have shown similar quantitative results in terms
of reducing risk of recurrence, with hazard ratios of 0.62 and
0.68, respectively (Table 3).
These data confirm that risk of recurrence in hormonesensitive breast cancer does indeed persist on an ongoing
basis well beyond completion of 5 years of adjuvant tamoxifen. As such, careful consideration should be given to
offering longer durations of adjuvant therapy with AIs for
those deemed to be at greatest risk. Although all of these
studies looked at treatment following 5 years of tamoxifen,
increasingly, clinical practice is to either use AI therapy
up-front in higher risk node-positive patients, or a switch
approach of AIs following an initial 23 years of tamoxifen.

23

STEPHEN R. JOHNSTON

So how do we translate the data from the extended adjuvant


therapy studies into these settings of how AIs are being
used today? Can we safely use AIs beyond a total duration
of 5 years without, for example, compromising bone health?
The answer at present is unknown, although all the safety
data relating to the optimal duration of AIs indicate that
therapy should be given for a maximum of 5 years. The
ASCO guidelines recommend that AI therapy should not
exceed 5 years outside the setting of clinical trials and that
in the sequential setting, patients should receive an AI after
23 years of tamoxifen for a total of 5 years of adjuvant
endocrine therapy. The guidelines recognize that this may
yield an unfamiliar pattern of different durations of adjuvant treatment based on the treatment strategy used, and
that neither 5 years up-front AI or sequential switch strategies (23 years tamoxifen followed by 23 years of an AI)
have been compared against the longer overall duration of
the extended adjuvant therapy regimens where treatment
duration was up to 8 10 years. Two trials (MA.17R and
NSABP B-42) are addressing whether longer durations of AI
therapy improve outcomes without compromising safety, but
results are not yet available.

permanent amenorrhea. Optimum duration of the use of


reversible ovarian suppression is unknown, although studies in general have utilized 23 years of LHRH agonist with
5 years of tamoxifen.
Although the standard of care for ER-positive premenopausal breast cancer remains tamoxifen alone for 5 years,
prospective trials to address the added role (if any) of
ovarian suppression compared with tamoxifen alone have
been undertaken. The SOFT (Suppression of Ovarian Function Trial) randomized trial will assess the role of ovarian
suppression/ablation in combination with the aromatase
inhibitor exemestane, compared with either ovarian suppression plus tamoxifen or tamoxifen alone. More than 3,000
women were randomized into this study, which completed
accrual in January 2011. The TEXT trial (Tamoxifen and
EXemestane Trial) assesses an LHRH agonist with the
addition of either tamoxifen or exemestane for 5 years
(chemotherapy is optional), and accrual of more than 2,600
women was completed in March 2011. It is hoped that both
these trials will provide important additional information
about the optimal endocrine therapy for premenopausal
women with ER-positive early-stage breast cancer.

Ovarian SuppressionIs It Necessary for


Premenopausal Women?

Adjuvant Endocrine TherapyIs It Enough on Its Own?

LHRH agonists, which initially stimulate and then exhaust the LHRH receptors in the pituitary, cause reversible
suppression of ovarian function, and are currently used as
an alternative to ovarian ablation for treatment of advanced
breast cancer in premenopausal women. The Early Breast
Cancer Trialists Collaborative Group (EBCTG)1 reviewed
trials involving almost 8,000 women with ER-positive or
ER-unknown early-stage breast cancer who were randomized to ovarian ablation by surgery or irradiation or ovarian
suppression with an LHRH agonist. Overall, there was a
definite beneficial effect of ovarian ablation/suppression
both on recurrence and breast cancer mortality. However,
the effects of ovarian treatment appear smaller in the trials
where both groups got chemotherapy than in the trials
where neither did, probably because chemotherapy-induced
amenorrhea attenuated any additional effect of ovarian
suppression. This was best demonstrated in the Intergroup
0101 trial, where in premenopausal women with ER-positive
node-positive early-stage breast cancer, the addition of the
LHRH agonist goserelin to CAF chemotherapy appeared
to have a greater effect in improving disease-free survival
in women younger than 40 compared with those older than
40 years.37 Likewise, the IBCSG trial VIII randomized
premenopausal women with node-negative ER-positive
early-stage breast cancer to either adjuvant CMF chemotherapy, goserelin for 2 years, or CMF followed by goserelin
for 18 months.38 The addition of goserelin overall only had
a minimal effect on 5-year disease-free survival, and again
the benefit was maximal in women younger than 40 years
with a hazard ratio of 0.34.
A more recent meta-analysis looked at only trials where
ER status was known and that used LHRH agonists as the
method of ovarian suppression.39 The primary endpoints
were any recurrence or death after recurrence, with a
median follow-up of 6.8 years. In particular, a benefit was
observed when LHRH agonists were used after chemotherapy (either alone or with tamoxifen) in women younger than
40 years in whom chemotherapy is less likely to induce

24

Perhaps the hottest topic for current debate in the management of ER-positive early-stage breast cancer is not the
choice of agent (tamoxifen or aromatase inhibitor, or the role
of ovarian suppression), or indeed the optimal duration of
therapy, but rather the threshold for using adjuvant chemotherapy in addition to adjuvant endocrine therapy. As we
have come to better understand the various intrinsic subtypes of breast cancer and their differential prognoses,40
oncologists have come to debate the relative benefit of
adjuvant chemotherapy compared with endocrine therapy,
and ask whether for many patients with endocrine responsive breast cancer, a hormonal approach alone will be
sufficient to maximize a patients chance of cure. This has
been reflected in the recent 2011 St. Galen Consensus
guidelines on the management of early-stage breast cancer41previous guidelines in 2007 and 2009 had started to
characterize what might be considered truly endocrineresponsive breast cancer based on levels of receptor expression for both ER and PgR with absence of proliferation
markers. In these so-called endocrine responsive tumors,
the addition of adjuvant chemotherapy to endocrine therapy
was only recommended if other risk features related to
tumor burden were present (i.e., tumor size above 5 cm,
greater than 4 nodes, extensive vascular invasion).
The ability to sub-classify ER-positive breast cancer into
Luminal A or Luminal B subtypes based on either clinicopathologic determination (i.e., ER, PgR, HER2 and Ki-67)
or gene expression profiling is likely to identify ER-positive
cancers with different prognoses and altered levels of endocrine responsiveness. In addition, the 21-gene signature
(Oncotype DX) may also be used to predict chemotherapy
benefit in a patient with an ER-positive breast cancer based
on similar biologic and pathologic features, and in clinical
practice is increasingly being used to identify good prognosis
ER-positive breast cancer with a low recurrence score,
where the addition of chemotherapy to endocrine treatment
may yield no additional benefit.42 This is now being tested
prospectively in the Trial Assigning IndividuaLized Options
for Treatment (Rx) (TAILORx) where the Oncotype DX

ADJUVANT ENDOCRINE THERAPY

assay is being used in more than 10,000 patients to guide


treatment decisions. As we come to understand breast cancer subtypes better, it is hoped that these molecular tools
will allow us to stratify women with ER-positive early-stage
breast cancer much more effectively into those where chemotherapy has a real role to play, and those with truly
endocrine-sensitive disease where the optimal strategy for
endocrine therapy alone discussed above is all that is required to cure the disease.
Conclusion

Endocrine therapy for early-stage breast cancer has had


the biggest single effect on enhancing survival from the
disease, with tamoxifen alone contributing to saving many
thousands of lives. In postmenopausal women, enormous

progress has been made by the incorporation of aromatase


inhibitors into the treatment of early-stage ER-positive
breast cancer, and large well-conducted trials have established up-front or switch strategies that are now widely
used in clinical practice. Increasingly, extended adjuvant
therapy is being considered, as longer may be better for
some women who have an ongoing risk of recurrence beyond
year 5. For others less may be more in terms of molecular
profiling informing us of those women who do not need
chemotherapy. As such, we are refining how to use our
therapies beyond the one strategy fits all approach of old.
Endocrine therapy will continue to evolve, and current
research is now exploring novel approaches to enhance
endocrine responsiveness even further through combination
approaches with novel targeted therapies.

Authors Disclosure of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Stephen R. Johnston

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

AstraZeneca;
GlaxoSmithKline

REFERENCES
1. Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of
chemotherapy and hormonal therapy for early breast cancer on recurrence
and 15-year survival: An overview of the randomised trials. Lancet. 2005;365:
1687-1717.
2. Dignam JJ, Dukic V, Anderson SJ, et al. Hazard of recurrence and
adjuvant treatment effects over time in lymph node negative breast cancer.
Breast Cancer Res Treat. 2009;116:595-602.
3. Early Breast Cancer Trialists Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of
adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet.
2011;378:771-784.
4. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five
years of tamoxifen for lymph node-negative breast cancer: Updated findings
from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684-690.
5. Peto R. ATLAS (Adjuvant Tamoxifen, Longer Against Shorter); international rndomised trial of 10 versus 5 years of adjuvant tamoxifen among 11
500 women - preliminary results. Presented at: 2007 San Antonio Breast
Cancer Symposium; Late breaking abstract 48.
6. Gray RG, Handley A, et al. aTTom (adjuvant tamoxifen- to offer more?)
: Randomised trial of 10 versus 5 years of adjuvant tamoxifen among 6,934
women with etrogen receptor positive (ER) or ER untested breast cancerpreliminary results. J Clin Oncol. 2008;26:15S (suppl; abstr 513).
7. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl
J Med. 2003;348:2431-2442.
8. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer
outcomes in adjuvant trials or aromatase inhibitors vs tamoxifen. J Clin
Oncol. 2010;28:509-518.
9. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of
Clinical Oncology Clinical Practice Guideline: Update on adjuvant endocrine
therapy for women with hormone-receptor-positive breast cancer. J Clin
Oncol. 2010;28:3784-3796.
10. The ATAC Trialists Group. Anastrozole alone or in combination with
tamoxifen versus tamoxifen alone for adjuvant treatmnet of postmenopausal
women with early breast cancer: First results of the ATAC randomised trial.
Lancet. 2002;359:2131-2139.
11. The Arimidex, Tamoxifen, Alone or in combination (ATAC) Trialists
Group. Effect of anastrozole and tamoxifen as adjuvant treatment for earlystage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol.
2008;9:45-53.
12. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen
as adjuvant treatment for early stage breast cancer: 10-year analysis of the
ATAC trial. Lancet Oncol. 2010;11:1135-1141.
13. The ATAC (Arimidex, Tamoxifen, Alone or in Combination) Trialists
Group. Anastrozole alone or in combination with Tamoxifen versus Tamox-

ifen alone for adjuvant treatment of postmenopausal women with early stage
breast cancer. Cancer. 2003;98:1802-1810.
14. Eastell R, Adams JE, Coleman RE, et al. Effect of anastrozole on bone
mineral density; 5-year resulst from the anastrozole, tamoxifen, alone or in
combination trial 18233230. J Clin Oncol.2008;26:1051-1058.
15. The Breast International Group (BIG) 1-98 Collaborative Group. A
comparison of letrozole and tamoxifen in postmenopausal women with early
breast cancer. N Engl J Med. 2005;353:2747-2757.
16. The BIG 1-98 Collaborative Group. Letrozole therapy alone or in
sequence with tamoxifen in women with breast cancer. N Engl J Med.
2009;361:766-776.
17. Coombes RC, Hall E, Gibson LJ, et al. A randomised trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women
with primary breast cancer. N Engl J Med. 2004;350:1081-1092.
18. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of
exemestane versus tamoxifen after 2-3 years tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007;369:
559-570.
19. Jackesz R, Jonat W, Gnant M, et al. Switching of postmenopausal
women with endocrine-responsive early breast cancer to anastrozole after 2
years adjuvant tamoxifen; combined resulst of ABCSG trial 8 and ARNO 95
trial. Lancet. 2005;366:455-462.
20. Boccardo F, Rubagotti A, Puntoni M, et al. Switching to anastrozole
versus continued tamoxifen treatment of early breast cancer. preliminary
results of the Italian Tamoxifen Anastrozole (ITA) trial. J Clin Oncol.
2005;23:5138-5147.
21. Jonat W, Gnant M, Boccardo F, et al. Effectiveness of switching form
adjuvant tamoxifen to anastrozole in postmenopausal women with hormonesensitive early-stage breast cancer: A meta-analysis. Lancet Oncol. 2006;7:
991-996.
22. Van de Velde CJH, Rea D, Seynaeve C, et al. Adjuvant tamoxifen and
exemestane in early breast cancer (TEAM): a randomised phase 3 trial.
Lancet. 2011;377:321-331.
23. Dowsett M, Allred C, Knox J, et al. Relationship between quantitative
estrogen and progesterone receptor expression and human epidermal growth
factor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or
in Combination Trial. J Clin Oncol. 2008; 26:1059-1065.
24. Viale G, Regan MM, Maiorano E, et al. Prognostic and predictive value
of centrally reviewed expression of estrogen and progesterone receptors in a
randomised trial comparing letrozole and tamoxifen adjuvant therapy for
postmenopausal early breast cancer: BIG 1-98. J Clin Oncol. 2007;25:38463852.
25. Bartlett JMS, Brookes CL, Billingham LJ, et al. A prospectively
planned pathology study within the TEAM trial confirms that progesterone
receptor expression is prognostic, but is not predictive for differential re-

25

STEPHEN R. JOHNSTON
sponse to exemestane vs tamoxifen. Presented at: 2008 San Antonio Breast
Cancer Symposium.
26. Viale G, Giobbie-Hurder A, Regan MM, et al. Prognostic and predictive
value of centrally reviewed Ki-67 labelling index in postmenopausal women
with endocrine-responsive breast cancer: Results form Breast International
Group trial 1-98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol.
2008;26:5569-5575.
27. Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant
recurrence using the 21-gene recurrence score in node-negative and nodepositive postmenopausal patients with breast cancer treated with anastrozole
or tamoxifen: A TransATAC study. J Clin Oncol. 2010;28:1829-1834.
28. Buzdar A, Howell A, Cuzick J, et al. Comprehensive side-effect profile
of anastrozole and tamoxifen as adjuvant treatment for early-stage breast
cancer: Long-term safety analysis of the ATAC trial. Lancet Oncol. 2006;7:
633-643.
29. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of
Clinical Oncology 2003 update on the role of bisphosphonates and bone health
issues in women with breast cancer. J Clin Oncol. 2003;21:4042-4057.
30. Goss PE, Ingle JN, Chapman J-AW, et al. Final analysis of NCIC
MA.27; a randomised phase III trial of exemestane versus anastrozole in
postmenopausal women with hormone receptor positive primary breast
cancer. Presented at San Antonio Breast Cancer Symposium 2010, Abstract
S1-1.
31. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in
postmenopausal women after five years of tamoxifen therapy for early-stage
breast cancer. N Engl J Med. 2003;349:1793-1802.
32. Goss PE, Ingle JN, Martino S, et al. Randomised trial of letrozole
following tamoxifen as extended adjuvant therapy in receptor-positive breast
cancer: Updated findings from NCIC CTG MA. 17. J Natl Cancer Inst.
2005;97:1262-1271.
33. Goss PE, Ingle JN, Martino S, et al. Efficacy of letrozole extended
adjuavnt therapy according to estrogen receptor and progesterone receptor
status of the primary tumour: National Cancer Institute of Canada Trials
Group MA. 17. J Clin Oncol. 2006;25:2006-2011.

26

34. Goss PE, Ingle JN, Pater JL, et al. Late extended adjuvant treatment
with letrozole improved outcome in women with early stage breast cancer who
completes 5 years of tamoxifen. J Clin Oncol. 2008;26:1948-1955.
35. Jakesz R, Greil R, Gnant M, et al. Extended adjuvant therapy with
anastrozole among postmenopausal breast cancer patients; results from the
randomised Austrian Breast and Colorectal Cancer Study Group Trial 6a.
J Natl Cancer Inst. 2007;99:1845-1853.
36. Mamounas EP, Jeong J-H, Wickerham L, et al. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen;
intention-to-treat analysis of the National Surgical Adjuvant Breast and
Bowel Project B-33 Trial. J Clin Oncol. 2008;26:1965-1971.
37. Davidson NE, ONeill AM, Vukov AM, et al. Chemoendocrine therapy
for pre-menopausal women with axillary lymph-node positive, steroid hormone receptor positive breast cancer: Results from INT 0101 (E5188). J Clin
Oncol. 2005;23:2973-2982
38. International Breast Cancer Study Group. Adjuvant chemotherapy
followed by goserelin versus either modality alone for pre-menopausal lymph
node negative breast cancera randomised trial. J Natl Cancer Inst. 2003;
95:1833-1846.
39. Cuzick J, Ambroisine L, Davidson N, et al. Use of luteinising-hormonereleasing hormone agonists as adjuvant treatment in premenopausal patients
with hormone-receptor-positive breast cancer: A meta-analysis of individual
patient data from randomised adjuvant trials. Lancet. 2007;369:1711-1723.
40. Sotiriou C and Pusztai L. Gene expression signatures in breast cancer.
N Engl J Med. 2009;360:790-800.
41. Goldhirsch A, Wood WC, Coates RD, et al. Strategies for subtypes dealing with the diversity of breast cancer; highlights of the St Galen
International Expert Consensus on the Primary Therapy of Early Breast
Cancer 2011. Ann Oncol. 2011;22:1736-1747.
42. Albain K, Barlow WE, Shak S, et al. Prognostic and predictive value of
the 21-gene recurrence score assay in postmenopausal women with nodepositive, oestrogen-receptor positive breast cancer on chemotherapy; a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:55-65.

A DICKENS TALE OF THE TREATMENT OF


ADVANCED BREAST CANCER:
THE PAST, THE PRESENT, AND THE FUTURE
CHAIR
George W. Sledge Jr., MD
Indiana University Simon Cancer Center
Indianapolis, IN
SPEAKERS
Fatima Cardoso, MD
Champalimaud Cancer Center
Lisbon, Portugal
Martine J. Piccart, MD, PhD
Jules Bordet Institute
Brussels, Belgium
Eric P. Winer, MD
Dana-Farber Cancer Institute
Boston, MA

A Dickens Tale of the Treatment of Advanced


Breast Cancer: The Past, the Present, and
the Future
By George W. Sledge Jr., MD, Fatima Cardoso, MD, Eric P. Winer, MD,
and Martine J. Piccart, MD

Overview: Metastatic breast cancer (MBC), a usually incurable disease, continues to vex physicians and patients. Recent
decades have seen great improvements in the treatment of
MBC, based on the availability of novel targeted therapeutics
and more standard chemotherapeutic agents. This article

describes the goals of therapy for MBC, the progress made


against MBC in recent decades, the current standard of care,
and the ongoing efforts of basic and translational researchers
to transfer the fruits of modern scientific discovery to patients
in the clinic.

Palliation of Symptoms and Maintenance of


Quality of Life

OTENTIAL GOALS of care in MBC include cure, prolongation of survival, palliation of symptoms and maintenance of quality of life, the development of new treatment
options, and what might be termed a good death for
patients with advanced disease.

Cure

Metastatic breast cancer is usually incurable. Nevertheless, there are patients who are long-term survivors of the
disease (whether the word cure should be applied to such
patients is contentious). Though the overall percentage of
patients is small (1% to 2% of patients in the largest
reported series), their existence is inarguable and suggests
that long-term survival represents a possible goal, if a rare
one.1
Prolongation of Survival

If cure is rare, prolongation of survival nevertheless represents a reasonable goal. How much does therapy improve
survival in metastatic breast cancer? We lack trials comparing active therapy with best supportive care. Studies suggesting an improvement over time in median survival2
imply that this improvement is related to therapy, but are
potentially flawed because of earlier detection of metastatic
disease. A recent study by the Eastern Cooperative Oncology
Group has suggested that, adjusted for disease relapse-free
interval, overall survival (OS) of patients with metastatic
disease has not improved.3
The best evidence for improvements in survival comes
from studies comparing active therapies. These include
comparisons of anthracycline- with nonanthracycline-based
therapies, of chemotherapy with chemotherapy plus HER2targeted therapy, of aromatase inhibitor therapy with tamoxifen in estrogen receptor-positive disease, and of
eribulin with doctors best choice.4-7 In each of these cases,
the improvement associated with the new intervention is
measurable in months. The cumulative effect of such improvements is hard to quantify.
As current patients are more heavily pretreated (because
of increasingly intensive adjuvant therapies) than their
predecessors, it may become increasingly difficult to demonstrate improvements in OS. The availability of multiple
lines of systemic therapy in the metastatic setting may also
dilute or hide the benefit of individual new agents, whether
in the front-line or refractory disease settings.8

28

Metastatic breast cancer impairs quality of life through its


symptom-producing effects on organ-specific function (e.g.,
bone metastasis-related fractures and pain) and general
effects on quality of life (both physical and psychologic). An
important part of the physicians role is to maintain patient
quality of life and palliate cancer-related symptoms.
The tools available for this task have expanded in recent
decades. These include appropriate pain control, treatment
of isolated metastases (e.g., brain metastases and epidural
cord compression), antiemetic therapy, bone maintenance
therapy (with bisphosphonates and denosumab), and psychosocial and dietary interventions. Appropriate pain control in particular is critical, and prompt referral to pain
specialists and palliative care experts is valuable in complex
cases.
Systemic therapies obviously play a role in maintenance of
quality of life and palliation of symptoms. Measuring the
effects of systemic therapy on health-related quality of life in
the metastatic setting has been difficult because of the
general lack of placebo-controlled trials, the inherent difficulty of measuring health-related quality of life over time,
and the competing toxicities of systemic therapy.
Psychosocial support, often for the patient and the family,
is equally important, and symptoms of insomnia, anxiety,
and depression often require treatment. In the optimal
situation, palliative and psychosocial care should be seamlessly integrated into the medical care provided by the
primary oncologist after discussion with a multidisciplinary
team.
Developing New Agents

The metastatic setting has played an important role in the


cure of micrometastatic breast cancer through the development of novel agents applicable to early disease. Physicians,
patients, and society in general owe much to the altruism of
patients with MBC. All patients with MBC should be offered
clinical trials of novel agents as an appropriate treatment

From the Indiana University Simon Cancer Center, Indianapolis, IN; Breast Unit,
Champalimaud Cancer Center, Lisbon, Portugal; Dana-Farber Cancer Institute, Boston,
MA; Institut Jules Bordet, Universite Libre de Bruxelles, Belgium.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to George Sledge, Jr., MD, Indiana Cancer Pavilion, 535
Barnhill Dr., RT-473, Indianapolis, IN 46202; email: gsledge@iupui.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

TREATMENT OF ADVANCED BREAST CANCER

option. New trials represent an important source of hope


and offer potential therapeutic benefitfor patients with
advanced breast cancer. The National Institutes of Healths
clinicaltrials.gov website represents an invaluable resource
in this regard.
A Good Death

Because MBC is generally incurable, it is important for


physicians to be honest with patients regarding their prognosis, particularly as treatment options dwindle. Advanced
care planning should be part of a physicians discussion with
patients. Appropriate end-of-life care includes the discussion
of hospice care as a therapeutic option. The American
Society of Clinical Oncologys Advanced Care Planning booklet, available freely through its Cancer.net website, is a good
starting point for patients with MBC.
Treatment Past: Lessons Learned, but Lets Move On

One of the major criticisms raised nowadays of the older


clinical trials is the fact that most of them were run in
all-comers without a biologic-based patient selection. However, it was in the metastatic setting where the first targeted
trials were conducted. Our oldest form of targeted therapy
endocrine therapywas first used in MBC patients. The
understanding of the crucial predictive role of the estrogen
receptor (ER) led to selection based on ER status. The first
studies of the anti-HER2 agent trastuzumab were performed in patients with MBC selected by HER2 receptor
status. In the trials of cytotoxic agents, patient selection
according to biology is only a recent phenomenon.
Multidisciplinary and Locoregional Treatments

An important change in oncology occurred with the understanding of the crucial role of a multidisciplinary approach
to cancer treatment, with active cooperation among all
specialists involved in the care of these patients. Unfortunately, this multidisciplinary approach is often forgotten in
the advanced setting. With the development of efficacious
locoregional treatments to several types of metastases
(mainly brain, bone, and liver) the multimodal approach has
become more prominent.
Many unanswered questions remainthe role of locoregional therapy of the primary cancer for patients diagnosed
with stage IV breast cancer (a survival benefit is suggested

KEY POINTS

The goals of care in metastatic breast cancer (MBC)


include cure, prolongation of survival, palliation of
symptoms, development of new agents, and a good
death.
The roots of targeted therapy lie in past decades of
clinical trials.
These trials also did much to elucidate the proper role
of systemic chemotherapy regimens in MBC.
Current treatment approaches are based on the
proper use of knowledge regarding growth factor
receptors (estrogen receptor and HER2).
Novel treatments for MBC attack increasing portions
of the hallmarks of cancer.

by retrospective series,9 and there are three ongoing trials);


the best candidates, timing, and approach (surgery, radiofrequency, a combination of both) for liver and lung metastases; and the best sequence of therapies for brain
metastases (surgery, radiotherapy, radio-surgery, combination with a systemic therapy).
Systemic Therapy: Best Endpoints, Survival Benefits

Though many new agents have been developed and incorporated into the treatment of MBC, very few provided a
survival benefit,10 and when they did, it was almost exclusively as first-line therapy (doxorubicin paclitaxel vs.
5-FU doxorubicin cyclophosphamide; letrozole vs. tamoxifen) or when compared with very old and abandoned
drugs (i.e., melphalan or mitomycin plus vinblastine) or in
trials that compared combination regimens with single
agents, although neglecting planned cross-over (docetaxel
capecitabine vs. docetaxel alone or paclitaxel gemcitabine
vs. paclitaxel alone).
Although OS benefit is undoubtedly the most desired
outcome, progression-free survival (PFS) has been the most
widely used endpoint. However, it is not a good surrogate for
OS benefit,11 and no good surrogate has yet been developed.
Heated discussions regarding the merits of OS or PFS as the
most adequate endpoint are ongoing, as is the incorporation
of validated quality-of-life measurements and patientreported outcomes.
Endocrine Therapy (ET): Optimal Agents and Optimal Sequence
of Therapies

For ER-positive premenopausal women, some relatively


small trials and a meta-analysis found statistically significant survival benefits with third-generation aromatase inhibitors (AIs) (letrozole, exemestane, and anastrozole)
(relative hazard (RH) 0.87, CI 95%: 0.82 to 0.93; p
0.001). In first-line trials, in which AIs were compared with
tamoxifen, the survival benefit was of 11% RH reduction
(95% CI: 1% to 19%; p 0.03). Their benefit in second and
subsequent line trials, in which they were compared with
other treatments, was similar.12 However, these trials have
been performed in a era when tamoxifen was the gold
standard adjuvant ET, and currently the great majority of
postmenopausal women receives an AI in the adjuvant
setting. Trials in MBC patients pretreated with AIs have
shown that another AI, fulvestrant, and tamoxifen are
viable options at progression.
For ER-positive premenopausal women, tamoxifen with or
without ovarian suppression/ablation (OS/OA) has remained
the standard adjuvant therapy, and some relatively small
trials and a meta-analysis provide evidence that for first-line
therapy for MBC ER-positive premenopausal patients, the
combination of OS/OA with tamoxifen is superior to tamoxifen alone. Although frequently used in the clinic, the
combination OS/OA with an AI has not been properly
evaluated in the metastatic setting, and, unfortunately,
randomized trials of fulvestrant for MBC have not included
premenopausal women.
Chemotherapy: Optimal Drug/Regimen for First, Second, and More
Lines of Therapy; Combination Versus Sequential Monotherapy;
Optimal Sequence of Drugs

One of the most challenging and controversial issues in


MBC treatment relates to chemotherapy use. Almost all

29

SLEDGE, CARDOSO, WINER, AND PICCART

available data comes from an era when taxane adjuvant use


was not yet standard, and even anthracycline-based regimens were not always used. These data may not apply to our
current MBC patient population.
Available trials have produced the following conclusions:
for taxane-naive and anthracycline-naive/minimally exposed patients, single-agent anthracycline or single-agent
taxane yield similar results; for taxane-naive and anthracycline-resistant/refractory patients, single-agent taxane led
to better outcomes than single-agent anthracyclines; combinations of anthracyclines plus taxanes in the metastatic
setting consistently led to higher response rates, sometimes
higher time to progression or PFS, higher toxicity, but not
better OS. Because of this, sequential single agent therapy
is not only appropriate, but preferred for most patients. A
2008 meta-analysis of individual patient data concludes that
taxanes do not improve survival when compared with anthracyclines, either as single agents or in anthracycline
combinations and that taxanes in combination with anthracyclines modestly improve response rate (RR) and PFS but
not OS.13
For patients pretreated with both anthracyclines and
taxanes, the most consistent data concerns capecitabine use.
Vinorelbine has been compared head-to-head with docetaxel
and yielded similar efficacy and significantly less toxicity.
Given that both these agents are available as oral formulations and are associated with much less toxicity including
alopecia, they are attractive options. Although there is also
some data supporting rechallenging with taxanes as firstline therapy, the wealth of other available options and
toxicity concerns make this a less appealing option.
A common question relates to the use of combination of
cytotoxic agents compared with their sequential use as
monotherapy. Available evidence14 suggests monotherapy
as the preferred option (even in the presence of visceral
metastases) in all cases except those with a rapid progressive or highly symptomatic disease.
It is important to know that there are no data to support
an optimal sequence of therapies and that only eribulin led
to an OS benefit. Therefore, treatment decisions must be
individualized, taking into account many other factors beyond efficacy.
Chemotherapy: Optimal Duration and Number of Lines of Therapy

Many studies have looked into the question of optimal


duration of systemic therapy, mainly chemotherapy, for
which the balance between efficacy and toxicity is perhaps
more difficult to achieve. Recently, a meta-analysis of published trials15 has looked into this issue and concluded that
longer first-line chemotherapy duration is associated with
marginally longer OS and a substantially longer PFS, and
treatment should be prescribed until progression or unacceptable toxicity.
Treatment Present: Metastatic Breast Cancer in 2012

Todays systemic treatment decisions are guided by a


range of factors: 1) the subtype of the breast cancer (defined
by ER status and HER2) 2) sites of disease 3) disease tempo
4) presence and extent of symptoms 5) prior therapy 6)
availability of effective local therapy and 7) patient preferences.

30

Hormone Receptor-Positive MBC

Hormone therapy is the preferred first-line treatment for


most. Several options are available, including the AIs
tamoxifen and fulvestrant (not U.S. Food and Drug Administration (FDA)-approved for first-line use). In postmenopausal patients who present de novo with metastatic disease
or those who have only received tamoxifen in the adjuvant
setting, treatment with an AI is standard of care.16 A
substantial number of these patients remain on an AI with
disease control for prolonged periods. In a minimally symptomatic patient without an extensive disease burden, it is
reasonable to try a second-line agent, even if there has been
no or little benefit with the initial treatment. Among patients who develop disease progression after an objective
response or prolonged disease stabilization on first-line
treatment, another endocrine agent is generally preferred.
Treatment with fulvestrant, a steroidal AI (assuming a
nonsteroidal agent was used initially) or tamoxifen (unless
there had been prior progression on tamoxifen) are reasonable.17 Unfortunately, clinical benefit from second-line therapy in the metastatic setting is less impressive than with
first-line treatment. Some patients will continue to derive
benefit from hormone therapy and can go on to receive thirdand fourth-line therapy.
Many patients with a new diagnosis of MBC will have
already progressed on an adjuvant aromatase inhibitor. For
these, options are more limited. In general, fulvestrant is
used as the first-line metastatic treatment in such patients.
A recent study conducted by the Southwest Oncology Group
that compared anastrozole alone with anastrozole plus fulvestrant in the first-line setting18 suggested an advantage
both in terms of PFS and OS for the combination.
In premenopausal women with MBC, tamoxifen remains
the standard treatment, often administered in conjunction
with a luteinizing hormone releasing hormone (LHRH) agonist.19 For premenopausal women who develop metastatic
disease while on tamoxifen, the usual approach is a combination of an LHRH agonist and an AI. AIs are ineffective in
women with functioning ovaries.
Ultimately, women with hormone receptor-positive disease become refractory to endocrine therapy. At that point,
chemotherapy is administered. A wide variety of choices are
available, and treatment options are similar to those that
are available for women with triple-negative disease. Both
the taxanes and capecitabine are commonly given in the
first-line setting. Although capecitabine does not have FDA
approval for first-line therapy, several small studies comparing capecitabine with other agents have suggested that
capecitabine is a reasonable initial approach.20
Triple-Negative Breast Cancer

Options are limited to chemotherapy in patients with


triple-negative breast cancer. Most patients have received
adjuvant chemotherapy, often with a short disease-free
interval. For these reasons, chemotherapy options in the
metastatic setting are often limited. Survival from the time
of metastatic disease tends to be relatively short, with a
median of approximately 1 year.21
Treatment options for metastatic triple-negative disease
include all of the available chemotherapeutic agents and
regimens. Given the widespread use of anthracyclines in the
adjuvant setting, these agents are not commonly used in the

TREATMENT OF ADVANCED BREAST CANCER


Table 1. Targeting Breast Cancer Cells
Compound

Molecular Target

Clinical Trials

Pharmaceutical

HER2
Pertuzumab

HER2

-Phase I pertuzumab, T-DM1 and paclitaxel in HER2 MBC (NCT00951665)


-Phase I/II T-DM1 with pertuzumab in trastuzumab pretreated HER2 MBC (NCT00875979)
-Phase II Pertuzumab, trastuzuman and weekly paclitaxel in HER2 MBC (NCT01276041)
-Phase III pertuzumab T-DM1 versus T-DM1placebo versus trastuzumab taxane in
HER2 MBC (MARIANNE) (NCT01120184)
-Phase II trastuzumab capecitabine pertuzumab in HER2 MBC (PHEREXA)
(NCT01026142)
-Phase II pertuzumab with trastuzumab and AI in HRHER2 MBC (NCT01491737)
-Phase II of pertuzumab and trastuzuman with neoadjuvant chemotherapy in HER2 BC
(NCT00976989)
-Phase III, trastuzumab chemotherapy pertuzumab in early stage HER2 BC (APHINITY)
(NCT01358877)

Genentech

Trastuzumab-DM1

HER2

-Phase I pertuzumab, T-DM1 and paclitaxel in HER2 MBC (NCT00951665)


-Phase I T-DM1 monotherapy in HER2 MBC in patients with normal or reduced hepatic
function (NCT01513083)
-Phase I with T-DM1 GDC0941 versus trastuzumab GDC0941 in trastuzumab pretreated
HER2 MBC (NCT00928330)
-Phase I T-DM1 docetaxel in HER2MBC (NCT00934856)
-Phase I/II T-DM1 with pertuzumab in trastuzumab pretreated HER2 MBC (NCT00875979)
-Phase II T-DM1 sequentially with anthracycline-based chemotherapy, as adjuvant or
neoadjuvant therapy in HER2 BC (NCT01196052)
-Phase III pertuzumab T-DM1 versus T-DM1 placebo versus trastuzumab taxane in
HER2 MBC (MARIANNE) (NCT01120184)
-Phase III T-DM1 versus lapatinib capecitabine in HER2 MBC (EMILIA) (NCT00829166)

Genentech

HER2/HER3 bispecific
moAb

-Phase I with cisplatin, capecitabine, trastuzumab or lapatinib, trastuzumab or paclitaxel,


trastuzumab in HER2 MBC (NCT01304784)
-Phase I with trastuzumab in HER2 MBC (NCT01097460)
-Phase I monotherapy in HER2 MBC (NCT00911898)

Merrimack

MM-121

HER3

-Phase
-Phase
-Phase
-Phase

Merrimack

Neratinib

EGFR, HER2 and HER4


TKI

-Phase I neratinib with trastuzumab and weekly paclitaxel in HER2 MBC (NCT01423123)
-Phase I/II neratinib with temsirolimus in HER2 or TN MBC (NCT01111825)
-Phase II neratinib with paclitaxel in HER2 MBC (NCT00445458)
-Phase I/II neratinib with trastuzumab in HER2 MBC (NCT00398567)
-Phase I/II neratinib with vinorelbine in HER2 MBC (NCT00706030)
-Phase II neratinib with capecitabine in HER2 MBC (NCT00741260)
-Phase II neratinib versus lapatinib with capecitabine in HER2 MBC
-Phase II monotherapy in HER2 MBC pts with CNS mets (NCT01494662)
-Phase II of neoadjuvant chemotherapy with neratinib or trastuzumab followed by
postoperative trastuzumab in HER2 BC (NCT01008150)
-Phase II of neratinib plus paclitaxel versus trastuzumab plus paclitaxel in HER2 MBC
(NEFERTT) (NCT00915018)
-Phase III of neratinib after adjuvant trastuzumab in HER2 BC (ExteNET) (NCT00878709)

Pfizer

Afatinib

EGFR, HER2 TKI

-Phase I afatinib with vinorelbine in EGFR and/or HER2 overexpressing advanced solid
tumors (NCT00906698)
-Phase II afatinib or afatinib with chemotherapy (paclitaxel or vinorelbine weekly) in HER2
MBC (LUX-Breast 2) (NCT01271725)
-Phase II Afatinib in HER2 inflammatory breast cancer (NCT01325428)
-Phase II afatinib alone or in combination with vinorelbine in HER2 MBC with CNS mets
(Lux-Breast 3) (NCT01441596)
-Phase III afatinib plus vinorelbine versus trastuzumab plus vinorelbine in HER2 MBC after
trastuzumab failure (Lux-Breast 1) (NCT01125566)

Boehringer Ingelheim

HGF/cMET
Foretinib

VEGFR2/cMET

-Phase I/II with lapatinib in HER2MBC (NCT01138384)


-Phase II monotherapy in met TNBC (NCT01147484)

GSK

Cabozantinib

c-Met/VEGFR2/AXL/
KIT/TIE2/FLT3/RET

-Phase II monotherapy in HR MBC (NCT01441947)

Exelixis

Onartuzumab (MetMAb)

c-Met

-Phase II of onartuzumab and/or bevacizumab in combination with paclitaxel in met TNBC


(NCT01186991)

Genentech

IGFR
Ganitumab (AMG 479)

IGF-1R

-Phase I/II with trastuzumab in HER2 MBC ( NCT01479179)


-Phase II with exemestane or fulvestrant in HR MBC (NCT00626106)

Takeda with Amgen

IGF-1R and InsR dual


Inhibition

-Phase II letrozole in HR MBC (NCT01225172)


-Phase I/II with trastuzumab in HER2MBC (NCT00788333)

Bristol Myers Squibb

HER Family
MM-111

BMS-754807

II of MM121 exemestane in HER2- MBC (NCT01151046)


II with paclitaxel in HER2- MBC (NCT01421472)
I with paclitaxel in HER2- MBC (NCT01209195)
I with XL147 (SAR245408) in advanced solid tumors (NCT01436565)

OSI-906

IGF-1R

-Phase II with OSI-906 letrozole/goserelin erlotinib in HR MBC (NCT01205685)

Astellas

Cixutumumab (IMC-A12)

IGF-1R

-Phase I/II with temsirolimus in advanced or MBC (NCT00699491)


-capecitabine and lapatinib Cixutumumab in HER2 locally advanced or MBC (stages IIIB
IV) (NCT00684983)
-Phase II cixutumumab antiestrogens in HR MBC (NCT00728949)

Lilly

Dalotuzumab

IGF1R

-Phase I monotherapy in the neoadjuvant setting (NCT00759785)


-Phase II dalotuzumab ridaforolimus (MK-8669) in HR MBC (NCT01234857)

Merck

31

SLEDGE, CARDOSO, WINER, AND PICCART


Table 1. Targeting Breast Cancer Cells (Contd)
Compound

Molecular Target

Clinical Trials

Pharmaceutical

BMS-754807

IGF-1R/InsR TKI

-Phase II letrozole in HR MBC (NCT01225172)


-Phase I/II with trastuzumab in HER2 MBC (NCT00788333)

Bristol Myers Squibb

MEDI-573

IGF anti-ligand mAb

-Phase Ib/II with AI versus AI monotherapy in HR MBC (NCT01446159)

MedImmune

FGFR
Dovitinib (TKI 258)

FGF-R and VEGFR

-Phase I with AI in HR MBC (NCT01484041)


-Phase II salvage monotherapy in inflammatory MBC (NCT01262027)

Novartis

BGJ398

Pan-FGF-R TKI

-Phase I trial for advanced solid tumors bearing FGFR1 or FGFR2 amplification or FGFR3
mutation (NCT01004224)

Novartis

PI3K
XL147 (SAR245408)

Pan-PI3K inhibition

-Phase I/II with HER or HERTaxol in MBC 2nd line ( NCT01042925)


-Phase I with letrozole (NCT01082068)
-Phase I with MSC1936369B (MEK inhibition) in advanced solid tumors (NCT01357330)

Exelixis with Sanofi-Aventis

GDC-0941

Pan-PI3K Inhibition

-Phase I with paclitaxel and bevacizumab (NCT00960960)


-Phase Ib with trastuzumab or T-DM1 in MBC (NCT00928330)
-Phase II with fulvestrant versus fulvestrant (NCT01437566) in hormone resistant MBC

Genentech/Roche

BKM120

Pan-PI3K Inhibition

-Phase I with fulvestrant in HR MBC ( NCT01339442)


-Phase I with letrozole in HR MBC (NCT01248494)
-Phase I/II with trastuzumab in TzRes MBC ( NCT01132664)

Novartis

GDC-0032

PI3Ka

-Phase I monotherapy in advanced solid tumors ( NCT01296555)

Genentech

GDC-0980

PI3K-mTOR Inhibition

-Phase Ib with paclitaxel, bevacizumab and trastuzumab in MBC (NCT01254526)


-Phase II with fulvestrant versus fulvestrant (NCT01437566) in hormone resistant MBC

Genentech

BEZ235

PI3K-mTOR Inhibition

-Phase
-Phase
-Phase
-Phase
-Phase
-Phase
-Phase

Novartis

I/II in advanced solid tumors enriched for MBC (NCT00620594)


I with everolimus in advanced solid tumors enriched for MBC (NCT01482156)
I/II with trastuzumab versus lapatinib capecitabine in MBC (NCT01471847)
I with paclitaxel trastuzumab in HER2 MBC (NCT01285466)
I with letrozole in MBC (NCT01248494)
I/II with paclitaxel in HER2- MBC (NCT01495247)
I/II monotherapy in HER2-/HR MBC (NCT01288092)

XL765

PI3K-mTOR Inhibition

-Phase I with letrozole ( NCT01082068)

Exelixis/Aventis

PF04691502

PI3K-mTOR Inhibition

-Phase Ib with letrozole in MBC (NCT01430585)

Pfizer

mTOR
INK128

Pan-mTOR

-Phase I with paclitaxel and trastuzumab in HER2 MBC (NCT01351350)

Intellikine

Akt
MK-2206

Akt

-Phase I with paclitaxel in MBC (NCT01263145)CTCs analysiscleaved caspase 3 analysis


-Phase I with paclitaxel and trastuzumab in HER2 advanced solid tumors (NCT01235897)
-Phase II monotherapy in MBC with mutPI3K or mutAkt and/or PTEN loss (NCT01277757)
-Phase I with trastuzumab lapatinib in HER2 advanced solid tumors
(NCT00963547)completed
-Phase I with AI or fulvestrant in HR MBC (NCT01344031)
-Phase I with lapatinib in HER2 MBC (NCT01245205)

Merck

Ras/MEK/ERK
AZD6244 (ARRY-142886)

MEK/ERK

-Phase I with docetaxel in MBC (NCT00600496)


-Phase II monotherapy in stage Ic-III ER- BC to induce ER expression (NCT01313039)
-Phase II fulvestrant AZD6244 in HR MBC ( NCT01160718)

AstraZeneca

GSK1120212

MEK1/2

- Defining the triple negative breast cancer kinome response to GSK1120212 in stage Ic-III
TNBC (NCT01467310)

GlaxoSmithKline

-Phase I/II letrozole PD 0332991 in HR MBC (NCT00721409)


-Phase I PD 0332991 with paclitaxel in MBC (NCT01320592)

Pfizer

CDK (Cyclin Dependent Kinase)


PD 0332991
CDK4, 6
Dinaciclib (SCH 727965)

CDK1, 2, 5, 9

-Phase I veliparib and dinaciclib carboplatin in advanced solid tumors (BRCA1,2 mutation
carriers included) (NCT01434316)

Merck

Seliciclib (CYC202)

CDK2, 7, 9

-Phase I seliciclib with sapacitabine in advanced solid tumors (NCT00999401)


-Phase I liposomal doxorubicin with seliciclib in met TNBC (NCT01333423)

Cyclacel

Aurora Kinases
Alisertib

Aurora-A Kinase

-Phase I/II momotherapy in advanced solid tumors (NCT01045421)


-Phase I alisertib with paclitaxel in metastatic ovarian and breast cancer (NCT01091428)

Millennium Pharmaceuticals

AMG 900

Aurora-A, -B, -C Kinase

-Phase I monotherapy in advanced solid tumors (NCT00858377)

Amgen

Apoptosis
Navitoclax (ABT-263)

Bcl-2, Bcl-XL, and Bcl-w

-Phase I with paclitaxel in advanced solid tumors (NCT00891605)

Abbott

MDM2 Antagonist

-Phase I monotherapy in advanced solid tumors (NCT00559533)

Roche

HDAC

-Phase
-Phase
-Phase
-Phase
-Phase

Merck

RG7112
HDAC
Vorinostat

32

II with lapatinib in HER2 MBC (NCT01118975)


I with ixabepilone in MBC (NCT01084057)
II with tamoxifen in stage I-III BC (NCT01194427)
II with tamoxifen in HR MBC (NCT00365599)
II with AI in HR MBC (NCT01153672)

TREATMENT OF ADVANCED BREAST CANCER


Table 1. Targeting Breast Cancer Cells (Contd)
Compound

Molecular Target

Clinical Trials

Pharmaceutical

Entinostat (SNDX-275 or
MS-275)

HDAC class I

-Phase II with lapatinib in trastuzumab resistant HER2 MBC (NCT01434303)


-Phase II with azacitidine in MBC (NCT01349959)
-Phase II exemestane entinostat in HR MBC ( NCT00676663)
-Phase II trial completed (ENCORE 301) of continuing AI upon progression of HR MBC with the
addition of entinostat (NCT00828854)

Syndax

HSP90Geldanamycin
derivative

-Phase II with trastuzumab in HER2 MBC (NCT00817362) completed (02.01.2012)


-Phase II with trastuzumab in trastuzumab pretreated HER2 MBC (NCT00773344) completed

Infinity

AUY922

HSP90 (nongeldanamycin
derivative)

-Phase I/II trial monotherapy in HER2 or ER MBC (NCT00526045)


-Phase I/II with trastuzumab in HER2 MBC (NCT01271920)
-Phase I/II trial with lapatinib and letrozole in HER2 MBC (NCT0136194)

Novartis

Retaspimycin (IPI-504)

HSP90

-Phase II with trastuzumab in trastuzumab pretreated HER2 MBC (NCT00817362) completed

Infinity

AR
Bicalutamide

AR

-Phase II monotherapy in ARER-PR- MBC (NCT00468715)

AstraZeneca

-Phase II abiraterone exemestane in ER MBC after AI failure (NCT01381874)

Johnson & Johnson

-Phase I monotherapy in PRL MBC (NCT01338831)

Novartis

HSP90
Tanespimycin (17-AAG)

Abiraterone
PRL
LFA 102

PRL-R

Abbreviations: MBC, metastatic breast cancer; AI, aromatase inhibitor; BC, breast cancer; MoAb, monoclonal antibody; EGFR, epidermal growth factor receptor; CNS,
central nervous system; GSK, GlaxoSmithKline; PTEN, phosphatase and tensin homolog; HDAC, histone deacetylase; AR, androgen receptor; FGF, fibroblast growth
factor; VEGFR, vascular endothelial growth factor receptor; PI3K, phosphatidylinositol 3-kinase; CDK, cyclin-dependent kinase; ER, estrogen receptor; PR,
progesterone receptor; IGF, insulin-like growth factor.

metastatic setting. If not previously used, an anthracycline


is an appropriate option. The taxanes (particularly weekly
paclitaxel) are a mainstay of treatment and one of the most
commonly employed first-line regimens, particularly as a
backbone for new treatment approaches with combined
biologic agents. Other active agents include capecitabine,
gemcitabine, eribulin, and vinorelbine. The platinum salts,
both carboplatin and cisplatin, are also used in patients with
metastatic triple-negative disease.22
A variety of biologic agents have been evaluated in patients with triple-negative disease in conjunction with chemotherapy. Bevacizumab was commonly administered with
a taxane for metastatic triple-negative disease, but the
benefits of this approach have been called into question
based on the results of recent trials and a meta-analysis, and
the FDA withdrew approval for bevacizumab as a treatment
for MBC.23,24 Although there is great interest in the PARP
inhibitors, and an initial randomized phase II clinical trial
suggested a substantial benefit when iniparib was combined
with carboplatin-based chemotherapy;25 a subsequent phase
III trial failed to support these preliminary results.26
HER2-Positive Breast Cancer

Trastuzumab, a humanized monoclonal antibody directed


against HER2, plus chemotherapy represents the standard
first-line approach for patients who have ER-negative disease or have had progression on endocrine therapy.4 In
initial trials, trastuzumab was combined with a taxane, but
more recent studies have suggested that other chemotherapeutic agents, such as vinorelbine, yield similar results.27
Recent evidence suggests that continued suppression of
HER2 with trastuzumab is useful even after disease progression.28
Lapatinib, a small molecule tyrosine kinase inhibitor
directed against EGFR and HER2, is also approved for
the treatment of HER2-positive breast cancer in combination with capecitabine.29 Many patients receive a combination of lapatinib and capecitabine at some point in their
treatment course, after the first or second trastuzumabbased regimen, and subsequently return to trastuzumab. Of
interest, the combination of trastuzumab and lapatinib

without chemotherapy has also been shown to be an active


regimen and substantially more effective than lapatinib
alone.30
The development of central nervous system (CNS) disease
is a major challenge that is faced by more than a third of all
women with HER2-positive metastatic disease. As women
live longer with HER2-positive metastatic disease, the incidence of CNS disease increases. Treatment options include
whole brain irradiation, stereotactic radiosurgery, surgery,
and a number of systemic approaches. Of the available
medical therapies, single-agent lapatinib results in rare
objective responses, but a combination of capecitabine plus
lapatinib appears to be more active.31
The development of trastuzumab (and, subsequently,
lapatinib) for MBC is an example of the problem of leaving
unanswered questions in the metastatic setting once therapy has moved to the adjuvant setting. It took almost a
decade to gather evidence about the best dose and regimen
(weekly and 3-weekly regimens with a loading dose are
similar), the best timing of introduction, the best agent to
combine it with (several options now known to exist), and
the efficacy of this treatment beyond progression. For patients with ER-positive, HER2-positive disease, the combination of aromatase inhibitor therapy with HER2-targeted
therapy is superior to aromatase inhibitor therapy alone.
This combination may be considered as an alternative to a
chemotherapy plus HER2-targeted therapy in selected patients.
Treatment Future: Newer Targeted Agents in
Metastatic Breast Cancer

Gene-expression profiling analysis studies32 have fundamentally changed the way we think about breast cancer,
which is now considered a group of diseases with distinct
genetic and epigenetic alterations. The translation of this
improved molecular knowledge into effective molecularlytargeted agents is slower than expected. The advent of
next-generation sequencing technologies has generated new
enthusiasm,33 with the promise of better identification of the
molecular defects responsible for carcinogenesis.

33

SLEDGE, CARDOSO, WINER, AND PICCART

RTK

PIK3CA gene mutations


(exon 9 or 20)
PIK3CA gene
amplification

Truncating mutations
(Deletions)
Epigenetic silencing

PTEN
PAN-PI3K inhib.

PI3K

Dual PI3KmTor
inhibitors

PI3K inhibitors

AKT1 gene mutations


AKT2 gene amplification

BEZ 235
BGT 226
SF1126
GSK 1059615
GDC-0980
XL765
PF-4691502

mTORC2

BKM120
GDC-0941
XL147
PKI-587

AKT
mTORC1

Isoform specific
PI3K inhib.

AKT inhibitors
GSK 690693
MK 2206

mTOR CATALYTIC SITE


inhibitors
AZD 8055
OSI 027
INK 128

mTORC1 inhibitors
Everolimus
Fig. 1.

Genetic aberrations of the PI3K pathway in BC and PI3K pathway inhibitors.

Targeting Breast Cancer Cells

Lessons learned from the recent randomized testing of new


strategies for treating MBC. Recent months have witnessed
three striking advances and one failure with the investigation of novel strategies for MBC: dual receptor blockage, use
of an antireceptor antibody-drug conjugate, use of drugs
targeting the PI3K/AKT/mTOR pathway, and exploitation of
genome instability.
Dual receptor blockage was first explored in heavily pretreated patients with HER2-positive disease, using the combination of trastuzumab and lapatinib, which was superior
to lapatinib alone in a relatively small, although provocative, randomized trial.30 The recently published phase III
CLEOPATRA study34 testing dual HER2 blockade with
trastuzumab and pertuzumab along with docetaxel compared with docetaxel plus trastuzumab, represents a major
advance in the treatment of HER2-positive MBC. The combined strategy achieved an impressive PFS prolongation of
6.1 months and is likely to become a new standard of care.
Others are building on this concept to design cocktails of
monoclonal antibodies directed at several HER family members in pairs, such as two antibodies targeting two different
domains of each receptor,35 or at the design of bispecific
monoclonal antibodies, which target two HER family members simultaneously (e.g., HER2 and HER3 simultaneously)
(Table 1).
The hope is to induce downregulation of surface membrane receptors and reduce activation of compensatory pathways. It is unclear whether this strategy will be tolerable

34

and superior to the use of small molecules that potently


inhibit the tyrosine kinase of HER1-HER2 (afatinib) or
HER1-HER2-HER4 (neratinib). These oral agents are currently in phase III trials for HER2-positive MBC.
Three receptors are attracting growing interest as therapeutic targets: HER3, cMET, and FGFR. HER3 is not only a
key player in driving the growth of HER2-positive breast
cancer through the formation of the potent HER2-HER3
heterodimer (able to stimulate growth in a ligand-dependent
or independent manner), but also as a mediator of resistance
to antiestrogen therapies.36 Pertuzumab does not prevent
dimerization of HER3 with HER1 or other potential partners. Several anti-HER3 monoclonal antibodies in early
clinical development (Table 1) will be tested in HER2positive and luminal MBC.
C-MET and its stromal ligandthe hepatocyte growth
factorplay a key role in cell survival, mobility, and invasion. They have been proposed as drivers of resistance to
EGFR kinase inhibitors37 and first-line trastuzumabtreatment.38 New agents targeting C-MET alone (anti C-MET
MAb) or together with an angiogenic receptor such as
VEGFR2 (TKIs) are currently being explored in MBC (Table
1).
FGFR overexpression is robustly associated with FGFR1
amplification, and the latter occurs in triple-negative39 and
in luminal B-type40 breast cancer, where it is observed in
16% to 27% of the cases. FGFR1 overexpression promotes
endocrine therapy resistance. Two FGFR inhibitors have
entered the clinic, and a recently reported phase II study of

TREATMENT OF ADVANCED BREAST CANCER


Table 2. Targeting Cancer Stem Cells
Compound

Molecular Target

Preclinical/Clinical Data

Pharmaceutical

Hedgehog
Sarigedib (IPI-926)

Smo Antagonist

-Phase I trials in pancreatic cancer and HNSCC

Infinity

XL139 (BMS-833923)

Smo Antagonist

-Phase I monotherapy in advanced solid tumors (NCT01413906)

Exelixis

LDE225

Smo Antagonist

-Phase I and II trials for pancreatic AdenoCa, medulloblastoma and basal cell Ca

Novartis

PF-04449913

Smo Antagonist

-Phase I monotherapy in advanced solid tumors (NCT01286467)

Pfizer

Notch
MK-0752

Gamma Secretase Inhibition

-Phase I with letrozole or tamoxifen in the neoadjuvant setting (NCT00756717)


-Phase I with ridaforolimus in advanced solid tumors (NCT01295632)
-Phase I/II with docetaxel in MBC (NCT00645333)

Merck

RO4929097

Gamma Secretase Inhibition

-Phase
-Phase
-Phase
-Phase
-Phase

Roche

Wnt
PRI-724

CBP--catenin

-Phase I monotherapy in advanced solid tumors (NCT01302405)

I/II with exemestane in HR MBC (NCT01149356)


I with paclitaxel and carboplatin in the neoadjuvant TNBC (NCT01238133)
I with capecitabine in advanced solid tumors (NCT01158274)
I with cediranib in advanced solid tumors (NCT01131234)
II monotherapy in met TNBC (NCT01151449)

Prism Biolab

Abbreviations: HNSCC, head and neck squamous cell carcinoma; AdenoCa, adenocarcinoma; Ca, carcinoma.

dovitinib (a dual FGFR1 and VEGFR TKI) demonstrated


antitumor activity in heavily pretreated MBC patients with
FGFR1 amplified tumors.41
Finally, there is a strong rationale for blocking IGF1R
signaling, which plays an important role in MBC growth and
is hyperactivated as a result of the release of a negative
feedback loop observed with mTORC1 inhibition. Agents
blocking IGF1R signaling are in clinical development with
early signs of clinical activity seen in a phase I trial combining ridaforolimus (a rapalog) and dalotuzumab (an antiIGF1R monoclonal antibody). A randomized phase II of this
combination compared with exemestane is ongoing.
The use of an antireceptor antibody-drug conjugate is
another striking advance in strategies for MBC.
Trastuzumab-DM1 (T-DM1) consists of trastuzumab covalently bound via a linker to DM1, a derivative of the
antimicrotubule cytotoxic drug maytansine. This elegant
way of localizing an active chemotherapy inside HER2positive tumor cells minimizes harm to normal cells, while
maintaining the full properties of the monoclonal antibody
(such as ADCC). This translates not only into improved

antitumor activity in a randomized phase II trial42 compared with the standard combination of docetaxel and trastuzumab, but also into a better toxicity profile as well as
improved patient reported outcomes in terms of quality of
life.
The use of drugs targeting the PI3K/AKT/mTOR pathway
is a novel strategy for MBC with future ramifications. The
central role of PI3K signaling in several cellular processes
critical for cancer progression has been clearly established.
Genetic alterations in several components of the PI3K pathway (Fig. 1) lead to aberrant pathway activation and mediate resistance to endocrine and anti-HER2 drugs. Among
the rapidly growing number of potential therapeutics targeting the PI3K signaling cascade, mTORC1 inhibitors are
the most advanced.
The BOLERO-2 phase III randomized clinical trial compared the efficacy of exemestane combined with the
mTORC1 inhibitor everolimus with exemestane alone in the
setting of hormone receptor-positive MBC in patients refractory to non-steroidal AIs.43 The biologic rationale involved
ligand-independent activation of ER through a cross-talk

Table 3. Targeting Tumor Stroma


Compound

Angiogenesis Inhibition
MEGF0444A/RG7414

Molecular Target

EGFL7

Preclinical/Clinical Data

Pharmaceutical

-Phase I with bevacizumab paclitaxel in advanced solid tumors (NCT01075464)

Genentech

MNRP1685/RG7347

NRP1

-Phase I with bevacizumab paclitaxel in advanced solid tumors (NCT00954642)

Genentech

TB-403/RG7334

PlGF

-Phase I monotherapy in advanced solid tumors (NCT00702494) completed

BioInvent International AB
with Genentech

Integrin Inhibitors
Cilengitide

v3

-Phase I with paclitaxel in MBC (NCT01276496)

Merck

PF-04605412

51 Integrin

-Phase I monotherapy in advanced solid tumors (NCT00915278)

Pfizer

IMGN388

av

-Phase I monotherapy in advanced solid tumors (NCT00721669)

ImmunoGen, Inc.

Adhesion Signalling Molecules


Removab (catumaxomab)
Ep-CAM and CD3

-Phase I monotherapy in advanced solid tumors (NCT01320020)

Trion

Hypoxia
Aminoflavone (AFP464)

HIF-1 mRNA

-Phase I monotherapy in advanced solid tumors (NCT00369200)

Tigris

EZN-2968

HIF-1 mRNA

-Phase I monotherapy in advanced solid tumors with hepatic mets (NCT01120288)

Enzon

Abbreviation: mets, metastases; HIF, hypoxia-inducible factor; Ep-CAM, epithelial cell adhesion membrane; NRP1, neuroplin1; PIGF, placental growth factor.

35

SLEDGE, CARDOSO, WINER, AND PICCART


44

with the mTOR pathway. The combined treatment led to


an impressive 6.5 month extension of PFS.43
There are four additional classes of PI3K pathway inhibitors in clinical development: dual PI3K-mTOR inhibitors,
PI3K inhibitors that do not inhibit mTOR, AKT inhibitors,
and mTOR catalytic inhibitors (also called pan-mTOR inhibitors because they inhibit mTORC2 in addition to mTORC1)
(Fig. 1). The future will tell if these newer agents are
effective and tolerable pathway inhibitors or are able to
overcome feedback inhibition normally observed with
mTORC1 inhibitors.
Of critical importance will be the identification of populations in which the benefits of these PI3K pathway inhibitors
will justify their manageable but real toxicitythe current
assumption is that PI3KCA-mutated cancers and PTENdeficient cancers will be at the top of the list. This would
suggest that this family of compounds may find a role in all
three types of breast cancer.
Recently, there has been growing interest in combining
PI3K with MEK pathway inhibitors. Many cancers sensitive
to PI3K pathway inhibitors show tumor stasis rather than
regression. The MEK pathway can represent an escape
route in the presence of effective downregulation of the PI3K
pathway. Therapeutic inhibition of both pathways is under
clinical investigation with the use of MEK and PI3K inhibitors (Table 1).
Instability of the genome is inherent to the great majority
of human cancer cells and is instrumental for tumor progression. It has been proposed as a fundamental hallmark of
cancer.45
Although PARP inhibitors have clearly demonstrated
striking antitumor activity in BRCA mutation carriers with
advanced breast cancer, their activity in sporadic triplenegative breast cancer, alone or in combination with chemotherapy, has been less consistent. Myelosuppression has
been an obstacle to their development. It remains uncertain
whether PARP inhibitors will find an application beyond the
treatment of BRCA-mutated tumors.
Strategies directed at hallmarks of cancer in early development for MBC. Cyclin-dependent kinase inhibitors target
evasion from growth suppressors by directly interfering with
the cell cycle, downstream of the receptor tyrosine kinase
signaling cascades. Several CDK inhibitors are in phase I or
II trials, in combinations with either endocrine therapy in
luminal cancers or chemotherapy for basal-like cancers. A
randomized trial of letrozole with or without a CDK-4, -6
inhibitor25 has generated promising results.46
A similar anticancer strategy is inhibition of Aurora
kinases. These serine/threonine kinases play an essential
role in cellular proliferation, through control over chromatid
segregation. Agents targeting Aurora kinases have entered
early clinical trials.
Proapoptotic agents aim at antagonizing resistance to
cell death, and a number of them are in phase I clinical
trials (Table 1). Triple-negative breast cancer seems to be a
priority given the high prevalence of p53 mutations seen in
this subtype.
Strategies directed at epigenetic aberrations or at downregulation of key intracellular targets. As our understanding
of the deregulation of epigenetic mechanisms evolves, growing interest in targeting these aberrations has emerged.
Histone deacetylase inhibitors are progressing from phase I
to phase II trials with interesting results seen when these

36

agents are combined with endocrine agents or anti-HER2


drugs.
Heat shock protein 90 (HSP90) represents another interesting anticancer target in MBC.47 A molecular chaperone,
HSP90 plays a vital role in the intact function of several
oncogenic proteins and, thus, promotes key molecular events
in malignant progression. Several agents have been tested
with promising results in HER2-positive MBC.
Antihormone strategies. The androgen and prolactin receptors are being explored in advanced breast cancer. The
androgen receptor (AR) has recently been shown to play a
role in HER2-positive/estrogen receptor-negative breast
cancers, which can get stimulated by testosterone and also
show upregulation of the Wnt signaling pathway.48 Moreover, AR positivity has been found in approximately 20% of
triple-negative breast cancers,49 and a phase II study with
bicalutamide for ER-negative breast cancer expressing AR
has recently been performed.
Targeting Breast Cancer Stem Cells

The identification of a cellular subpopulation in breast


cancer with a specific immunophenotype (i.e., CD44
CD24-)50 bearing a tumor-initiating capacity was the first
identification of cancer stem cells (CSCs) in the setting of a
solid tumor. Ever since, a detailed exploration of this cellular compartment of breast cancer has been undertaken, and
this expanding knowledge provides novel therapeutic targets51 for this therapy-resistant cellular population.
One of the fundamental aspects of CSCs is their capacity
for self-renewal, mediated through well-conserved developmental signaling pathways52 (the Notch, Hedgehog, and
Wnt pathways) amenable to therapeutic targeting. The
Notch signaling pathway, frequently deregulated in breast
cancer,53 can be targeted by gammasecretase inhibitors
(Table 2). These small molecules block the translocation of
the intracellular part of the Notch receptor to the nucleus
and corresponding signaling pathway activation. The
Hedgehog signaling pathway has also been shown to promote the tumor-initiating ability of breast CSCs.54 A class of
compounds called Smo-antagonists has entered clinical trials (Table 2).
A second approach targeting breast CSCs is based on
high-throughput screening methods. A population of breast
cancer cells enriched for CSCs are screened either for
druggable targets through shRNA/siRNA technology or
through the testing of extended small molecule compound
collections. Based on the latter approach, Gupta and colleagues55 recently discovered that salinomycin is able to
eradicate breast CSCs.
Targeting the Tumor Microenvironment

Tumor cells are integrated into their microenvironment,


constantly interacting with it.56 These components are
appealing therapeutic targets, with antiangiogenic factors
being the most clinically advanced. The failure of bevacizumab, a humanized monoclonal antibody targeting
VEGF-A, to extend OS of MBC patients23,57 should not be
regarded as a proof of failure of the concept of antiangiogenic
therapy in breast cancer. The assumption that bevacizumab
administration potentiates the delivery of higher intratumor
chemotherapy concentrations proved incorrect.58 Moreover,
the redundancy of different angiogenic mechanisms and
proangiogenic factors could explain this clinical failure, as

TREATMENT OF ADVANCED BREAST CANCER

inhibition of VEGF-A rapidly leads to compensatory activation of alternative pathways.59,60 Other compounds targeting the tumor microenvironment can be found in Table 3.

subtyping continues to advance therapy. The twin revolutions of cancer genomics and computational chemistry
should lead to many new treatment options for patients in
coming years.

Conclusion

Acknowledgments

MBC represents a continuing challenge to physicians and


patients. An improved understanding of breast cancer biology has improved prognosis, and progress based on biologic

M. Piccart would like to thank Jose Baselga, MD, PhD for


useful advice and Dimitrios Zardavas, MD, for great help in
preparation of the tables listing newer targets and drugs.

Authors Disclosures of Potential Conflicts of Interest

Author
George W. Sledge Jr.*
Fatima Cardoso

Eric P. Winer
Martine J. Piccart

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Abraxis
BioScience;
AstraZeneca;
Celgene; Eisai;
GlaxoSmithKline;
Johnson &
Johnson;
Novartis; Pfizer;
Roche
Novartis; Roche/
Genentech (U)
Amgen; Bayer
Schering
Pharma;
Boehringer
Ingelheim;
Bristol-Myers
Squibb;
GlaxoSmithKline;
PharmaMar;
Roche; Sanofi

Honoraria
Abraxis
BioScience;
AstraZeneca;
Celgene; Eisai;
GlaxoSmithKline;
Johnson &
Johnson;
Novartis; Pfizer;
Roche

Research
Funding

Expert
Testimony

Other
Remuneration

AstraZeneca;
Novartis

Roche/Genentech
Amgen; Bayer
Schering
Pharma;
Boehringer
Ingelheim;
Bristol-Myers
Squibb;
GlaxoSmithKline;
PharmaMar;
Roche; Sanofi

Bristol-Myers
Squibb; Pfizer;
Roche

*No relevant relationships to disclose.

REFERENCES
1. Greenberg P, Hortobagyi G, Smith T, et al. Long-term follow-up of
patients with complete remission following combination chemotherapy for
metastatic breast cancer. J Clin Oncol. 1996;14:2197-2205.
2. Giordano S, Buzdar A, Smith T, et al. Is breast cancer survival improving? Cancer. 2004;100(1):44-52.
3. Tevaarwerk A, Gray R, Schneider B, et al. Survival in Metastatic Breast
Cancer (MBC): No Evidence for Improved Survival Following Distant Recurrence after Adjuvant Chemotherapy. Presented at: San Antonio Breast
Cancer Symposium. 2011; San Antonio, TX.
4. Slamon D, et al. Use of chemotherapy plus a monoclonal antibody
against HER2 for metastatic breast cancer that overexpresses HER2. N Engl
J Med. 2001;344:783-792.
5. Cortes J, OShaughnessy J, Loesch D, et al. Eribulin monotherapy
versus treatment of physicians choice in patients with metastatic breast
cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;
377:914-923.
6. AHern R, Smith I, Ebbs S. Chemotherapy and survival in advanced
breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J
Cancer. 1993;67:801-805.
7. Gibson L, Lawrence D, Dawson C, et al. Aromatase inhibitors for
treatment of advanced breast cancer in postmenopausal women. Cochrane
Database Syst Rev. 2009; CD003370.
8. Broglio K, Berry D. Detecting an overall survival benefit that is derived
from progression-free survival. J Natl Cancer Inst. 2009;101:1642-1649.
9. Pagani O, Senkus E, Wood W, et al. International guidelines for
management of metastatic breast cancer (MBC) from the European School of
Oncology (ESO)-MBC Task Force: Can metastatic breast cancer be cured?
J Natl Cancer Inst. 2010;102(7):456-463.
10. Cardoso F, Di Leo A, Lohrisch C, et al. Second and subsequent lines of
chemotherapy for metastatic breast cancer: What did we learn in the last two
decades? Ann Oncol. 2002;13:197-207.
11. Burzykowski T, Buyse M, Piccart-Gebhart M, et al. Evaluation of
tumor response, disease control, progression-free survival, and time to pro-

gression as potential surrogate end points in metastatic breast cancer. J Clin


Oncol. 2008;26:1987-1992.
12. Mauri D, Pavlidis N, Polyzos N, et al. Survival with aromatase
inhibitors and inactivators versus standard hormonal therapy in advanced
breast cancer: Meta-analysis. J Natl Cancer Inst. 2006;98:1285-1291.
13. Piccart-Gebhart M, Burzykowski T, Buyse M, et al. Taxanes alone or in
combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol. 2008;26:1980-1986.
14. Cardoso F, Bedard P, Winer E, et al. International guidelines for
management of metastatic breast cancer: Combination vs. sequential singleagent chemotherapy. J Natl Cancer Inst. 2009;101:1174-1181.
15. Gennari A, Stockler M, Puntoni M, et al. Duration of chemotherapy for
metastatic breast cancer: A systematic review and meta-analysis of randomized clinical trials. J Clin Oncol. 2011;29:2144-2149.
16. Riemsma R, Forbes C, Kessels A, et al. Systematic review of aromatase
inhibitors in the first-line treatment for hormone sensitive advanced or
metastatic breast cancer. Breast Cancer Res Treat. 2010;123:9-24.
17. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized
placebo controlled trial of fulvestrant compared with exemestane after prior
nonsteroidal aromatase inhibitor therapy in postmenopausal women with
hormone receptor-positive, advanced breast cancer: Results from EFECT.
J Clin Oncol. 2008;26:1664-1670.
18. Mehta R, Barlow W, Albain K, et al. A Phase III Randomized Trial of
Anastrozole Versus Anastrozole and Fulvestrant as First-Line Therapy for
Postmenopausal Women with Metastatic Breast Cancer: SWOG S0226.
Presented at: San Antonio Breast Cancer Symposium; 2011; San Antonio, TX.
19. Klijn J, Blarney R, Boccardo F, et al. Combination LHRH-agonist plus
tamoxifen treatment is superior to medical castration alone in premenopausal
metastatic breast cancer. Breast Cancer Res Treat. 1998;50:227.
20. Talbot D, Moiseyenko V, Van Belle S, et al. Randomised, phase II trial
comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer.
2002;86:1367-1372.
21. Lin N, Claus E, Sohl J, et al. Sites of distant recurrence and clinical

37

SLEDGE, CARDOSO, WINER, AND PICCART


outcomes in patients with metastatic triple-negative breast cancer: High
incidence of central nervous system metastates. Cancer. 2008;113:2638-2645.
22. Isakoff S, Goss P, Mayer E, et al. TBCRC009: A multicenter phase II
study of cisplatin or carboplatin for metastatic triple-negative breast cancer
and evaluation of p63/p73 as a biomarker of response. J Clin Oncol. 2011;29
(suppl; abstr 1025).
23. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus
paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:26662676.
24. Miles D, Chan A, Dirix L, et al. Phase III study of bevacizumab plus
docetaxel compared with placebo plus docetaxel for the first-line treatment of
human epidermal growth factor receptor 2-negative metastatic breast cancer.
J Clin Oncol. 2010;28:3239-3247.
25. OShaughnessy J, Osborne C, Pippen J, et al. Iniparib plus chemotherapy in metastatic triple negative breast cancer. N Engl J Med. 2011;364:205214.
26. OShaughnessy J, Schwartzberg L, Danso M, et al. A randomized phase
III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin
(G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol.
2011;29:(suppl; Abstr 1007).
27. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study
comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as
first-line therapy of metastatic or locally advanced human epidermal growth
factor receptor 2-positive breast cancer: The HERNATA study. J Clin Oncol.
2011;29:264-271.
28. Von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond
progression in human epidermal growth factor receptor 2-positive advanced
breast cancer: A German Breast Group 26/Breast International Group 03-05
study. J Clin Oncol. 2009;27:1999-2006.
29. Geyer C, Forster J, Lindquis TD, et al. Lapatinib plus capecitabine for
HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2744.
30. Blackwell K, Burstein H, Storniolo A, et al. Randomized study of
Lapatinib alone or in combination with trastuzumab in women with ErbB2positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol.
2010;28:1124-1130.
31. Lin N, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib
in patients with brain metastases from HER2 breast cancer. Clin Cancer
Res. 2009;15:1452-1459.
32. Perou C, Sorlie T, Eisen M, et al. Molecular portraits of human breast
tumours. Nature. 2000;406:747-752.
33. Metzker M. Sequencing technologies - the next generation. Nat Rev
Genet. 2010;11:31-46.
34. Baselga J, Cortes J, Kim S, et al. Pertuzumab plus trastuzumab plus
docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.
35. Pedersen M, et al. Sym004: a novel synergistic anti-epidermal growth
factor receptor amtibody mixture with superior anticancer efficacy. Cancer
Res. 2010;70:588-597.
36. Baselga J, Swain S. Novel anticancer targets: Revisiting ERBB2 and
discovering ERBB3. Nat Rev Cancer. 2009;9:463-475.
37. Engelman JA, et al. MET amplification leads to gefitinib resistance in
lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-1043.
38. Liu L, et al. Synergistic effects of foretinib with HER-targeted agents in
MET and HER1- or HER2-coactivated tumor cells. Mol. Cancer Ther. 2011;
10:518-530.
39. Turner N, Lambros M, Horlings H, et al. Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential
therapeutic targets. Oncogene. 2010;29:2013-2023.
40. Turner N, Pearson A, Sharpe R, et al. FGFR1 amplification drives
endocrine therapy resistance and is a therapeutic target in breast cancer.
Cancer Res. 2010;70:2085-2094.

38

41. Andre F, Bachelot T, Campone M, et al. A multicenter, open-label phase


II trial of dovitinib, an FGFR1 inhibitor, in FGFR1 amplified and nonamplified metastatic breast cancer. J Clin Oncol. 2011;29(suppl; abstr 508).
42. Bianchi G, Kocsis J, Dirix L, et al. Patient-Reported Outcomes From a
Randomized Phase II Study (TDM4450g/BO21976) of Trastuzumab
Emtansine vs Trastuzumab Plus Docetaxel in Previously Untreated Human
Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.
Presented at: San Antonio Breast Cancer Symposium; 2011; San Antonio, TX.
43. Baselga J, Campone M, Piccart M, et al. Everolimus in Postmenopausal
Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2012;
366:520-529.
44. Yamnik R, Holz M. mTOR/S6K1 and MAPK/RSK signaling pathways
coordinately regulate estrogen receptor alpha serine 167 phosphorylation.
FEBS Lett. 2010;584:124-128.
45. Hanahan D, Weinberg R. Hallmarks of cancer: The next generation.
Cell. 2011;144:646-674.
46. Finn R, Boer K, Lang I, et al. A randomized phase II study of PD
0332991, cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with
letrozole for first-line treatment of patients with postmenopausal, estrogen
receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)negative advanced breast cancer. J Clin Oncol. 2011;29 (suppl; abstr
TPS100).
47. Neckers L, Workman P. Hsp90 Molecular Chaperone Inhibitors: Are
We There Yet? Clin Cancer Res. 2012;16:64-76.
48. Ni M, Chen Y, Lim E, et al. Targeting androgen receptor in estrogen
receptor-negative breast cancer. Cancer Cell. 2011;20:119-131.
49. Doane A, Danso M, Lal P, et al. An estrogen-receptor negative breast
cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene. 2006;25:3994-4008.
50. Al-Hajj M, Wicha M, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A.
2003;100:3983-3988.
51. McDermott S, Wicha M. Targeting breast cancer stem cells. Mol Oncol.
2010;4:404-419.
52. Izrailit J, Reedijk M. Developmental pathways in breast cancer and
breast tumor-initiating cells: Therapeutic Implications. Cancer Lett. 2012;
317:115-126.
53. Stylianou S, Clarke R, Brennan K. Aberrant activation of notch
signaling in human breast cancer. Cancer Res. 2006;66:1517-1525.
54. Kasper M, Jaks V, Fiaschi M, et al. Hedgehog signaling in breast
cancer. Carcinogenesis. 2009;30:903-911.
55. Gupta P, Onder T, Jiang G, et al. Identification of selective inhibitors of
cancer stem cells by high-throughput screening. Cell. 2009;138:645-659.
56. Joyce J, Pollard J. Microenvironmental regulation of metastasis. Nature Rev Cancer. 2009;9:239-252.
57. Robert N, Dieras V, Glaspy J, et al. RIBBON-1: randomized, doubleblind, placebo-controlled, phase III trial of chemotherapy with or without
bevacizumab for first-line treatment of human epidermal growth factor
receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin
Oncol. 2011;29:1252-1260.
58. Van der Veldt A, Lubberink M, Bahce I, et al. Rapid Decrease in
Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications
for Scheduling of Anti-Angiogenic Drugs. Cancer Cell. 2012;21:82-91.
59. Ebos J, Lee C, Kerbel RS. Tumor and host-mediated pathways of
resistance and disease progression in response to antiangiogenic therapy.
Clin Cancer Res. 2009;15:5020-5025.
60. Ebos J, Lee C, Christensen J, et al. Multiple circulating proangiogenic
factors induced by sunitinib malate are tumor-independent and correlate with
antitumor efficacy. Proc Natl Acad Sci U S A. 2007;104:17069-17074.

A FRESH LOOK AT DUCTAL CARCINOMA IN SITU:


BASIC SCIENCE TO CLINICAL MANAGEMENT
CHAIR
Eun-Sil S. Hwang, MD, MPH
Duke University Medical Center
Durham, NC
SPEAKERS
Victoria Seewaldt, MD
Duke University Medical Center
Durham, NC
Beth A. Virnig, PhD
University of Minnesota, School of Public Health
Minneapolis, MN

Ductal Carcinoma In Situ: Challenges,


Opportunities, and Uncharted Waters
By Abigail W. Hoffman, MD, Catherine Ibarra-Drendall, PhD, Virginia Espina, MS,
Lance Liotta, MD, PhD, and Victoria Seewaldt, MD

Overview: Ductal carcinoma in situ (DCIS) is a heterogeneous group of diseases that differ in biology and clinical
behavior. Until 1980, DCIS represented less than 1% of all
breast cancer cases. With the increased utilization of mammography, DCIS now accounts for 15% to 25% of newly
diagnosed breast cancer cases in the United States. Although
our ability to detect DCIS has radically improved, our understanding of the pathophysiology and factors involved in its
progression to invasive carcinoma is still poorly defined. In
many patients, DCIS will never progress to invasive breast
cancer and these women are overtreated. In contrast, some
DCIS cases are clinically aggressive and the women may be
undertreated. We are able to define some of the predictors of
aggressive DCIS compared with DCIS of low malignant poten-

UCTAL CARCINOMA in situ is defined as a breast


lesion in which neoplastic mammary epithelial cells
are confined to the mammary ductal-lobular system without
invasion into the surrounding stroma. DCIS accounts for
approximately 15% to 25% of all female breast cancers. The
primary clinical goal in the management of DCIS is to
prevent the development of invasive breast cancer. In order
to individualize treatment of DCIS, there is a need for
biomarkers to prospectively identify DCIS with aggressive
biologic potential.
DCIS is highly variable in its clinical presentation, pathology, genetic/epigenetic alterations, and biologic potential.1,2
Although DCIS is a heterogeneous disease, until recently,
treatment of DCIS was relatively uniform. There is emerging evidence that DCIS has a wide range of biologic phenotypes; however, we lack biomarkers to definitively identify
DCIS that will progress to invasive disease. As a result,
there is considerable debate regarding how best to manage
patients with DCIS. The current primary management
options for women with DCIS include lumpectomy plus
radiation therapy; total mastectomy, with or without sentinel node biopsy, with or without reconstruction; or lumpectomy alone followed by clinical observation. Mastectomy is
an effective therapy for most patients; however, for many
women it represents overtreatment, particularly those with
minimal lesions identified by mammography. Randomized
clinical trials comparing breast-conserving surgery and radiation versus breast-conserving surgery alone show that
radiation therapy reduces local recurrence by approximately
50%.3,4 Conversely, it is possible that a subgroup of patients
with DCIS may not benefit from radiation following breastconserving surgery.
Women with biologically aggressive DCIS are at high risk
of local-regional recurrence or progression to invasive breast
cancer and are logically best served by mastectomy. However, it is also clear that there are women with DCIS at a low
risk for local-regional recurrence and/or progression who
might be adequately treated by breast-conserving surgery
alone, without radiation therapy. Emerging evidence suggests that there are also women whose DCIS is at such low
risk for recurrence or progression to invasive breast cancer

40

tial. However, our ability to risk-stratify DCIS is still in its


infancy. Clinical risk factors that predict aggressive disease
and increased risk of local recurrence include young age at
diagnosis, large lesion size, high nuclear grade, comedo
necrosis, and involved margins. Treatment factors such as
wider surgical margins and radiation therapy reduce the risk
of local recurrence. DCIS represents a key intermediate in the
stepwise progression to malignancy, but not all aggressive
breast cancers appear to have a DCIS intermediate, notably
within triple-negative breast cancer. Ongoing studies of the
genetic and epigenetic alterations in precancerous breast
lesions (atypia and DCIS) as well as the breast microenvironment are important for developing effective early detection
and individualized targeted prevention.

that they might be observed following a diagnostic biopsy


and undergo watchful waiting.5 However, at this time, we
cannot accurately predict the course of each patients DCIS.
Herein, we review our current understanding of 1) clinical
risk factors that predict local recurrence in patients with
DCIS treated with breast-conserving therapy, 2) evidence
for invasive breast cancers that potentially emerge from
intraepithelial neoplasia of lower grade than DCIS, and
3) molecular studies that aim to improve our understanding
of the biologic potential and diversity of DCIS lesions.
Clinical, Treatment, and Pathologic Risk
Factors That Predict Local Recurrence and
Invasion in Women with DCIS
Diagnosis and Prognosis

Until 1980, DCIS represented less than 1% of all breast


cancer cases. With the increased utilization of mammography during the 1980s, DCIS now accounts for 15% to 25% of
newly diagnosed breast cancer cases in the United States.6
Currently over 90% of DCIS is diagnosed by mammographic
examination alone; however, mammograms detect calcifications and frequently do not identify the neoplasm size
accurately.7 Precise preoperative evaluation is required to
determine the size and extent of the disease to optimize
surgical management. The recommended work-up and staging of DCIS includes a history and physical examination,
bilateral diagnostic mammography, pathology review, and
tumor estrogen receptor (ER) determination. Breast Magnetic Resonance Imaging (MRI) is increasingly being used
to evaluate DCIS; however, the exact use of breast MRI in
the preoperative management of DCIS remains a matter of
debate.8
With a follow-up period of 25 years, it is estimated that
14% to 60% of women with untreated DCIS will develop

From Duke University, Durham, NC; George Mason University, Manassas, VA.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Victoria Seewaldt, MD, Duke University, Box 2628, Room
221A MSRB, Durham, NC 27710; email: seewa001@mc.duke.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

DCIS: OPPORTUNITIES AND UNCHARTED WATERS

invasive breast cancer.1 In women who receive standard


treatment for DCIS, women with microinvasion have a
prognosis almost identical to women with DCIS alone, and
mastectomy is curative in 95% to 100% of women.9 Furthermore, approximately 50% of the local recurrences following
initial treatment for a pure DCIS is invasive cancer.1
Clinical and Treatment Risk Factors

Some of the clinical manifestations and treatment factors


associated with an increased risk of local recurrence following breast-conserving treatment for DCIS have been identified. Young women are at increased risk for local-regional
recurrence and invasive disease.6-10 Women with nonpalpable mammographically detected DCIS have a better prognosis than women with palpable DCIS, which is often
associated with microinvasion and occasionally with axillary
nodal involvement. Women who undergo mastectomy are at
low risk for local-regional recurrence. The use of radiation
therapy following breast-conserving surgery is associated
with approximately 50% reduction in the risk of local
recurrence.2-4 In the National Surgical Adjuvant Breast and
Bowel Project (NSABP) B-24 trial, the addition of tamoxifen
further reduced the risk of local-regional recurrence in
women treated with lumpectomy and radiation therapy.11
However, tamoxifen did not reduce the risk of local-regional
recurrence in a second randomized trial.4 Currently, tamoxifen treatment may be considered as a strategy to reduce the
risk of breast cancer recurrence in women with ER-positive
DCIS.1,5 The benefit of tamoxifen for ER-negative DCIS is
not known.
Prospective and retrospective analyses have identified
pathologic characteristics of DCIS that correlate with an
increased risk of local recurrence following breastconserving therapy. Pathologic features that are associated
with an increased risk of local-regional recurrence include

KEY POINTS

DCIS is a heterogeneous disease with a complex


array of biologic potential, clinical behavior, and
prognosis.
Although the biologic behavior of DCIS is heterogeneous, our clinical management has remained relatively uniform.
Biomarkers are needed to tailor clinical treatment of
DCIS to biologic potential for recurrence and invasion, but the genomic and pathologic nature of the
neoplasia that emerges during local recurrence compared with the original DCIS lesion is unknown.
Triple-negative breast cancers may not appear to
have a DCIS intermediate.
Numerous studies comparing the gene expression,
genetic, and epigenetic profiles of DCIS and invasive
breast carcinomas reported a high degree of similarity between the molecular alterations in the DCIS
and the invasive cancer in the same patient. This
provides evidence that the aggressive phenotype of
the breast cancer may be determined at the level of
the preinvasive lesion.

high nuclear grade, comedo necrosis, larger tumor size, and


involved margins of excision.1-3 The effect of pathologic
factors on the risk of local recurrence in patients with DCIS
varies with treatment as well as length of follow-up.10-13
Studies by Silverstein and colleagues provide evidence that
DCIS size, nuclear grade, and margin status are associated
with the risk of local-regional recurrence, but only in cases
with small surgical margin widths.12,13 For women with
DCIS who undergo surgical excision leaving margin widths
of 10 mm or more, the risk of local recurrence is unchanged
by size, grade, the presence of comedo necrosis, and radiation therapy.12 The effect of grade on local-regional recurrence of DCIS appears to be related to the length of followup.10 The NSABP B17 trial provides evidence that comedo
necrosis in DCIS is associated with an increased risk of
local-regional recurrence in women treated with excision
alone.3 Local recurrence rates in women undergoing excision
alone, after 8 years, was 40% for those with moderate or
marked comedo necrosis compared with 23% for women
without comedo necrosis. In women who underwent surgical
excision and radiation therapy, local recurrence rates were
similar for women with moderate or marked comedo necrosis relative to women without comedo necrosis (14% compared with 13%, respectively).3 In summary, these studies
suggest that there are multifaceted interactions between
pathologic factors and other elements that ultimately determine the risk of local recurrence.1-3,10-13
Evidence That Triple-Negative Breast Cancers May
Lack a DCIS Precursor

Triple-negative breast cancers are defined as tumors that


lack ER, PR, and HER2 expression. These tumors account
for 10% to 15% of all breast carcinomas, depending on the
thresholds used to define ER and PR positivity and the
methods used for HER2 assessment.14-16 The clinical interest in these tumors stems from the lack of targeted therapies
for patients affected by this breast cancer subtype, which is
more prevalent in younger women,14 black women,16 and
BRCA1 mutation carriers,17 and more aggressive than tumors of other molecular subtypes.14 Patients with triplenegative cancers also have a significantly shorter survival
following the first metastatic event when compared with
those with non-triple-negative controls (p 0.0001).14 A
predictive rather than prognostic classification system is
required for the success of targeted therapy, and therefore,
the origins and developmental mechanisms must also be
clearly defined.
The biologic developments of triple-negative breast cancers have debatable beginnings. Triple-negative breast cancers are thought to develop either from cells that are
triple-negative from the early phase of intraductal proliferation, leading to invasion, or cells that have lost hormone
receptor expression before invasion.18 A group of high-grade
DCIS lacking ER, PR ,and HER2, and expressing basal
markers has been identified.18 Bryan and colleagues studied
66 cases of high-grade DCIS and found a small proportion
(four cases, 6%) that exhibited the triple-negative phenotype
with increased invasion.18 In a study by Meijnen and colleagues, only eight out of 163 cases (5%) demonstrated
triple-negative lesions.19 In addition, tumors with BRCA1
germ-line mutations are significantly more likely to be
triple-negative breast cancers (p 0.005) and have early
high-grade DCIS (p 0.0045).17 However, it is important to

41

HOFFMAN ET AL

recognize that there are large discrepancies in the relative


frequency of triple-negative subtype between DCIS and
invasive disease. The prevalence of DCIS is substantially
lower than invasive triple-negative breast cancers, suggesting that the latter often lack an obvious in situ element.
Without supporting evidence or definitive conclusions, many
studies have attributed this discrepancy as a result of
triple-negative breast cancers progressing rapidly from
DCIS to invasive cancer or obliterating the DCIS precursor
from which they arose.17,18
Molecular Studies of the Biologic Potential and
Diversity of DCIS Lesions

Although the transition from DCIS to invasive cancer is


central to understanding the origins of breast cancer, little is
known about the time of onset or the triggering mechanisms
that promote invasion of DCIS. Some DCIS progresses to
invade the stroma, but other DCIS lies dormant. This raises
the question of whether there are subsets of precancerous
lesions that are preprogrammed to invade and metastasize
or whether the ability to invade and metastasize is acquired
late in the process of progression.20
Molecular Markers Predicting Invasion of DCIS

Numerous studies have compared the gene expression,


genetic, and epigenetic profiles of DCIS and invasive breast
carcinomas, showing a high degree of similarity between
DCIS and invasive cancer in the same patient.21 As expected, there is a significant difference in gene expression
between normal mammary epithelial cells and DCIS, but
surprisingly, DCIS and invasive breast cancer of the same
histologic subtype essentially share the same genetic/epigenetic alterations and gene expression patterns. In contrast,
the molecular profiles of breast tumors of distinct subtypes
(e.g., luminal, HER2) are significantly different. The expression and mutation status of numerous tumor suppressor
and oncogenes have been analyzed in DCIS and invasive
breast cancer including TP53, PTEN, PIK3CA, ERBB2,
MYC; differences in the frequency of these changes were
associated with tumor subtype, but none were associated
with invasion.20,22 For example, amplification of ERBB2 is
specific for the HER2 subtype; however, amplification of
ERBB2 is observed in both DCIS and invasive breast cancer.
The expression of several selected candidate genes based
on their biologic function has been analyzed in DCIS.23 Two
recent studies identified molecular markers that hold promise for identifying the risk of recurrence of DCIS.24,25 Gauthier and colleagues demonstrated that high expression of
COX-2 and Ki67 in DCIS correlates with higher risk of local
in situ and invasive recurrence.24 Lu and colleagues identified a molecular synergy between ERBB2 and 14 3-3 that
may increase the risk of invasive progression via epithelialto-mesenchymal transition regulation.25 A major limitation
of both of these studies was the use of small cohorts. Despite
the promise and need of DCIS risk biomarkers, prospective
validation is difficult. Validation of a predictive biomarker
may require a long waiting period to see if a patients DCIS
lesion will progress to invasive cancer. Most patients diagnosed with DCIS do not even want to experience a delay
before surgical therapy. Therefore, patients judged at low
risk may be unwilling to forego treatment. Since the population of DCIS and other preinvasive proliferative lesions is

42

heterogeneous in the same patient, the portion of the DCIS


lesion sampled at the initial biopsy diagnosis, which is used
for the predictive biomarker measurement, may not be the
same region of the lesion that has malignant potential.
There is very little data comparing the molecular genetic
characteristics of the cancers that recur to the original DCIS
lesion.
Evidence for Acquired Invasive Potential and
Intratumor Heterogeneity

The stepwise model of breast tumorigenesis assumes a


stepwise transition from epithelial hyperproliferation, to
atypical hyperplasia, to DCIS, and finally to invasive and
metastatic cancer.22,23 This progression model is supported
by human clinical and epidemiologic data and molecular
clonality studies addressing the relationships between in
situ and invasive regions of the same tumor and between
DCIS and its local invasive recurrence.21 There is emerging
evidence that neoplastic cells with invasive potential arise
frequently within DCIS lesions, but are held in check and
only invade when further molecular changes occur.20
Emerging data suggest a critical role for the microenvironment in promoting invasion of DCIS.
Numerous studies have shown that DCIS exhibits intratumoral heterogeneity. The prevailing model for explaining
this heterogeneity, the clonal evolution model, has recently
been challenged by proponents of the cancer stem cell
hypothesis.26 To investigate this issue, Kornelia Polyaks
group performed combined analyses of markers associated
with cellular differentiation states and genotypic alterations
in DCIS and invasive breast cancer and evaluated diversity
with ecological and evolutionary methods. Such studies
demonstrated a high degree of genetic heterogeneity both
within and between distinct tumor cell populations that
were defined based on markers of cellular phenotypes including stem cell-like characteristics.26 The degree of diversity correlated with clinically relevant breast tumor
subtypes.26 This supports the concept that molecular alterations at the level of DCIS may precede and determine the
breast tumor subtype.
There is emerging evidence that adaptation to hypoxic
and metabolic stress promotes progression of DCIS to invasive breast cancer. It is hypothesized that premalignant and
malignant cells down-regulate proteins that induce apoptosis or senescence and upregulate pro-survival pathways that
protect against hypoxia, DNA damage, metabolic and genotoxic stress.20 Nevertheless, even if a cell can resist programmed cell death or senescence it will still not survive in
a hypoxic, nutrient-deprived environment unless it can find
alternative sources of energy for cellular functions, such as
through autophagy, anaerobic respiration, or increasing the
efficiency of aerobic respiration.20 To appreciate how DCIS
might progress and circumvent stress-induced death or
senescence, and use alternative sources of energy, it is
important to consider the stresses that affect DCIS cells and
molecular signaling pathways that may act to protect
against these stressors.20 Autophagy promotes survival in
the face of hypoxic and nutrient stress and is an emerging
target for cancer therapy.20 Autophagy is upregulated and
colocalizes with areas of hypoxic stress, and immortalized
mammary epithelial cells are more susceptible to cell death
under conditions of metabolic stress.20 DCIS growth or the
growth of any intraductal proliferative lesion is limited

DCIS: OPPORTUNITIES AND UNCHARTED WATERS

because of confinement within the duct and the absence of


a blood supply. Espina and colleagues proposed that autophagy is a major survival mechanism that is used by DCIS
cells to persist and proliferate in the high-stress environment of the intraductal space and can be a main determinant of acquired DCIS cell fate in response to metabolic
stress.20
Evidence for Preprogramming of Precancerous Breast Lesions

Triple-negative breast cancers frequently exhibit aggressive clinical behavior and are many times metastatic at
diagnosis. In addition to being poorly differentiated, as
outlined above, triple-negative breast cancers are thought to
have a lower proportion of associated DCIS compared with
other types of breast carcinoma. These observations challenge whether the stepwise model of mammary carcinogenesis adequately models initiation and progression of triplenegative breast cancer. In contrast to the stepwise model,
aggressive cancers may emerge from low-grade DCIS or
atypical proliferative lesions. There is growing recognition
that the activated (e.g., phosphorylated) state of cellular
protein signaling networks can play a key role in breast
cancer initiation and progression27 and provide information
about the functional state of the cancer cell that cannot be
accurately predicted based on genomic sequencing alone.
Likewise, it has been recently shown that single biomarkers
are not adequate to capture the complex changes in signaling networks activated during breast cancer initiation.28
Ibarra-Drendall et al. are currently testing the hypothesis
that mammary atypia from high-risk women exhibits activation of phospho-protein signaling networks activated in
aggressive triple-negative breast cancer.29 We performed
Reverse-Phase Protein Microarray (RPMA) profiling of cyto-

logic atypia obtained prospectively from unaffected highrisk women in our cohort.30,31 We observed coactivation of
Akt/mTOR/insulin- and IL6/Stat3/vimentin-network signaling in cytologic atypia and found a statistically significant
association between body mass index of 30 kg/m2 and
vimentin expression (p 0.028).30,31 Limited immunohistochemistry studies demonstrated vimentin expression in
atypical mammary epithelial cells,31 which in turn correlates with activation of Stat3 and IL6 levels in patientmatched mammary fluids.32 Both Akt/mTOR and IL6/Stat3
signaling have been implicated in the aggressive biology of
triple-negative breast cancer and epithelial-to-mesenchymal
transition. These studies provide preliminary evidence that
the biologically aggressive atypia may be present before the
development of an invasive triple-negative breast cancer.
Conclusion

Currently, there are many unanswered questions regarding the diagnosis and management of DCIS. Despite the
complexity and heterogeneous nature of DCIS, all women
are treated with a one size fits all scenario that includes
mastectomy versus breast-conserving surgery with radiation therapy. Most recently, Oncotype DX Breast Cancer
Assay for DCIS33 has been developed and is being utilized to
obtain an estimate of 10-year risk of local recurrence, with
the hope of providing guidance to treatment decision. But
the success of this multigene assay in predicting the fate
of DCIS remains to be seen. An essential goal of future
research should focus on the development of accurate riskstratification methods based on a comprehensive understanding of the biologic, pathologic, radiologic, and clinical
factors associated with DCIS.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Abigail W. Hoffman*
Catherine Ibarra-Drendall*
Virginia Espina

Theranostics
Health

Lance Liotta*
Victoria Seewaldt*
*No relevant relationships to disclose.

REFERENCES
1. Burstein HJ, Polyak K, Wong JS, et al. Ductal carcinoma in situ of the
breast. N Engl J Med. 2004;350:1430-1441.
2. Schnitt SJ. Local outcomes in ductal carcinoma in situ based on patient
and tumor characteristics. J Natl Cancer Inst Monogr. 2010;41:158-161.
3. Fisher ER, Dignam J, Tan-Chiu E, et al. Pathologic findings from the
National Surgical Adjuvant Breast Project (NSABP) eight-year update of
Protocol B-17: intraductal carcinoma. Cancer. 1999;86:429-438.
4. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in
women with completely excised ductal carcinoma in situ of the breast in the
UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;
362:95-102.
5. Chen YY, DeVries S, Anderson J, et al. Pathologic and biologic response
to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ. BMC Cancer. 2009;9:285.
6. Brinton LA, Sherman ME, Carreon JD, et al. Recent trends in breast
cancer among younger women in the United States. J Natl Cancer Inst.
2008;100:1643-1648.
7. Evans A, Pinder S, Wilson R, et al. Ductal carcinoma in situ of the

breast: correlation between mammographic and pathologic findings. AJR


Am J Roentgenol. 1994;162:1307-1311.
8. Kuhl CK, Schrading S, Bieling HB, et al. MRI for diagnosis of pure
carcinoma in situ: a prospective observational study. Lancet. 2007;370:485492.
9. Silver SA, Tavassoli FA. Mammary ductal carcinoma in situ with
microinvasion. Cancer. 1998;82:2382-2390.
10. Solin LJ, Fourquet A, Vicini FA, et al. Long-term outcome after
breast-conservation treatment with radiation for mammographically detected
ductal carcinoma in situ of the breast. Cancer. 2005;103:1137-1146.
11. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of
intraductal breast cancer: National Surgical Adjuvant Breast and Bowel
Project B-24 randomised controlled trial. Lancet. 1999;353:1993-2000.
12. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for
ductal carcinoma in situ of the breast. Cancer. 1996;77:2267-2274.
13. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin
width on local control of ductal carcinoma in situ of the breast. N Engl J Med.
1999;340:1455-1461.

43

HOFFMAN ET AL
14. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer:
clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:44294434.
15. Haffty BG, Yang Q, Reiss M, et al. Locoregional relapse and distant
metastasis in conservatively managed triple negative early-stage breast
cancer. J Clin Oncol. 2006;24:5652-5657.
16. Harris LN, Broadwater G, Lin NU, et al. Molecular subtypes of breast
cancer in relation to paclitaxel response and outcomes in women with
metastatic disease: results from CALGB 9342. Breast Cancer Res. 2006;8:R66.
17. Arun B, Vogel KJ, Lopez A, et al. High prevalence of preinvasive lesions
adjacent to BRCA1/2-associated breast cancers. Cancer Prev Res. 2009;2:122127.
18. Bryan BB, Schnitt SJ, Collins LC. Ductal carcinoma in situ with
basal-like phenotype: a possible precursor to invasive basal-like breast
cancer. Mod Pathol. 2006;19:617-621.
19. Meijnen P, Peterse JL, Antonini N, et al. Immunohistochemical categorisation of ductal carcinoma in situ of the breast. Br J Cancer. 2008;98:137142.
20. Espina V, and Liota LA. What is the malignant nature of human ductal
carcinoma in situ? Nature Reviews Cancer. 2011;11:68-75.
21. Polyak K. Molecular markers for the diagnosis and management of
ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;41:210-213.
22. Sgroi DC. Preinvasive breast cancer. Annu Rev Pathol. 2010;5:193-221.
23. Kuerer HM, Albarracin CT, Yang WT, et al. Ductal carcinoma in situ:
state of the science and roadmap to advance the field. J Clin Oncol.
2009;27:279-288.
24. Gauthier ML, Berman HK, Miller C, et al. Abrogated response to

44

cellular stress identifies DCIS associated with subsequent tumor events and
defines basal-like breast tumors. Cancer Cell. 2007;12:479-491.
25. Lu J, Guo H, Treekitkarnmongkol W, et al. 14-3-3zeta cooperates with
ErbB2 to promote ductal carcinoma in situ progression to invasive breast
cancer by inducing epithelial-mesenchymal transition. Cancer Cell. 2009;16:
195-207.
26. Polyak K. Breast cancers: origins and evolution. J Clin Invest. 2007;
117:3155-3163.
27. Sachs K, Perez O, Peer D, et al. Causal protein-signaling networks
derived from multiparameter single-cell data. Science. 2005;308:523-529.
28. Chen FL, Xia W, and Spector NL. Acquired resistance to small molecule
ErbB2 tyrosine kinase inhibitors. Clin Cancer Res. 2008;14:6730-6734.
29. Ibarra-Drendall C, Seewaldt V. Evidence for the Warburg Effect in
Mammary Atypia from High-Risk Women. Oral presentation at: Gordon
Conference in Mammary Gland Biology; June 2011; Newport, RI.
30. Ibarra-Drendall C, Troch MM, Barry WT, et al. Pilot and feasibility
study: prospective proteomic profiling of mammary epithelial cells from
high-risk women provides evidence of activation of pro-survival pathways.
Breast Cancer Res Treat. Epub 2011 Jun 7.
31. Pilie PG, Ibarra-Drendall C, Troch MM, et al. Protein microarray
analysis of mammary epithelial cells from obese and nonobese women at high
risk for breast cancer: Feasibility data. Cancer Epidemiol Biomarkers Prev.
2011 20:476-482.
32. Seewaldt V. Evidence for the Warburg Effect in Mammary Atypia from
High-Risk Women. Oral presentation at: Gordon Conference in Mammary
Gland Biology; June 2011; Newport, RI.
33. Oncotype DX Breast Cancer Assay for DCIS (www.oncotypedx.com).
Accessed March 15, 2012.

D u c t a l C a r c i n o m a I n S i t u , a n d t h e I n fl u e n c e
of the Mode of Detection, Population
Characteristics, and Other Risk Factors
By Beth A. Virnig, PhD, MPH, Shi-Yi Wang, MD, MS, and Todd M. Tuttle, MD, MS

Overview: Approximately 25% of breast cancers in the United


States are diagnosed as ductal carcinoma in situ (DCIS). Rates
of DCIS have risen from 5.8 per 100,000 women in the 1970s to
32.5 per 100,000 in 2004. This pattern is generally attributed to
increased use of screening mammography. DCIS is a major
risk factor for invasive breast cancer, and considerable controversy remains about whether DCIS should be considered a
direct precursor of invasive breast cancer. There is, however,
a general consensus that DCIS represents an intermediate
step between normal breast tissue and invasive breast cancer.
Although the majority of major risk factors are similar for DCIS
and invasive breast cancer, prognostic factors including estrogen and progesterone receptor status and HER2 positivity

UCTAL CARCINOMA in situ (DCIS) is noninvasive


breast cancer that encompasses a wide spectrum of
diseases ranging from low-grade lesions that are not life
threatening to high-grade lesions that may harbor foci of
invasive breast cancer. DCIS is typically classified according
to architectural pattern (solid, cribriform, papillary, and
micropapillary), tumor grade (high, intermediate, and low),
and the presence or absence of comedo necrosis. Approximately 25% of breast cancers diagnosed in the United States
are DCIS.1
The fundamental question underlying treatment and detection of DCIS is whether it should be considered a direct
precursor of invasive breast cancer. There is general consensus that DCIS represents an intermediate step between
normal breast tissue and invasive breast cancer. However,
because of general treatment patterns and the recognition
that even a biopsy may remove an important portion of the
tumor, the natural history of untreated DCIS is unknown
and likely is unknowable. This article provides updates on a
report requested by the National Institutes of Health Office
of Medical Applications of Research, which is available at
www.ahrq.gov//clinic/epcix.htm and summarized by Virnig.2
The report addresses key questions about the incidence of
DCIS and the associated risk factors, the effect of magnetic
resonance imaging (MRI) and sentinel lymph node biopsy
(SLNB) on patient outcomes, and the effect of tumor and
patient characteristics, surgery, radiation, and systemic
treatment on outcomes.
The incidence of DCIS has increased dramatically since
the early 1970s from 5.8 per 100,000 in 1975 to 32.5 per
100,000 in 2004. Yet, the rate of DCIS is considerably less
than the invasive breast cancer incidence, estimated to be
124.3 per 100,000 in 2004.1 The incidence of the most
aggressive subtype of DCIS comedo has not increased as
rapidly as the less aggressive noncomedo form. It is not clear
whether these patterns reflect screening picking up more
noncomedo tumors or pathologists using the comedo classification less often.
The increased risk of invasive breast cancer associated
with hormone replacement therapy (HRT) with estrogen
plus progestin is well established. The reported association
between HRT and DCIS is inconsistent across studies.3-5

are less well studied but look to have similar value in both
cases. The use of postdiagnostic MRI, sentinel lymph node
biopsy, surgery, radiation, and endocrine therapy are all
evolving as evidence from randomized and observational
studies continues to accumulate. Treatment of DCIS requires
a balance between risk of overtreatment and undertreatment.
Ongoing studies are focusing on whether partial-breast irradiation is as effective as whole-breast irradiation and whether
treatment with endocrine therapies can reduce the likelihood
of either invasive breast cancer or DCIS recurrence. In general, treatment decisions should take into account the likelihood that an apparent case of DCIS could harbor foci of
invasive disease.

The strongest evidence that the increased incidence of


DCIS can be attributed to the use of screening mammography comes from eight population-based trials of mammography screening. Mammographic screening consistently was
more likely to lead to the diagnosis of invasive breast cancer
than of DCISall trials reported that less than 20% of
screen-detected breast cancers were DCIS. There is considerable evidence that the detection of DCIS is greatest at
baseline screening. For example, the breast cancer surveillance consortium reported DCIS incidence of 150 per 1,000
screening mammograms on first screening and incidence of
0.83 per 1,000 for subsequent screening mammograms.6
Although several trials have assessed the value of tamoxifen or raloxifene for preventing DCIS, the trials, in reality,
were designed to assess the value of the agents for preventing invasive breast cancer, with DCIS as a secondary outcome. Two large, controlled trials showed that tamoxifen
had a protective role on the development of DCIS (and
invasive breast cancer), though the magnitude of effects
varied somewhat.7,8 The Study of Tamoxifen and Raloxifene
(STAR) trial found 40% higher incidence of DCIS for women
treated with raloxifene than with tamoxifen. The study also
found both treatments decreased the risk of invasive breast
cancer by half. The women randomly assigned to raloxifene
had 36% fewer uterine cancers and 29% fewer blood clots
than the women assigned to tamoxifen.9
The Continuing Outcomes Relevant to Evista (CORE)/
Multiple Outcomes of Raloxifene Evaluation (MORE) study
found significantly reduced incidence of invasive breast
cancer associated with raloxifene (hazard ratio [HR] 0.41),
but a nonsignificant increase in the incidence of DCIS
among the treated women (HR 1.78).10 The inconsistent
effect of raloxifene and tamoxifen on DCIS and invasive

From the University of Minnesota School of Public Health and University of Minnesota
Medical School, Minneapolis, MN.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Beth A. Virnig, PhD, MPH, University of Minnesota School of
Public Health, 420 Delaware Street SE, MMC 729, Minneapolis, MN 55455; email:
virni001@umn.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

45

VIRNIG, WANG, AND TUTTLE

breast cancer incidence deserves further investigation and


may, ultimately, shed light on the biology of DCIS and
invasive breast cancer and the factors that control invasive
progression.
The use of breast MRI for patients with DCIS is not yet
established. MRI can influence treatment recommendations
for some patients by identifying occult disease not visualized
with mammography. Among patients with DCIS, three
studies found that the sensitivity of detecting multicentric
disease is higher with MRI compared with mammography.11,12 Breast MRI can potentially influence treatment
decisions by providing more accurate information on the size
and extent of the known DCIS. Such findings may determine
the choice of breast-conserving surgery (BCS) compared
with mastectomy or the width of excision margins. Studies
have been mixed when comparing whether MRI overestimates or underestimates tumor size relative to mammography. The potential benefits of MRI include fewer re-excisions
after BCS and decreased local recurrence rates after excision. However, no studies to date have reported that MRI
yields these improved patient outcomes. Breast MRI may
also have potential disadvantages such as increased patient
anxiety, costs, and unnecessary use of breast biopsy; for
example, one study of MRI for women with DCIS reported
that 47.6% of the biopsies stemming from a positive MRI
were negative.13 If MRI leads to overestimation of the extent
and size of DCIS in some patients, it points to MRI use
resulting in more mastectomies and, for BCS, wider excisions and their associated less favorable cosmetic outcomes.
SLNB is recommended for patients with invasive breast
cancer to determine prognosis and to guide adjuvant treatment decisions. The risk of SLN metastasis is higher for
patients with a final diagnosis of DCIS with microinvasion
compared with pure DCIS (9.3% vs. 4.8%).14 In addition,
approximately 15% of patients who are initially diagnosed
with DCIS on core needle biopsy have invasive breast cancer
identified in the excision or mastectomy specimen.15 Thus,
some patients may require axillary lymph node staging
after definitive surgical treatment for presumed DCIS. Although SLNB is feasible for most patients after excision,
it is not feasible after mastectomy.16 Thus, some authors
recommend routine SLNB for women with high-risk DCIS
(palpable mass, comedo necrosis) and for those patients
undergoing mastectomy.17
The 10-year breast cancer mortality rate from DCIS is less

KEY POINTS

46

Most of the risk factors for DCIS and invasive breast


cancer are similar.
Rates of DCIS have risen and are associated with
rising use of mammography.
The value of breast MRI for women diagnosed with
DCIS is not clear.
Sentinel lymph node biopsy is thought to be most
valuable for women with high-risk disease or undergoing mastectomy.
Treatment of DCIS includes surgery, radiation, and
endocrine therapy. Studies of the optimal treatment
are ongoing.

18

than 2%. Therefore, the primary outcomes for DCIS are


ipsilateral and contralateral breast cancer recurrence. Many
of the prognostic factors are shared between DCIS and
invasive cancer. The local and recurrence rates for DCIS are
between 10% and 24% after 10 years. Younger age at
diagnosis is a consistent adverse prognostic factor. Women
older than 40 or 50 years consistently have reduced risk of
DCIS or invasive recurrence than younger women. This increased risk may reflect the observation that DCIS in younger
women is more often symptomatic and more extensive.
Studies of racial differences in DCIS recurrence point to a
somewhat complex story. Studies of single treatments that
only adjust for demographic factors alone,19,20 report that
black women with DCIS are more likely than white women
to die from breast cancer (response rate [RR] 1.35) or
experience an invasive recurrence (RR 1.4). However, the
studies that adjust for a more detailed set of tumor factors
find no difference between racial groups and risk of DCIS or
invasive recurrence (RR 1.12). This suggests that there
may be differences in the tumor characteristics between
black and white women. There also may be systematic
differences in aggressiveness of DCIS treatment by race.
Positive surgical margins are consistently associated with
increased DCIS and invasive breast cancer recurrence, although the magnitude of excess risk varies considerably.21
There is considerable debate regarding whether width of a
negative margin (width of a margin negative for tumor cells)
is associated with a decreased risk of recurrence. In general,
larger tumors were associated with higher rates of local
DCIS and invasive recurrence than smaller tumors.18,20
Although somewhat inconsistently labeled, a higher pathologic or nuclear grade (grade 3) was consistently associated
with a higher probability of local DCIS or invasive recurrence than an intermediate or low grade (grade 2 or 1).
Comedo necrosis, a factor unique to DCIS, is strongly and
consistently associated with poorer outcomes and increased
risk of DCIS or invasive recurrence.20
Few of the important markers of tumor aggressiveness in
invasive breast cancer are well studied in DCIS. Rates of
estrogen receptor (ER) testing for women with DCIS are
rising but still lag behind testing for invasive cancer. However, rates of ER positivity as a percentage of tumors tested
are similar for DCIS and invasive breast cancer with 81% to
85% positivity. ER positivity has been linked with a decreased risk of recurrence in several small studies. DCIS
is rarely tested for HER2 positivity, but, nonetheless, several small studies have linked it to increased risk of recurrence (RR 1.53.7) and reduced time to recurrence.22 The
possibility of treating HER2-positive tumors is being studied
in ongoing trials. Ongoing research is also focusing on
developing genetic markers of DCIS that has more or less
favorable biology.
In randomized trials including NSABP-17 and the European Organization for Research and Treatment of Cancer
(EORTC) randomized phase III trial 10853, whole-breast
radiation therapy (RT) following BCS was associated with
reduced local DCIS or invasive carcinoma recurrence. Although statistically significant, the number of events prevented per 1,000 treated women was less than 10%. Despite
the reduced recurrence, RT had no effect on either breast
cancer mortality or total mortality.23-25 Neither randomized
nor observational studies pointed to compelling evidence
that BCS plus radiation has differing relative effectiveness

DCIS AND INFLUENCE OF RISK FACTORS

in the presence or absence of adverse prognostic factors. This


lack of differential effect can be seen for the most important
prognostic factors, including tumor grade and size and
comedo necrosis.18 The key issue then becomes whether the
absolute benefit of RT for low-risk women is small enough to
justify use of BCS alone.
Although outcomes between mastectomy and BCS or BCS
plus RT were not studied in a randomized fashion, several
observational studies reported that women undergoing mastectomy were less likely than women undergoing BCS or
BCS plus RT to experience local DCIS or invasive recurrence.26,27 We found no study showing a mortality reduction
associated with mastectomy over BCS with or without
radiation.
The literature is still evolving regarding the use of accelerated partial-breast irradiation (APBI) delivered via MammoSite or balloon-based brachytherapy28-30 and whether
it is associated with similar levels of control as whole-breast
irradiation.
The NSABP-24 assessed the value of tamoxifen following
DCIS diagnosis and found tamoxifen was associated with
statistically significant reductions in local recurrence (RR
0.60) and contralateral disease (RR 0.56). However, the
absolute risk reduction in ipsilateral and contralateral disease was small. Ongoing studies such as the NSABP-37 are
examining the comparative effectiveness of tamoxifen and
aromatase inhibitors, and the NSABP B-43 is examining use
of trastuzumab for women with HER2-positive tumors.

DCIS and is part of an active policy discussion related to


invasive breast cancer. There is also an aspect of underdiagnosis that must be considered. In some instances, DCIS
may be underdiagnosed invasive cancer for which the pathology sections simply missed the invasive area. Overall,
the arguments for a close relationship between in situ and
invasive breast cancer can be found in the similarity of risk
factors for both the incidence of the diseases and their
similar responses to treatment.
From a clinical perspective, it seems prudent to approach
DCIS and invasive breast cancer as being related. Given the
rate of sampling error in needle biopsies, presumptive DCIS
should be treated as potential invasive cancer until a more
definitive pathologic sample is available. In clinical settings,
efforts should be made to make full use of markers such as
estrogen and progesterone receptor status, and necrosis to
differentiate women at high risk from those at lower risk of
developing invasive disease. Effort should be undertaken to
evaluate whether HER2 status offers any promise for clinical decision-making. Ultimately, these markers would allow
for focusing aggressive treatment on those who have the
greatest probability of benefit.
Note: Because of space limitations, the reference list is
necessarily incomplete. See the article by Virnig and colleagues2 for a more complete review.

Discussion

Funding: Agency for Healthcare Research and Quality, US


Department of Health and Human Services (contract number
290-02-10064-I). The authors of this report are responsible for
its content. Statements in the report should not be construed as
endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

It is clear that many cases of DCIS either would not


develop into invasive disease or would do so much later in
life, perhaps never becoming clinically relevant. This issue
of overdiagnosed DCIS because of screening is not limited to

ACKNOWLEDGMENTS

Authors Disclosures of Potential Conflicts of Interest

Author
Beth A. Virnig*
Shi-Yi Wang*
Todd M. Tuttle*

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

*No relevant relationships to disclose.

REFERENCES
1. Brinton LA, Sherman ME, Carreon JD, Anderson WF. Recent trends in
breast cancer among younger women in the United States. J Natl Cancer Inst.
2008;100:1643-1648.
2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ
of the breast: A systematic review of incidence, treatment, and outcomes.
J Natl Cancer Inst. 2008;102:170-178.
3. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus
progestin on breast cancer and mammography in healthy postmenopausal
women: The Womens Health Initiative Randomized Trial. JAMA. 2003;289:
3243-3253.
4. Collaborative Group on Hormonal Factors in Breast Cancer. Breast
cancer and hormone replacement therapy: Collaborative reanalysis of data
from 51 epidemiological studies of 52,705 women with breast cancer and
108,411 women without breast cancer. Lancet. 1997;350:1047-1059.
5. Reeves GK, Pirie K, Green J, et al. For the Million Women Study
Collaborators. Comparison of the effects of genetic and environmental risk
factors on in situ and invasive ductal breast cancer. Int J Cancer. Epub ahead
2011 Sept 27.
6. Ernster VL, Ballard-Barbash R, Barlow WE, et al. Detection of ductal
carcinoma in situ in women undergoing screening mammography. J Natl
Cancer Inst. 2002;94:1546-1554.

7. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen


prophylaxis for breast cancer96-month follow-up of the randomized IBIS-I
trial. J Natl Cancer Inst. 2007;99:272-282.
8. Powles TJ, Ashley S, Tidy A, et al. Twenty-year follow-up of the Royal
Marsden randomized, double-blinded tamoxifen breast cancer prevention
trial. J Natl Cancer Inst. 2007;99:283-290.
9. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs
raloxifene on the risk of developing invasive breast cancer and other disease
outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial.
JAMA. 2006;295:2727-2741.
10. Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes
relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic
women in a randomized trial of raloxifene. J Natl Cancer Inst. 2004;96:17511761.
11. Hwang ES, Kinkel K, Esserman LJ, et al. Magnetic resonance imaging
in patients diagnosed with ductal carcinoma-in-situ: Value in the diagnosis of
residual disease, occult invasion, and multicentricity. Ann Surg Oncol.
2003;10:381-388.
12. Menell JH, Morris EA, Dershaw DD, et al. Determination of the
presence and extent of pure ductal carcinoma in situ by mammography and
magnetic resonance imaging. Breast J. 2005;11:382-390.

47

VIRNIG, WANG, AND TUTTLE


13. Allen LR, Lago-Toro CE, Hughes JH, et al. Is there a role for MRI in the
pre-operative assessment of patients with DCIS? Ann Surg Oncol. 2010;17:
2395-2400.
14. Katz A, Gage I, Evans S, et al. Sentinel lymph node positivity of
patients with ductal carcinoma in situ or microinvasive breast cancer. Am J
Surg. 2006;191:761-766.
15. Bruening W, Fontarosa J, Tipton K, et al. Systematic review: Comparative effectiveness of core-needle and open surgical biopsy to diagnose breast
lesions. Ann Intern Med. Epub 2009 Dec 15.
16. Wong SL, Edwards MJ, Chao C, et al. The effect of prior breast biopsy
method and concurrent definitive breast procedure on success and accuracy of
sentinel lymph node biopsy. Ann Surg Oncol. 2002;9:272-277.
17. Schneider C, Trocha S, McKinley B, et al. The use of sentinel lymph
node biopsy in ductal carcinoma in situ. Am Surg. 2010;76:943-946.
18. Fisher ER, Dignam J, Tan-Chiu E, et al. Pathologic findings from the
National Surgical Adjuvant Breast Project (NSABP) eight-year update of
Protocol B-17: intraductal carcinoma. Cancer. 1999;86:429-438.
19. Joslyn SA. Ductal carcinoma in situ: Trends in geographic, temporal,
and demographic patterns of care and survival. Breast J. 2006;12:20-27.
20. Li CI, Malone KE, Saltzman BS, Daling JR. Risk of invasive breast
carcinoma among women diagnosed with ductal carcinoma in situ and lobular
carcinoma in situ, 1988-2001. Cancer. 2006;106:2104-2112.
21. Dick AW, Sorbero MS, Ahrendt GM, et al. Comparative effectiveness of
ductal carcinoma in situ management and the roles of margins and surgeons.
J Natl Cancer Inst. 2011;103:92-104.
22. Holmes P, Lloyd J, Chervoneva I, et al. Prognostic markers and
long-term outcomes in ductal carcinoma in situ of the breast treated with
excision alone. Cancer. 2011;117:3650-3657.
23. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving treatment
with or without radiotherapy in ductal carcinoma-in-situ: Ten-year results of

48

European Organisation for Research and Treatment of Cancer randomized


phase III trial 10853a study by the EORTC Breast Cancer Cooperative
Group and EORTC Radiotherapy Group. J Clin Oncol. 2006;24:3381-3387.
24. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for
local recurrence after postoperative radiotherapy after sector resection for
ductal carcinoma in situ of the breast. J Clin Oncol. 2008;26:1247-1252.
25. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive
ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24
randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103:478-488.
26. Meijnen P, Oldenburg HS, Peterse JL, et al. Clinical outcome after
selective treatment of patients diagnosed with ductal carcinoma in situ of the
breast. Ann Surg Oncol. 2008;15:235-243.
27. Schouten van der Velden AP, van Vugt R, Van Dijck JA,et al. Local
recurrences after different treatment strategies for ductal carcinoma in situ of
the breast: A population-based study in the East Netherlands. Int J Radiat
Oncol Biol Phys. 2007;69:703-710.
28. Jeruss JS, Kuerer HM, Beitsch PD, et al. Update on DCIS outcomes
from the American Society of Breast Surgeons accelerated partial breast
irradiation registry trial. Ann Surg Oncol. 2011;18:65-71.
29. Israel PZ, Vicini F, Robbins AB, et al. Ductal carcinoma in situ of the
breast treated with accelerated partial breast irradiation using balloon-based
brachytherapy. Ann Surg Oncol. 2010;17:2940-2944.
30. Keisch M, Vicini F, Beitsch P, et al. American Society of Breast
Surgeons MammoSite Radiation Therapy System Registry Trial: Ductal
carcinoma-in-situ subset analysis-4-year data in 194 treated lesions. Am J
Surg. 2009;198:505-507.
31. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast
cancer in women with ductal carcinoma in situ: An update of the national
surgical adjuvant breast and bowel project experience. Semin Oncol. 2001;28:
400-418.

KEY QUESTIONS IN THE LOCO-REGIONAL


TREATMENT OF BREAST CANCER
CHAIR
Richard C. Zellars, MD
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
Baltimore, MD
SPEAKERS
Thomas A. Buchholz, MD
University of Texas M. D. Anderson Cancer Center
Houston, TX
Monica Morrow, MD
Memorial Sloan-Kettering Cancer Center
New York, NY

Postmastectomy Radiation and Partial


Breast Irradiation
By Richard C. Zellars, MD

Overview: Between 1997 and 1999, three modern postmastectomy radiation therapy (PMXRT) trials were published.
These trials showed a significant benefit with respect to
local control and survival in women who received adjuvant
radiation after mastectomy. Despite two decades of follow-up,
reanalyses, meta-analyses and vigorous and often acrimonious debate, questions about the benefit of PMXRT in women
with one to three positive lymph nodes (LNs) remain unanswered for many. This persistent debate has limited the use

ETWEEN 1997 and 1999, three randomized prospective trials of postmastectomy radiation therapy
(PMXRT) were published, the Danish Premenopausal and
Postmenopausal trials (82b and 82c, respectively) and the
British Columbia trial.1-3 The Danish trials (19821989),
with approximately 1,400 patients each and the smaller
Canadian trial (1978 1985) with 318 patients randomly
assigned women receiving treatment with mastectomy and
adjuvant systemic therapy to receive or not receive PMXRT.
As seen in the earlier studies, these modern trials showed a
significant difference in locoregional recurrence (LRR) rate
in favor of PMXRT. However, for the first time, all three
trials showed a significant improvement in overall survival
(OS) also in favor of radiation. These trials, in contrast to
their predecessors, benefited from modern standardized radiation therapy techniques, as well as modern chemotherapy.
There was general agreement with the results of the trials
with respect to patients with four or more positive lymph
nodes (LNs). However, the true benefit of PMXRT in patients with one to three positive LNs was called into question. All three trials had LRR rates of 30 to 33% at 10 to 15
years in patients with one to three positive LNs who did not
undergo radiation. This rate is in contrast to a 13% 10-year
LRR rate in similarly staged and treated disease as reported
in retrospective reviews of prospective Eastern Cooperative
Oncology Group (ECOG) and National Surgical Adjuvant
Breast and Bowel Project (NSABP) trials.4,5 Commonly
proposed reasons for the LRR discrepancies center on what
some critics would consider the nonstandard systemic and
local therapy administered in these trials.
The criticisms of systemic therapy concern the use of CMF
(cyclophosphamide, methotrexate, fluorouracil) in two of the
trials, and tamoxifen in the third. One may argue that the
results of these PMXRT trials are not applicable to todays
breastpatient with cancer because 1) CMF is no longer the
most common first-line chemotherapy regimen in breast
cancer and 2) tamoxifen was administered without knowledge of the patients estrogen-(ER) and progesteronereceptor (PR) status and was prescribed for only 1 year as
opposed to todays recommended 5-year course. When one
considers that systemic therapy can influence local control
(e.g., B-06, B-21) the argument that substandard systemic
therapy may affect LRR rate seems wholly reasonable.
With respect to local therapy, some have argued that an
inadequate axillary dissection may be the cause of the high
rate of LRR (30 to 33%) seen in the patients with one to three

50

of PMXRT. A treatment concept certain to be as vigorously


debated as that of PMXRT is that of partial breast irradiation
(PBI). However, unlike PMXRT, the acceptance of PBI, by
community physicians, has been nothing short of meteoric
and represents the first major shift in the local therapy
paradigm in more than 10 years. Herein, information will be
presented that will suggest we are nearing the end of one
debatePMXRT in patients with one to three positive LNs
and beginning anotherappropriateness of PBI.

positive LNs. The median numbers of LNs removed were


seven and 11 in these trials, respectively. In contrast, the
median numbers of LNs removed in the retrospective analyses of ECOG and NSABP trials, both of which reported a
13% LRR rate, were 15 and 16, respectively.4,5 The extent of
axillary surgery has been shown to have a local therapy
benefit.5 With that in mind, some concluded that the
radiation in the modern PMXRT trials compensated for
less-than-ideal surgery, and thus the benefit of radiation is
exaggerated for patients with one to three positive LNs. It is
this belief that prevents many physicians from offering
PMXRT to patients with breast cancer who have one to three
positive LNs.6
Meta-analyses can often provide insight when there are
apparent discrepancies between studies. The Early Breast
Cancer Trialists Cooperative Group (EBCTCG) reviewed
the records of more than 3,000 postmastectomy patients
with breast cancer who had one to three positive LNs and
were randomly assigned to receive or not receive adjuvant
radiation. The majority of the patients received systemic
therapy. In this meta-analysis the authors reported an
absolute reduction in breast cancer mortality and all-cause
mortality with PMXRT of 7.6% (log-rank 2p 0.002) and
5.3% (log-rank 2p 0.05), respectively.7
There is also indirect evidence supporting PMXRT in
patients with one to three positive LNs. In the NCIC trial
MA.20, 1,800 women were randomly assigned after lumpectomy to whole-breast irradiation (WBI) with or without
regional nodal irradiation (RNI).8 The results of this trial
were recently presented at ASCOs 47th Annual Meeting
(June 37, 2011, Chicago, IL). Of those enrolled onto MA.20,
85% had one to three positive LNs. With 5-year median
follow-up, the authors reported an improved locoregional
relapse-free survival (94.5% vs. 96.8%, p 0.02), distant
disease-free survival (87% vs. 92.4%, p 0.002) and OS
(90.7% vs. 92.4%, p 0.07) with the addition of RNI. By
showing that there are substantial benefits with the addition of RNI in women with one to three positive LNs, this

From the Departments of Radiation Oncology and Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Richard C. Zellars, MD, 401 North Broadway, Suite 1440,
Baltimore, MD 21231-2410; email: zellari@jhmi.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

POSTMASTECTOMY RADIATION AND PARTIAL BREAST IRRADIATION

trial indirectly validates the findings of the three modern


PMXRT trials.
It is likely that other factors can aid in predicting LRR
risk after mastectomy. For example, researchers have
shown that the 21-gene recurrence score assay (Oncotype
DX; Genomic Health, Inc., Redwood City, CA), commonly
used to determine the risk of distant recurrence, may also be
predictive of the risk of locoregional recurrence.9 Other
factors reported to be associated with increased locoregional
failure include tumor size, positive margins, extracapsular
extension, lymphovascular invasion, response to neoadjuvant chemotherapy, age, ER/PR status, p53 overexpression,
and breast cancer subtypes.5,8,9 While we await evaluation
of putative biologic, genetic and clinical factors predictive of
LRR such that we can judge a patients need for PMXRT, it
is perhaps prudent to at least seriously consider PMXRT for
women with one to three positive axillary LNs.
PBI

In-breast failures after breast-conserving therapy (defined


here as lumpectomy and WBI) occur in the vicinity of the
original primary tumor approximately 70 to 90% of the time.
This phenomenon gave birth to the concept of PBI. Benefits
of this proposed new treatment paradigm include shorter
overall treatment course, increased efficacy via the larger
biologically effective doses that are possible with PBI, and
decreased toxicity because less tissue is exposed to radiation. PBI can be divided into two general techniques: brachytherapy based (radiation close to the target) and teletherapy
based (external beam). Brachytherapy-based PBI normally
occurs postoperatively and may be delivered by interstitial
(needles) or intracavitary (mammosite, contura, etc.) techniques. Teletherapy-based PBI can be delivered either intraoperatively or postoperatively. Of the three largest
randomized controlled trials comparing various PBI techniques versus standard WBI, only one has been published;
another is closed to accrual but the results have not been

KEY POINTS

Three modern postmastectomy radiation therapy


(PMXRT) trials reported improved overall survival
with adjuvant radiation in patients with one to three
positive lymph nodes.
Meta-analyses support the conclusion of these modern PMXRT trials.
A new trial from the National Cancer Institute of
Canada (NCIC), which reported a survival benefit in
women receiving treatment with whole-breast irradiation (WBI) and regional nodal irradiation when
compared with WBI alone, indirectly supports
PMXRT.
Partial breast irradiation (PBI) has been shown to be
comparable with WBI in a single large randomized
controlled trial using intraoperative PBI.
Although smaller trials and retrospective studies
support PBI, it may be best to await the results of
other large randomized controlled trials evaluating
various PBI techniques.

presented, and a third remains open to accrual. The largest


trial published to date is the TARGIT trial in which more
than 2,000 women were randomly assigned to receive WBI
or intraoperative radiation therapy (IORT). Patients received 20 Gy (photons) to the surface of the lumpectomy
bed.10 Patients enrolled were generally low risk: More than
80% were 50 years of age or older, node negative, ERpositive, and HER2-negative. Interestingly, as a result of
various high-risk features, approximately 14% of the patients randomly assigned to receive PBI also received WBI.
Estimates of ipsilateral breast tumor recurrence rates at 4
years were 1.2% and 1.0% for PBI and WBI, respectively.
Although the results are promising, skepticism has prevented wide acceptance. There are concerns that the
follow-up period is too short, the prescribed dose is too low,
and delivery of IORT is logistically too difficult. Nonetheless,
the TARGIT trial supports the concept of PBI.
The second large randomized controlled trial of PBI is
from Milan. Similar to the TARGIT trial, PBI consists of 20
Gy (electrons) delivered to the lumpectomy bed intraoperatively. The accrual goal of approximately 1,306 women was
reached some time ago. So far, one of the investigators has
stated that the there is no difference in survival between the
two arms at 10 years.11 We eagerly await the results of this
important study.
The largest trial is that of NSABP B-39/Radiation Therapy Oncology Group (RTOG) 0413.12 This trial is unique not
only for its accrual goal of 4,300 women but also because
three separate PBI techniques are permitted. Women randomly assigned to receive PBI may be offered, depending on
the hosting institution, interstitial or intracavitary brachytherapy or postoperative teletherapy. Interestingly, with
more than 4,100 patients enrolled thus far (and on target to
complete accrual in 2012), more than 70% of the patients
receiving treatment with PBI received it via the postoperative teletherapy technique. The trial completed accrual of
low-risk patients, and now remains open to accrue patients
with a higher risk of recurrence (e.g., ER-negative, LNpositive, or age younger than 50 years).
Another potential benefit of PBI is that it could be combined with systemic therapy, thereby not only shortening
the course of radiation but shortening the the overall
treatment course. For example in a small feasibility study,
patients received treatment with PBI (2.7 Gy twice daily
for 15 days) and concurrent dose-dense doxorubicin and
cyclophosphamide.13 The authors reported that systemic
toxicity was minimal, radiation dermatitis was far less than
that seen in standard WBI without concurrent chemotherapy, and cosmetic outcome was good to excellent in more
than 90% of the patients. This small pilot study deserves
validation in larger trials but may hint to a new era of
combined-modality therapy in the management of breast
cancer.
Given the general public interest in PBI, and the fact that
smaller randomized controlled trials and retrospective
studies support its use, the American Society for Therapeutic Radiology and Oncology (ASTRO) published guidelines
defining patient characteristics most appropriate for this
new treatment option. Many practitioners have accepted
these guidelines and use them in daily practice. However, a
recent presentation of a study comparing brachytherapybased PBI versus WBI may have placed a pall over the

51

RICHARD C. ZELLARS

passionate pursuit of PBI. This study, presented at the


34th Annual San Antonio Breast Cancer Symposium (December 6 10, San Antonio, TX), reviewed the Medicare
records of 130,535 patients who received treatment with
brachytherapy-based PBI or standard WBI between 2001
and 2007.14 The authors reported that women receiving
treatment with brachytherapy-based PBI were almost twice
as likely to subsequently require a mastectomy, be hospital-

ized for complications, and acquire a treatment-induced


infection compared with those who received the more standard WBI. One must note that this study is retrospective
and covers a period in which new PBI brachytherapy techniques were just being introduced. Nonetheless, it is perhaps most prudent for practitioners to reserve PBI for the
protocol setting, or to wait for longer-term results from
randomized controlled trials.

Authors Disclosures of Potential Conflicts of Interest

Author
Richard C. Zellars*

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

*No relevant relationships to disclose.

REFERENCES
1. Overgaard M, Hansen PS, Overgaard J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive
adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial.
N Engl J Med. 1997;337:949-955.
2. Overgaard M. Overview of randomized trials in high risk breast cancer
patients treated with adjuvant systemic therapy with or without postmastectomy irradiation. Semin Radiat Oncol. 1999;9:292-299.
3. Ragaz J, Olivotto IA, Spinelli JJ, et al. Locoregional radiation therapy in
patients with high-risk breast cancer receiving adjuvant chemotherapy:
20-year results of the British Columbia randomized trial. J Natl Cancer Inst.
2005;97:116-126.
4. Taghian A, Jeong JH, Mamounas E, et al. Patterns of locoregional
failure in patients with operable breast cancer treated by mastectomy and
adjuvant chemotherapy with or without tamoxifen and without radiotherapy:
results from five National Surgical Adjuvant Breast and Bowel Project
randomized clinical trials. J Clin Oncol. 2004;22:4247-4254.
5. Recht A, Gray R, Davidson NE, et al. Locoregional failure 10 years after
mastectomy and adjuvant chemotherapy with or without tamoxifen without
irradiation: experience of the Eastern Cooperative Oncology Group. J Clin
Oncol. 1999;17:1689-1700.
6. Ceilley E, Jagsi R, Goldberg S, et al. RADIOTHERAPY for invasive
breast cancer in north America and Europe: results of a survey. Int J Radiat
Oncol Biol Phys. 2005;61:365-373.
7. McGale P. The 2006 worldwide overview of the effects of local treatments
for early breast cancer on long-term outcome: meta-analysis of the randomized trials of radiotherapy after mastectomy with axillary clearance. Pre-

52

sented at: 48th Annual Meeting of the American Society of Therapeutic


Radiology and Oncology; November 2006; Philadelphia, PA.
8. Whelan T. NCIC-CTG MA.20: an intergroup trial of regional nodal
irradiation in early breast cancer. J Clin Oncol. 2011;29 (suppl; abstr
LBA1003).
9. Voogd AC, Nielsen M, Peterse JL, et al. Differences in risk factors for
local and distant recurrence after breast-conserving therapy or mastectomy
for stage I and II breast cancer: pooled results of two large European
randomized trials. J Clin Oncol. 2001;19:1688-1697.
10. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative
radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A):
an international, prospective, randomized, noninferiority phase 3 trial. Lancet. 2010;376:91-102.
11. Oncology Times UK. June 2011 Volume 8.
12. Julian T. Early toxicity results with 3-D conformal external beam
therapy from the NSABP B-39/RTOG 0413 Accelerated Partial Breast Irradiation (APBI) Trial. Presented at: 53rd Annual Meeting of the American
Society of Therapeutic Radiology and Oncology; October 2011; Philadelphia,
PA.
13. Zellars RC, Stearns V, Frassica D, et al. Feasibility trial of PBI with
concurrent dose-dense doxorubicin and cyclophosphamide in early-stage
breast cancer. J Clin Oncol 2009;27:2816-2822.
14. Smith GL, Buchholz TA, Giordano SH et al. Partial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared
with whole breast irradiation in older patients. Presented at: 34th Annual San
Antonio Breast Cancer Symposium; December 2011; San Antonio, TX.

The Appropriate Extent of Surgery for


Early-Stage Breast Cancer
By Monica Morrow, MD

Overview: Attitudes regarding the appropriate extent of surgery for breast cancer and the effect of surgery on breast
cancerspecific survival have varied over time. Failure to
maintain local control is associated with decreased survival,
but the extent of surgery necessary for local control has
decreased as other treatment modalities, such as radiotherapy and systemic therapy, have become more widely used.
Both endocrine therapy and chemotherapy considerably re-

ERCEPTIONS OF the role of surgery in contributing to


the cure of breast cancer have varied over time. Until
the mid-1970s, surgery was performed with the intent of
curing breast cancer, and bigger was better. In the 1980s
and 1990s the popularization of the systemic disease
hypothesis by Dr. Bernard Fisher opened the door to smaller
surgical procedures, the widespread use of systemic therapy,
and the thought that surgery was primarily a staging procedure. In 2005 the Early Breast Cancer Trialists Collaborative
Group (EBCTCG) overview analysis1 demonstrated that failure to achieve local control in both node-positive and nodenegative women at 5 years after either lumpectomy or
mastectomy decreased breast cancer specific survival at 15
years, indicating that local therapy does affect survival. This
observation renewed interest in the appropriate extent of
surgery to maximize local control in the index breast and the
axilla, as well as the role of contralateral prophylactic
mastectomy (CPM) in breast cancer management.
Extent of Surgery in the Index Breast: Margins

The selection criteria for breast-conserving surgery (BCS)


developed in the 1980s and in use today are related to the
extent of the tumor burden in the breast and the ability to
safely deliver radiotherapy. Biologic tumor features such as
estrogen receptor (ER), histologic grade, and node status are
not used as selection criteria for lumpectomy compared with
mastectomy.2 The most important determinant of tumor
burden in the breast with a unicentric cancer is margin
status. Although it is clear that patients with positive
margins, defined as tumor cells touching ink, have an
increased risk of local recurrence compared with those with
negative margins;3 evidence that more widely clear margins
further reduce local recurrence is lacking.
In the prospective, randomized trials that established the
safety of BCS, only the National Surgical Adjuvant Breast
and Bowel Project (NSABP) B06 study required a microscopically negative margin, defined as tumor cells not touching
ink.4 After 20 years of follow-up, patients undergoing
lumpectomy and radiation therapy (RT) in this study had a
survival outcome equivalent to those having mastectomy,
and only 14% developed a local recurrence (LR).
Since the time of this study, the rates of LR in NSABP
trials have steadily declined, although the required margin
has not changed.5 This can largely be attributed to the
widespread use of adjuvant systemic therapy, although
improvements in pathologic evaluation and the quality of
mammography have also contributed to this trend. Data
from prospective randomized trials of adjuvant systemic

duce rates of local recurrence in the breast, as well as the


incidence of contralateral breast cancer, and as efficacy in
reducing metastatic disease increases, so does the benefit in
reducing local recurrence. The excellent rates of local control
in the ACOSOG Z11 trial after elimination of axillary dissection
in patients with positive sentinel nodes receiving whole-breast
irradiation and systemic therapy are a model for reducing
surgical morbidity in the era of multimodality therapy.

chemotherapy and endocrine therapy demonstrate reductions in LR rates from 13% to 15% in patients randomized to
no adjuvant therapy compared with 3% to 4% in those
receiving adjuvant therapy.6,7
As the efficacy of systemic therapy improves, LR is further
reduced. In the randomized trials of the addition of trastuzumab to chemotherapy in patients with HER2 overexpressing tumors, the addition of trastuzumab resulted in an
approximately 40% relative reduction in the risk of LR
compared with treatment with chemotherapy alone.8 Rates
of LR less than 5% at 8 10 years are regularly seen in
patients undergoing BCS in more recent time periods.5,9
Despite these favorable outcomes, there appears to be confusion regarding what constitutes an adequate margin of
resection as evidenced by the results of a population-based
survey of 318 surgeons in which only 11% endorsed tumor
not touching ink as an adequate margin, 42% endorsed an
adequate margin of greater than 12 mm, 28% endorsed an
adequate margin of greater than 5 mm, and 19% endorsed
an adequate margin greater than 1 cm.10 A similar lack of
consensus has been documented among radiation oncologists.11 This lack of consensus has made re-excision a
common procedure,12 and a study of 2,206 patients with
invasive breast cancer documented that although 23% of
patients had re-excision, almost half (47.5%) of the reexcisions were performed for margins where tumor was not
touching ink.13 A meta-analysis of 14,571 patients with
1,026 local recurrences found no difference in rates of local
recurrence for any negative margin width greater than
tumor not touching ink after adjusting for factors such as
the use of a boost dose of RT and endocrine therapy.3 Other
strategies, such as magnetic resonance imaging, that are
intended to reduce the subclinical tumor burden (the goal of
more widely clear margins) have also not been shown to
decrease LR.9,14 In addition, there is an increasing body of
evidence indicating that patients at high risk of LR after
BCS are also at high risk of LR after mastectomy.15,16 Two
studies examining LR after BCS and mastectomy for patients with triple-negative breast cancers have found no

From the Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer


Center, New York, NY.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Monica Morrow, MD, Breast Service, Department of Surgery,
Memorial Sloan-Kettering Cancer Center, 300 East 66th St., New York, NY 10065; email:
morrowm@mskcc.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

53

MONICA MORROW
17,18

advantage for mastectomy


in this patient subset at high
risk of distant relapse. In a retrospective study of the relationship of the 21-gene recurrence score (OncotypeDx) to the risk
of LR, the use of appropriate systemic therapy as predicted
by the 21-gene recurrence score, significantly reduced LR
(p 0.0001), and in a multivariate model, type of surgery
(lumpectomy compared with mastectomy) was not significantly
associated with LR after controlling for biologic variables.16
In aggregate, these findings indicate that local control is a
complex interaction between disease burden, tumor biology,
and the effectiveness of systemic therapy. In the current era
where multimodality treatment is routinely employed, there
is little evidence that larger surgical resections improve
patient outcomes.
Axilla

The multidisciplinary nature of breast cancer therapy


today has also affected our approach to the axilla. Axillary
dissection has traditionally been performed for staging and
local control. Its role in contributing to the cure of breast
cancer has been controversial since the NSABP B04 trial
demonstrated no difference in survival in patients treated
with and without axillary dissection in the prechemotherapy
era.19 Sentinel node biopsy is a reliable method of identifying axillary node involvement with a lower morbidity than
axillary dissection,20 and biologic tumor features, rather
than number of axillary lymph nodes involved with tumor,
are increasingly used to select systemic therapy. In patients
undergoing BCS, the tangent field RT, which is a standard
part of treatment, covers some of the axilla,21 and systemic
therapy also contributes to locoregional control.6-8 These
observations resulted in the American College of Surgeons
Group (ACOSOG) Z11 study in which clinically nodenegative women with T1 and T2 breast cancers undergoing
BCS and found to have hematoxylin and eosin-detected
metastasis in 3 sentinel nodes were randomized to completion axillary dissection or no further axillary treatment.22,23 All patients received tangent breast RT and
systemic therapy. After a median follow-up of 6.3 years, the

KEY POINTS

54

Rates of local recurrence after breast-conserving surgery and radiotherapy have decreased over time.
Evidence that lumpectomy margins more widely
clear further reduce local recurrence than tumor not
touching ink is lacking.
Local control can be achieved with removal of the
sentinel nodes and no further axillary treatment for
patients with involvement of one or two sentinel
nodes treated with whole-breast irradiation and systemic therapy.
The incidence of contralateral breast cancer has been
declining since the mid-1980s because of the increased use of adjuvant systemic therapy.
Systemic therapy has a major effect on local control,
offering the opportunity to decrease the extent and
morbidity of surgery as the effectiveness of systemic
therapy increases.

Table 1. Patient Groups for Whom Axillary Dissection Remains


Standard Management of a Positive Sentinel Node

Palpable Node Disease


Locally Advanced (Stage III) Breast Cancer
Treatment with Mastectomy
Treatment with Partial Breast Irradiation
Treatment with Neoadjuvant Therapy
Involvement of 3 Sentinel Nodes with Metastases
Gross Extranodal Tumor Extension in Sentinel Nodes

regional recurrence rate in the sentinel node only arm was


0.9% compared with 0.4% in the axillary dissection arm,
despite the fact that 27.4% of patients treated with axillary
dissection had additional positive nodes removed beyond the
sentinel node.23 No survival differences were seen between
groups,22 and morbidity was significantly lower in the sentinel node-only group.22,23 This study clearly indicates that
axillary dissection can be eliminated for patients meeting
the ACOSOG Z11 eligibility criteria, but does not apply to a
considerable number of women with breast cancer (Table 1).
There have been concerns expressed that because most of
the patients in Z11 were postmenopausal with ER-positive
tumors, these results cannot be extrapolated to younger
women and those with ER-negative tumors. However, large
studies of regional node recurrence do not identify age or ER
status as predictors,24,25 suggesting that they should not be
used to exclude women from this approach. Implementing
the results of Z11 necessitates some changes in practice. For
example, the identification of a single metastatic axillary
node with ultrasound and fine-needle aspiration no longer
changes the operative approach because the sentinel node
still must be surgically removed, and it should be abandoned. Frozen section of the sentinel node also is not necessary or appropriate in these cases because the finding of tumor
in a single node will not lead to dissection, and because
examination of all nodal tissue is necessary to determine the
number of nodes involved and the presence of extranodal
extension. Finally, based on the results of ACOSOG Z10 and
NSABP B32 indicating that micrometastases in the sentinel
node have minimal prognostic impact, the routine use of
immunohistochemistry to look for small tumor deposits can
be abandoned.
Contralateral Breast

The use of contralateral prophylactic mastectomy (CPM)


is increasing,26 with the most notable increases seen in
women less than 50 years of age and those treated in
hospitals managing a higher volume of patients with breast
cancer.27 This is somewhat surprising, considering that the
clinical incidence of contralateral breast cancer has been
declining since 1985 because of the widespread use of
adjuvant therapy.28 This decrease is most evident among
women with ER-positive cancers, where even for those in
their 20s and 30s at initial diagnosis, 10-year rates of
contralateral cancer are 2.5% 4.5%.28 With such a low
incidence rate, it is not surprising that evidence indicating
that CPM improves breast cancer mortality is lacking.29
Evidence suggests that level of anxiety, regardless of the
presence or absence of risk factors for contralateral breast
cancer, is a major predictor of undergoing CPM.30

SURGERY FOR EARLY-STAGE BREAST CANCER


Conclusion

Current risks for LR with lumpectomy to a margin of


tumor not touching ink, and in the axilla after management
of a positive node with sentinel node biopsy alone in patients
undergoing BCS, emphasize the powerful effect of systemic
therapy on local control. As the options for targeted therapy
expand and our ability to tailor the extent of systemic
therapy to an individual patients level of risk improves, not

only does survival improve, but local recurrence decreases as


well. These findings have important implications for the
future of local therapy. More aggressive surgical strategies
are unlikely to improve local outcomes for poor-prognosis
cancers in the absence of improved systemic therapies.
Strategies to reduce the extent of surgery in patient subsets
where systemic therapy is available should be sought to
reduce the morbidity of treatment.

Authors Disclosures of Potential Conflicts of Interest

Author
Monica Morrow*

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

*No relevant relationships to disclose.

REFERENCES
1. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of
differences in the extent of surgery for early breast cancer on local recurrence
and 15-year survival: An overview of the randomised trials. Lancet. 2005;
366(9503):2087-2106.
2. Morrow M, Harris JR. Practice guideline for breast conservation therapy
in the management of invasive breast cancer. J Am Coll Surg. 2007;205:362376.
3. Houssami N, Macaskill P, Marinovich ML, et al. Meta-analysis of the
impact of surgical margins on local recurrence in women with early-stage
invasive breast cancer treated with breast-conserving therapy. Eur J Cancer.
2010;46(18):3219-3232.
4. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a
randomized trial comparing total mastectomy, lumpectomy, and lumpectomy
plus irradiation for the treatment of invasive breast cancer. N Engl J Med.
2002;347(16):1233-1241.
5. Anderson SJ, Wapnir I, Dignam JJ, et al. Prognosis after ipsilateral
breast tumor recurrence and locoregional recurrences in patients treated by
breast-conserving therapy in five National Surgical Adjuvant Breast and
Bowel Project protocols of node-negative breast cancer. J Clin Oncol. 2009;
27(15):2466-2473.
6. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of
tamoxifen therapy for breast cancer patients with negative lymph nodes and
estrogen receptor-positive tumors. J Natl Cancer Inst. 1996;88(21):1529-1542.
7. Fisher B, Dignam J, Mamounas EP, et al. Sequential methotrexate and
fluorouracil for the treatment of node-negative breast cancer patients with
estrogen receptor-negative tumors: Eight-year results from National Surgical
Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings
from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol. 1996;
14(7):1982-1992.
8. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast cancer. N Engl J Med.
2005;353(16):1673-1684.
9. Solin LJ, Orel SG, Hwang WT, et al. Relationship of breast magnetic
resonance imaging to outcome after breast-conservation treatment with
radiation for women with early-stage invasive breast carcinoma or ductal
carcinoma in situ. J Clin Oncol. 2008;26(3):386-391.
10. Azu M, Abrahamse P, Katz SJ, et al. What is an adequate margin for
breast-conserving surgery? Surgeon attitudes and correlates. Ann Surg Oncol. 2010;17(2):558-563.
11. Taghian A, Mohiuddin M, Jagsi R, et al. Current perceptions regarding
surgical margin status after breast-conserving therapy: Results of a survey.
Ann Surg. 2005;241(4):629-639.
12. Morrow M, Jagsi R, Alderman AK, et al. Surgeon recommendations and
receipt of mastectomy for treatment of breast cancer. JAMA. 2009;302(14):
1551-1556.
13. McCahill LE, Single RM, Aiello Bowles EJ, et al. Variability in
Reexcision Following Breast Conservation Surgery. JAMA. 2012;307(5):467475.
14. Hwang N, Schiller DE, Crystal P, et al. Magnetic resonance imaging in
the planning of initial lumpectomy for invasive breast carcinoma: Its effect on
ipsilateral breast tumor recurrence after breast-conservation therapy. Ann
Surg Oncol. 2009;16(11):3000-3009.
15. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in

high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin
Oncol. 2008;26(9):1419-1426.
16. Mamounas EP, Tang G, Fisher B, et al. Association between the
21-gene recurrence score assay and risk of locoregional recurrence in nodenegative, estrogen receptor-positive breast cancer: Results from NSABP B-14
and NSABP B-20. J Clin Oncol. 2010;28(10):1677-1683.
17. Abdulkarim BS, Cuartero J, Hanson J, et al. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer
treated with modified radical mastectomy without adjuvant radiation therapy
compared with breast-conserving therapy. J Clin Oncol. 2011;29(21):28522858.
18. Ho AY, Gupta G, King TA, et al. Favorable Prognosis in Patients with
T1a/bN0 Triple Negative Breast Cancers Treated With Multimodality Therapy. Cancer. 2012 (In Press).
19. Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year follow-up of a
randomized trial comparing radical mastectomy, total mastectomy, and total
mastectomy followed by irradiation. N Engl J Med. 2002;347(8):567-575.
20. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of
sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: Results from the
NSABP B-32 randomised phase III trial. Lancet Oncol. 2007;8(10):881-888.
21. Reznik J, Cicchetti MG, Degaspe B, Fitzgerald TJ. Analysis of axillary
coverage during tangential radiation therapy to the breast. Int J Radiat
Oncol Biol Phys. 2005;61(1):163-168.
22. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no
axillary dissection in women with invasive breast cancer and sentinel node
metastasis: A randomized clinical trial. JAMA. 2011;305(6):569-575.
23. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after
sentinel lymph node dissection with or without axillary dissection in patients
with sentinel lymph node metastases: The American College of Surgeons
Oncology Group Z0011 randomized trial. Ann Surg. 2010;252(3):426-432;
discussion 32-33.
24. Grills IS, Kestin LL, Goldstein N, et al. Risk factors for regional nodal
failure after breast-conserving therapy: Regional nodal irradiation reduces
rate of axillary failure in patients with four or more positive lymph nodes. Int
J Radiat Oncol Biol Phys. 2003;56(3):658-670.
25. Yates L, Kirby A, Crichton S, et al. Risk Factors for Regional Nodal
Relapse in Breast Cancer Patients with One to Three Positive Axillary Nodes.
Int J Radiat Oncol Biol Phys (In Press). 2011.
26. Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of
contralateral prophylactic mastectomy for breast cancer patients: A trend
toward more aggressive surgical treatment. J Clin Oncol. 2007;25(33):52035209.
27. Yao K, Stewart AK, Winchester DJ, Winchester DP. Trends in contralateral prophylactic mastectomy for unilateral cancer: A report from the National
Cancer Data Base, 1998-2007. Ann Surg Oncol. 2010;17(10):2554-2562.
28. Nichols HB, Berrington de Gonzalez A, Lacey JV, Jr., et al. Declining
incidence of contralateral breast cancer in the United States from 1975 to
2006. J Clin Oncol. 2011;29(12):1564-1569.
29. Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for the
prevention of breast cancer. Cochrane Database Syst Rev. (Online). 2010(11):
CD002748.
30. Hawley ST, Jagsi R, Morrow M, Katz SJ. Correlates of contralateral
prophylactic mastectomy in a population-based sample. J Clin Oncol. 2011;29
(Abstract 6010).

55

How Does Biology Affect Local


Therapy Decisions?
By Thomas A. Buchholz, MD

Overview: Breast cancer represents a biologically diverse


set of diseases. Previous data suggest that the estrogen/
progesterone receptor (ER/PR) status and HER2/neu status
are important determinants of prognosis and response to
various systemic treatments. Recent data also suggest that
these receptors correlate with outcomes of local-regional
therapies. Specifically, patients with ER-positive HER2/neunegative disease have an excellent outcome with radiation

ENOMIC AND molecular analyses of breast cancer


have elucidated that breast cancer represents a biologically diverse group of diseases. Studies indicate that molecular subtypes of breast cancer differ with respect to tumor
biology, prognosis and response to hormone therapy, targeted therapy, and chemotherapy. In part, these subtypes
are driven by differences in ER signaling and HER2/neu
status. While breast cancer biology has had a major role in
determining systemic treatment approaches, it is less clear
how biologic markers of disease should affect surgery and
radiation decisions. Fewer data exist correlating breast
cancer biology and local-regional treatment outcome compared with the available data correlating molecular markers
with response to systemic treatments, overall recurrence,
distant metastases, and death. This article will highlight
some of the emerging data that suggest biology plays an
important role in local treatment outcome of breast cancer.

Breast Conservation

The local-regional treatment outcomes after breastconservation surgery and whole-breast radiation are excellent. Improvements in imaging techniques, increased
attention to surgical margins, and increased use of systemic
therapy have helped reduce recurrence rates to very low
levels. For example, our institutional experience of BCT
(lumpectomy plus whole-breast radiation) for 974 patients
treated between 1973 and 1993 noted a 5-year risk of
in-breast recurrence of 5.7%. This compared with a 5-year
recurrence risk of only 1.3% noted in the 381 patients
treated between 1994 and 1996.1
Despite these overall excellent outcomes, recent data have
demonstrated that some subtypes of breast cancer have
higher local recurrence rates. For example, investigators
from the Harvard Radiation Oncology program analyzed a
cohort of 1,223 patients treated with BCT and noted 5-year
breast recurrence rates of 4.4% for patients with triplenegative disease, 9% for those with HER2-positive disease
(predated trastuzumab), and only 1% for patients with
ER-positive disease.2 These data are similar to a report
from University of Texas M. D. Anderson Cancer Center
(MDACC) that analyzed 911 patients treated with BCT for
primaries under 1 cm and negative lymph nodes and found
8-year breast recurrence rates of 18% in HER2/neu-positive
disease (predated trastuzumab), 11% for those with ERnegative disease, and only 4% for those with ER-positive
disease.3 Finally, an elegant study from British Columbia
that investigated more than 1,400 patients with BCT reported a higher 10-year local-regional recurrence rate in

56

treatments, either given as a component of breast-conservative


therapy (BCT) or for those with more advanced disease, when
given after mastectomy. For patients with triple-negative
disease, data suggest that the proportional benefits offered
from radiation in reducing local-regional recurrences may be
less. This article will highlight some of these data and discuss
strategies for new local-regional research avenues that are
based on breast cancer biologic subtype.

patients with HER2/neu-enriched (21%) and basal-like (16%)


cancers compared with the much more common luminal A
subtype (8%).4
Some groups have analyzed local recurrence after BCT
using more sophisticated genomic signatures. For example,
a cDNA microarray-based wound signature successfully
classified patients into two groups with either high or low
risk of local-regional recurrence.5 In a different study, investigators from the National Surgical Adjuvant Breast and
Bowel Project (NSABP) analyzed the 21-gene profile (Oncotype DX) in more than 1,500 patients with node-negative
ER-positive disease and reported that patients with a higher
gene profile score had a higher risk of local recurrence.6
It remains a question how data such as these should affect
local-regional treatment decisions. The majority of patients
treated with BCT have ER-positive or luminal A type
tumors and these data collectively indicate very low rates of
breast recurrence. Accordingly, the focus of future studies
in this population should be aimed at minimizing the cost,
inconvenience, and toxicity of such treatments. For patients
with higher-risk biologic features, improvements in systemic
treatments may help mitigate risks. For example, the
NSABP study of oncotype noted only an 8% 10-year risk for
patients with high recurrence scores who received chemotherapy and tamoxifen compared with a 16% risk for those
who received tamoxifen alone.6 Systemic treatments also
likely overcome some of the adverse effects of HER2/neu
overexpression. Data from the B-31/N9831 trials indicated
the use of adjuvant trastuzumab reduced the risk of localregional recurrence in HER2/neu-positive cancers by 42%
(crude event rates, 47 of 1,679 for no trastuzumab compared
with 27 of 1,672 with trastuzumab).7 In addition, a study
from Memorial Sloan-Kettering Cancer Center noted 3-year
local-regional recurrence rates of 10% for patients with
HER2/neu-positive tumors treated before trastuzumab and
only a 1% rate in those receiving adjuvant trastuzumab.8
The one cohort of patients who remain at higher risk of
recurrence after BCT appears to be those with triplenegative disease. For such patients, it is reasonable to help

From the Division of Radiation Oncology, Department of Radiation Oncology, University


of Texas M. D. Anderson Cancer Center, Houston, TX.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Thomas A. Buchholz, MD, 1515 Holcombe Blvd., Division of
Radiation Oncology, Unit 97, University of Texas M. D. Anderson Cancer Center, Houston,
TX 77030; email: tbuchhol@mdanderson.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

BIOLOGY AND LOCAL THERAPY DECISIONS

mitigate this risk through routine use of chemotherapy,


achievement of negative surgical margin status, and use of
a tumor bed boost. Patients with triple-negative disease
should not be routinely recommended to undergo mastectomy. A recent study from Edmonton, Canada, evaluated
768 patients with T12N0 triple-negative disease and found
better 5-year local-regional recurrence-free survival after
BCT with radiation compared with mastectomy without
radiation (96% compared with 90%, respectively, p 0.027;
hazard ratio, 2.53; p 0.0264).9
Mastectomy with or without Radiation

Biologic subtypes also appear to affect the risk of localregional recurrence after mastectomy. For example, a British Columbia study that combined data from patients
treated with mastectomy alone and patients treated with
mastectomy plus radiation demonstrated that luminal A
subtype independently correlated with a lower risk of localregional recurrence after mastectomy compared with the
other subtypes.4 Interestingly, in an analysis of patients

KEY POINTS

Estrogen receptor (ER)-positive, HER2/neu-negative


breast cancers have very low local-regional recurrence rates after adjuvant radiation treatments.
Triple-negative breast cancer has higher rates of
local-regional recurrence after adjuvant radiation
compared with similar stages of ER-positive disease.
Breast-conservative therapy remains an appropriate
treatment option for patients with early-stage, triplenegative disease.

treated on the Danish postmastectomy radiation trials and


those who were randomly selected to not receive radiation,
the risks of local-regional recurrence for patients with ERpositive disease and those with ER-negative disease was
similar (34% and 31%, respectively).10 However, in the
patients randomly selected to receive postmastectomy radiation, the rates of local-regional recurrence were lower in
the patients with ER-positive disease compared with those
with ER-negative disease (4% and 14%, respectively).10
Similarly, a report of local-regional treatment outcome of
patients treated at MDACC with mastectomy, no radiation,
and adjuvant chemotherapy did not find ER status to independently correlate with local-regional recurrence (15% ER
positive and 12% ER negative).11 However, in a recursive
partition analysis of patients treated with postmastectomy
radiation, ER-negative disease proved to be the most powerful discriminator of local-regional recurrence risk.12
Radiation Resistance and Future Research

Collectively, the data from breast conservation and postmastectomy radiation raise the hypothesis that ER negativity or triple-negative disease may be a more radiationresistant histology than ER-positive disease. These data
were also supported by the most recent update of the Early
Breast Cancer Trialists Group meta-analysis of trials
comparing use with omission of radiation after breastconservation surgery. In these trials, the proportional reduction in the risk of recurrence with radiation was nearly
60% for ER-positive disease treated with tamoxifen, approximately 50% for ER-positive disease without tamoxifen
treatment, and only 35% for ER-negative disease. These
data indicate that additional research is needed to identify
potential molecular targets in triple-negative disease and to
design new therapeutic strategies to enhance radiation
effects in this subtype.

Authors Disclosure of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Thomas A. Buchholz*
*No relevant relationships to disclose.

REFERENCES
1. Cabioglu N, Hunt KK, Buchholz TA, et al. Improving local control with
breast-conserving therapy: A 27-year single-institution experience. Cancer.
2005;104:20-29.
2. Nguyen PL, Taghian AG, Katz MS, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated
with local and distant recurrence after breast-conserving therapy. J Clin
Oncol. 2008;26:2373-2378.
3. Albert JM, Gonzalez-Angulo AM, Guray M, et al. Estrogen/progesterone
receptor negativity and HER2 positivity predict locoregional recurrence in
patients with T1a,bN0 breast cancer. Int J Radiat Oncol Biol Phys. 2010;77:
1296-1302.
4. Voduc KD, Cheang MC, Tyldesley S, et al. Breast cancer subtypes and
the risk of local and regional relapse. J Clin Oncol. 2010;28:1684-1691.
5. Nuyten DS, Kreike B, Hart AA, et al. Predicting a local recurrence after
breast-conserving therapy by gene expression profiling. Breast Cancer Res.
2006;8:R62.
6. Mamounas EP, Tang G, Fisher B, et al. Association between the 21-gene
recurrence score assay and risk of locoregional recurrence in node-negative,
estrogen receptor-positive breast cancer: Results from NSABP B-14 and
NSABP B-20. J Clin Oncol. 2010;28:1677-1683.
7. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant

chemotherapy for operable HER2-positive breast cancer. N Engl J Med.


2005;353:1673-1684.
8. Kiess AP, McArthur HL, Mahoney K, et al. Adjuvant trastuzumab
reduces locoregional recurrence in women who receive breast-conservation
therapy for lymph node-negative, human epidermal growth factor receptor
2-positive breast cancer. Cancer. Epub 2011 Sep 1.
9. Abdulkarim BS, Cuartero J, Hanson J, et al. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer
treated with modified radical mastectomy without adjuvant radiation therapy
compared with breast-conserving therapy. J Clin Oncol. 2011;29:2852-2858.
10. Kyndi M, Sorensen FB, Knudsen H, et al. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in
high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin
Oncol. 2008;26:1419-1426.
11. Katz A, Strom EA, Buchholz TA, et al. Loco-regional recurrence
patterns following mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation. J Clin Oncol. 2000;18:2817-2827.
12. Woodward WA, Strom EA, Tucker SL, et al. Locoregional recurrence
after doxorubicin-based chemotherapy and postmastectomy: Implications for
breast cancer patients with early-stage disease and predictors for recurrence
after postmastectomy radiation. Int J Radiat Oncol Biol Phys. 2003;57:336-344.

57

THE MANY OPTIONS FOR BREAST IMAGING:


WHAT TO USE WHEN
CHAIR
Chris I. Flowers, MD
H. Lee Moffitt Cancer Center and Research Institute
Tampa, FL
SPEAKERS
Maxine Jochelson, MD
Memorial Sloan-Kettering Cancer Center
New York, NY
Karla Kerlikowske, MD
University of California, San Francisco
San Francisco, CA

Clinical and Imaging Surveillance Following


Breast Cancer Diagnosis
By Chris I. Flowers, MBBS, Blaise P. Mooney, MD, and Jennifer S. Drukteinis, MD

Overview: Breast cancer is the most common malignancy


affecting women worldwide. Women have a 1 in 8 lifetime risk
of breast cancer. Breast conservation therapy (BCT) is the
most common method of definitive treatment. Patients who
previously have had to undergo mastectomy may be now
eligible for BCT or a multitude of options for reconstruction,
either immediate or delayed. Surveillance imaging after a
breast cancer diagnosis is important because there is an
increased risk of recurrence developing in patients, and early
detection has been shown to improve survival. There is
currently no consensus on a protocol for imaging the postoperative breast. In patients who have undergone mastectomy,

OCAL RECURRENCE, second ipsilateral breast cancer, and contralateral breast cancer may develop in
women with a personal history of breast cancer.1-3 Lumpectomy followed by whole breast irradiation or BCT is the most
common treatment following a diagnosis of breast cancer.
BCT of clinical stage I and stage II breast cancer has become
a standard of care, with long-term studies showing no
significant difference (p 0.001) in survival rates between
those treated with BCT as opposed to mastectomy.4-10 Early
detection of local recurrence of breast cancer has been shown
to improve long-term survival (HR 2.44 [95% CI] if without
symptoms); therefore, it is important to optimize the use of
clinical and imaging tools for the patient with a history of
breast cancer to diagnose recurrence in its most early stages.
Locoregional recurrence occurs in approximately 5% of
patients at 5 years with a local failure rate of approximately
1% to 2.5% per year. In the immediate postoperative period,
suspicious findings likely represent residual disease, whereas
local recurrence typically occurs 37 years after BCT.11,12
Many factors affect local, regional recurrence and distant
metastasis. These include age at diagnosis, primary tumor
subtype and size, presence of local or regional node disease,
surgical treatment, use and type of radiation therapy, and
use of adjuvant hormonal therapy and chemotherapy.
With the increasing number and variability of oncoplastic
procedures, there are many potential ways in which local
recurrence can appear and be detected on imaging. Mammographic surveillance has shown utility in the detection
of recurrent disease, and in screening the contralateral
breast for early breast cancer. As a result, mammographic
follow-up has become the norm for women who have been
treated for breast cancer. There are, however, significant
variations in the way this has been implemented across the
United States and the world.
Most published data compare mammographic surveillance and physical examination. This combination has been
the standard of care and is most frequently used in discussion of follow-up protocols. In contrast, mammography of the
treated breast for recurrence is seldom performed routinely
for patients who have had a mastectomy and breast reconstruction, with physical examination being the primary tool
to detect recurrence. MRI has been shown to be a valuable
tool in evaluating the reconstructed breast following mastectomy. MRI may also have an increasing role in the

detection of recurrence has mostly been via clinical symptoms and physical exam, often at a later stage. New imaging
modalities, such as magnetic resonance imaging (MRI), ultrasound (US), and positron emission mammography (PEM) are
changing the way we image the postsurgical breast. MRI,
coupled with physical exam and mammography, approaches
100% sensitivity and high specificity for the identification of
recurrent disease. We present a review of major academic
institutions imaging protocols and discuss the advantages
of including MRI in traditional mammographic and clinical
exams.

treatment of patients who have undergone BCT or women


with an originally mammographically occult primary breast
cancer.
When discussing the follow-up examination of a patient
previously treated for breast cancer, we must remember that
the ultimate goal of imaging following a breast cancer
diagnosis is to detect recurrence or new primary cancer
before it is clinically detectable.
Surveillance of the contralateral breast is essentially a
type of screening exam, except that it is targeted to a
high-risk group. As a planned medical intervention, this
is often referred to as surveillance. However, in a patient
with breast conservation, the contralateral breast is being
screened.
There is very little data available to make specific guidelines about surveillance of the patient previously treated for
breast cancer. Therefore, a review of the limited literature
and surveillance protocols at a few selected academic centers
will be presented.
Effectiveness of Mammography

Mammography has been proven to be efficacious as a


screening modality in detecting breast cancer recurrence,
with various papers showing a 50% detection rate of recurrent tumors by mammography and the rest by physical
examination.13-15 Depending on the type of prior surgery,
there may be confounding and distracting features both on
physical examination and on imaging, and the number of
false-positive examinations may be higher than those for the
general population.
Recurrent tumors detected by surveillance mammography
are in general smaller and less invasive than those found
during clinical examination, as demonstrated by Lu and
colleagues.16 This systematic review compared isolated locoregional recurrence or contralateral cancers on survival.
The authors demonstrated better overall survival for mam-

From the H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, and
University of South Florida, Tampa, FL.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Chris Flowers, MBBS, H. Lee Moffitt Cancer Center and
Research Institute, 12902 Magnolia Dr., Tampa, FL 33612; email: chris.flowers@
moffitt.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

59

FLOWERS, MOONEY, AND DRUKTEINIS

mographically detected recurrence, or in asymptomatic patients. They also demonstrated an absolute reduction in
mortality of 17% to 28% in all patients with breast cancers
found early.
A recent review in the United Kingdom for the Health
Technology Assessment by Robertson and colleagues17 also
demonstrated that for screening for local recurrence, surveillance mammography sensitivity ranged from 64% to 67%
and specificity ranged from 85% to 97%. They also found
that for MRI, sensitivity ranged from 86% to 100% and
specificity was 93%. They concluded that mammography is
associated with a high sensitivity and specificity but that
MRI is the most accurate test for detecting local recurrence.
Developing Role of MRI Post-BCT Surveillance

MRI is emerging as a valuable tool in the treatment of


patients with a diagnosis of breast cancer. Conventional
imaging techniques of mammography and US can be difficult to interpret as a result of post-therapeutic changes, and
some centers are including breast MRI in the surveillance of
women who are post-BCT, as surveillance MRI in this
population has been shown to detect malignancy in 12%.18
In the Robertson review,17 MRI was found to be the most
accurate test for detecting ipsilateral tumor recurrence and
contralateral breast cancer in women previously treated for
primary breast cancer. MRI in combination with mammography, US, and clinical examination has been reported to
have a sensitivity as high as 100% and specificity of 89% for
detecting contralateral breast cancer in patients who have
undergone BCT.19 MRI has been shown to be extremely useful
in differentiating scar tissue from tumor recurrence, particularly in showing that nonenhancing areas have a high
negative predictive value for malignancy (88% to 96%).20,21
The use of MRI in the monitoring of the post-BCT breast
is variable and often at the discretion of the ordering
physician or surgeon. The American College of Radiology
practice guidelines state that breast MRI may be useful for
women with a prior history of breast cancer and suspicion of
recurrence when clinical, mammographic, and/or sonographic findings are inconclusive.22 Although women with
a previous diagnosis of breast cancer are at increased risk of
a second diagnosis, an American Cancer Society panel concluded that the increased risk due to a personal history of
breast cancer alone does not justify a recommendation for
overall screening in women post-BCT at the present time.23
Neither National Comprehensive Cancer Network nor

ASCO guidelines consider MRI for surveillance. Changes


occurring after BCT on MRI are similar to those described
on mammography and include architectural distortion,
edema, skin thickening, and occasionally a seroma. These
findings are typical and may stabilize or continue to decrease over time. Enhancement at the lumpectomy site can
be an expected finding depending on the time interval from
BCT. A minimal or small focal area of thin linear enhancement can be seen for up to 18 months, and in some cases
even longer.24,25 On follow-up imaging, enhancement should
demonstrate stability or decrease over time. Fat necrosis is
commonly present in the post-BCT breast and can be a
challenging pitfall, often leading to biopsy. Enhancement is
variable in appearance and kinetic patterns. Biopsy may be
avoided if the MRI signal is similar to that of adjacent fat on
unenhanced images and the lesion shows no internal enhancement. For this reason, nonfat-saturated T1-weighted
sequences should be included on all breast MRI patients.
Mass-like enhancement at the lumpectomy site is always
suspicious and requires biopsy. Similarly, clumped, new, or
increasing areas of nonmass-like enhancement (not associated with fat necrosis) should be considered suspicious.26
Much of the utilization of MRI is physician- or surgeondependent. Many centers stagger MRI and mammograms at
6-month intervals. The reasoning behind this is that the
breast is surveyed in a different modality every 6 months. At
our institution, we prefer that MRI be performed 1 year
following surgery, so that it coincides with the bilateral
mammographic exam. This clarifies indeterminate findings
in the contralateral breast and allows normal postsurgical/
radiation therapy enhancement to decrease. Either approach is acceptable, as there are no specific data-driven
guidelines or a consensus on recommendations for MRI
surveillance intervals in this population. Despite breast
cancer survivors having a high risk of second cancer,
Punglia and Hassett27 recommend against routine MRI,
suggesting selective use by lifetime risk estimates.
Breast Conservation Surveillance

All agree that surveillance of patients who are post-BCT is


necessary. However, there is a lack of consensus on how
frequently and for how long we should provide routine
surveillance after treatment. Subsequently, there are several ways that surveillance can take place and may vary
from institution to institution (Table 1). The majority of
centers surveyed for this article have a common initial
2-year pathway, changing to annual follow-up at year 3.

KEY POINTS

Benign Findings Mimicking Malignancy

There are many benign findings that can mimic malignancy in the postsurgical breast, but essentially they may be
broken down into two categories: a) developing microcalcification, and b) variants of fat necrosis. The aggressive variant of fat necrosis can produce a very hard, spiculate scar.
The matrix may also calcify without the characteristic
dystrophic calcification that is normally associated with it.
This variant often produces a fine, lace-like, rapidly developing calcification, prompting biopsy.
Calcifications may develop in a patient who has been
treated for ductal carcinoma in situ (DCIS), especially if
there was noncalcified disease followed by radiation therapy. There may be an increase in necrosis due to apoptosis of

60

Mammographic surveillance has a high sensitivity


and specificity for recurrent malignancy.
Magnetic resonance imaging is the most sensitive
and accurate tool for evaluation of the postoperative
breast.
Physical examination has an important role in surveillance.
Robust conclusions cannot be made because of the
limited evidence base.
Further research comparing surveillance mammography and newer diagnostic tests is required.

SURVEILLANCE FOLLOWING BREAST CANCER DIAGNOSIS


Table 1. Examples of Breast Conservation Surveillance Protocol by Institution
Institution

Mammography

Physical Examination

M. D. Anderson Cancer Center


University of California, San Francisco
University of California, Los Angelas
Moffitt Cancer Center
Brigham and Womens Hospital and
Dana-Farber Cancer Center

At 6 mo, then annual diagnostic for 5 yr; screening from year 6


Every 6 mo for 5 yr, then annual screening
Every 6 mo for 2 yr, then annual diagnostic
Every 6 mo for 2 yr, then annual diagnostic until yr 10
At 6 mo after completion of radiotherapy, then annual diagnostic

Every 6 mo for 5 yr, then annual


Every 6 mo for 5 yr, then annual
Left to primary care
Every 6 mo for 5 yr, then annual
Every 6 mo for 5 yr

Abbreviations: mo, months; yr, years.

cells in the ducts, with subsequent developing ductal microcalcifications. Some centers advocate a postsurgical, preradiation therapy mammogram of the treated side as a
baseline for just this purpose.
In general, calcifications developing in the first 2 years are
dystrophic and thereafter are more likely as a result of
recurrent disease.
For palpable findings, targeted breast US is the initial
imaging modality of choice. Findings are usually related to
scarring or to a lump caused by development of fat necrosis.
Imaging Appearances of Recurrent Disease

In general, a recurrent cancer shows similar appearances


to the original malignancy, such that a patient with DCIS
will have developing microcalcifications in the treated breast,
and high-grade tumors with DCIS may present as a developing focal asymmetry containing calcifications (Fig. 1).

We recommend that spot magnification views be part of


the initial post-lumpectomy mammogram for patients in
whom calcified DCIS is present, whether invasive or in situ.
This will act as the new baseline exam for comparison.
Developing microcalcifications usually ring alarm bells but
can be commonly seen in patients prone to developing fat
necrosis.
Special types of tumors, such as angiosarcomas, require
more specialized follow-up, which can be a combination of
Doppler US and MRI. The permeative vascular nature of the
recurrent tumor is best seen on MRI (Fig. 2).
Mastectomy without Reconstruction

A patient who has been treated by mastectomy has a


contralateral breast cancer risk of approximately 7%, and so
surveillance of the treated breast is almost entirely covered
by physical examination, with targeted US scan of any
palpable area. The contralateral breast will continue to be
monitored by a regular annual mammographic examination,
with additional imaging being reserved for patients who are
symptomatic or who have a palpable finding.
Male Survivors of Breast Cancer

These are the forgotten survivors of cancer. The surveillance protocol for a male patient should be the same as that
for a woman who has had a mastectomy without reconstruction. Most recurrences in men should be palpable, hence the
importance of a regular physical exam, and possibly breast
awareness on the part of the man. If the patient has had a

Fig. 1. Example of recurrent DCIS with a sharp margin corresponding to the edge of the radiotherapy boost site.
Abbreviation: DCIS, ductal carcinoma in situ.

Fig. 2. MRI image showing enhancing nodule adjacent to seroma/


lumpectomy site. Patient is 5 years post-surgery and 2 months
post-completion of 5 years of tamoxifen.
Abbreviation: MRI, magnetic resonance imaging.

61

FLOWERS, MOONEY, AND DRUKTEINIS

lumpectomy rather than mastectomy, then there is still no


reason to vary the protocol from that of a female patient.
The Reconstructed Breast

The reconstructed breast has not been the subject of


imaging surveillance until more recently. Some advise the
use of mammographic surveillance of transverse rectus
abdominus myocutaneous (TRAM) flap reconstructions,
sometimes called tramograms, which can be performed
just like any other surveillance mammogram.28,29 The findings of recurrent cancer are typical and have been reported
before they become palpable, advancing the stage of diagnosis. Others advocate for only selecting women with a high
risk-of-recurrence score to have tramograms (Fig. 3).
The most sensitive test for the reconstructed breast is
MRI, although it is a relatively expensive test that is not
always covered by health insurance in this situation, even

Fig. 4.
gram.

Developing microcalcifications in scar on routine mammo-

though it is the most effective test. According to Devon,30


MRI is useful in the detection of locally recurrent tumors in
patients who have undergone breast reconstruction with a
TRAM flap. It detects cancer recurrences at an earlier stage
than noncompliant annual surveillance.
Improved access to dedicated breast MRI is making evaluation of the reconstructed breast more affordable and
accessible. Early detection may potentially save health care
dollars by catching recurrence before loco-regional spread,
but there are no data to show that this improves survival.
False-Positive Examinations on Follow-up

Fig. 3. Tramogram image showing TRAM recurrence in the right


XCCL mammogram. Lesion was not initially not detected until the
mammogram finding showed the lesion.
Abbreviations: TRAM, transverse rectus abdominus myocutaneous;
XCCL, exaggerated craniocaudal view.

62

There are frequently false-positive clinical findings after


reconstruction, mainly with palpable lumps. Palpable lesions should be first evaluated with US. The palpable lumps
are generally multiple, appear in the upper outer quadrant
or 6 oclock positions, and are caused by fat necrosis. This is
more common in women with implant reconstruction than

SURVEILLANCE FOLLOWING BREAST CANCER DIAGNOSIS

Fig. 5. Palpable mass near scar; US shows typical features of fat


necrosis.
Abbreviation: US, ultrasound.

TRAM flaps in our practice but may vary according to the


distributions of types of reconstruction in your group. Mammography often demonstrates early dystrophic microcalcifications, which can simulate an aggressive recurrent DCIS
(Fig. 4 and Fig. 5).
Bilateral Mastectomy with Reconstruction

Little is known about the utility of MRI as a diagnostic or


surveillance tool after bilateral mastectomy with reconstruction. The current role of MRI in treating patients who have
had a mastectomy is primarily as a diagnostic tool when
clinical findings need clarification. Most recurrences adjacent to an implant are clinically palpable, and there is little
evidence to support the use of MRI in asymptomatic postmastectomy with reconstruction patients. Patients who
have undergone reconstruction with TRAM or deep inferior
epigastric perforator flaps can be evaluated with MRI;
however, routine surveillance is not common practice, as the
risk of nonpalpable recurrence is extremely low.30 MRI has
been found useful in differentiating benign from malignant
findings in patients with palpable abnormalities or pain
after TRAM reconstruction (Fig. 6).30
Possible Developing Methods for
Recurrence Detection

To detect additional tumors or metastatic disease at an


early stage, advanced imaging techniques, including diagnostic mammographic images, focused breast US, breast

Fig. 6. Vague nodularity on physical exam. US of nodularity


showed no correlation. MRI demonstrates obvious local recurrence
and metastases.
Abbreviations: US, ultrasound; MRI, magnetic resonance imaging.

MRI, and positron emission tomography imaging is often


required. Breast-specific gamma imaging, PEM, and molecular breast imaging may have a problem-solving role, especially in the dense breast or where there are complications
from ruptured silicone implants. Radiologists who have
completed advanced training in breast cancer detection
should interpret these imaging techniques. Imaging should
be coupled with clinical exams by specialty-trained clinicians familiar with signs and symptoms of recurrence and
should occur at set time intervals. The downside of these
newer techniques is the radiation dose from the radioisotopes currently used, although new techniques are focused
on reducing the radiation dose.
Advanced reconstruction and radiation techniques can be
difficult to interpret unless communication between members of the health care team is timely and accurate, and
the radiologist is familiar with expected appearances. To
achieve the goal of recurrence detection in the early stages,
before it is clinically evident, radiologists and clinicians
must be familiar with the behavior of subtypes of breast
cancer and different surgical/medical/oncoplastic approaches to their treatment.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Chris I. Flowers*
Blaise P. Mooney*
Jennifer S. Drukteinis*
*No relevant relationships to disclose.

REFERENCES
1. Voogd AC, van Tienhoven G, Peterse HL, et al. Local recurrence after
breast conservation therapy for early stage breast carcinoma: detection,
treatment, and outcome in 266 patients. Cancer. 1999;85:437-446.
2. Hietanen P, Miettinen M, Makinen J. Survival after first recurrence in
breast cancer. Eur J Cancer Clin Oncol. 1986;22:913-919.

3. Nomura Y, Tsutsui S, Murakami S, et al. Prognostic impact of second


cancer on the survival of early breast cancer patients. Int J Oncol. 1999;14:
1103-1109.
4. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a
randomized trial comparing total mastectomy, lumpectomy, and lumpectomy

63

FLOWERS, MOONEY, AND DRUKTEINIS


plus irradiation for the treatment of invasive breast cancer. N Engl J Med.
2002;347:1233-1241.
5. Fisher B, Jeong JH, Anderson S, et al. Twenty-five-year follow-up of a
randomized trial comparing radical mastectomy, total mastectomy, and total
mastectomy followed by irradiation. N Engl J Med. 2002;347:567-575.
6. Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or
without irradiation in the treatment of breast cancer. N Engl J Med.
1989;320:822-828.
7. Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a
comparison of conservation with mastectomy in the treatment of stage I and
II breast cancer. N Engl J Med. 1995;332:907-911.
8. van Dongen JA, Bartelink H, Fentiman IS, et al. Factors influencing
local relapse and survival and results of salvage treatment after breastconserving therapy in operable breast cancer: EORTC trial 10801, breast
conservation compared with mastectomy in TNM stage I and II breast cancer.
Eur J Cancer. 1992;28A:801-805.
9. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a
randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med. 2002;347:1227-1232.
10. Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breastpreserving surgery in women with localized cancer of the breast. N Engl
J Med. 1993;328:1587-1591.
11. Kurtz JM, Amalric R, Brandone H, et al. Local recurrence after
breast-conserving surgery and radiotherapy. Frequency, time course, and
prognosis. Cancer. 1989;63:1912-1917.
12. Recht A, Silen W, Schnitt SJ, et al. Time-course of local recurrence
following conservative surgery and radiotherapy for early stage breast cancer.
Int J Radiat Oncol Biol Phys. 1988;15:255-261.
13. Fowble B, Solin LJ, Schultz DJ, et al. Breast recurrence following
conservative surgery and radiation: patterns of failure, prognosis, and pathologic findings from mastectomy specimens with implications for treatment.
Int J Radiat Oncol Biol Phys. 1990;19:833-842.
14. Joseph E, Hyacinthe M, Lyman GH, et al. Evaluation of an intensive
strategy for follow-up and surveillance of primary breast cancer. Ann Surg
Oncol. 1998;5:522-528.
15. Orel SG, Troupin RH, Patterson EA, et al. Breast cancer recurrence
after lumpectomy and irradiation: role of mammography in detection. Radiology. 1992;183:201-206.
16. Lu WL, Jansen L, Post WJ, et al. Impact on survival of early detection
of isolated breast recurrences after the primary treatment for breast cancer:
a meta-analysis. Breast Cancer Res Treat. 2009;114:403-412.
17. Robertson C, Ragupathy SK, Boachie C, et al. Surveillance mammography for detecting ipsilateral breast tumour recurrence and metachronous

64

contralateral breast cancer: a systematic review. Eur Radiol. 2011;21:24842491.


18. Brennan S, Liberman L, Dershaw DD, et al. Breast MRI screening of
women with a personal history of breast cancer. AJR Am J Roentgenol.
2010;195:510-516.
19. Viehweg P, Rotter K, Laniado M, et al. MR imaging of the contralateral
breast in patients after breast-conserving therapy. Eur Radiol. 2004;14:402408.
20. Nunes LW, Schnall MD, Orel SG. Update of breast MR imaging
architectural interpretation model. Radiology. 2001;219:484-494.
21. Schnall MD, Blume J, Bluemke DA, et al. Diagnostic architectural and
dynamic features at breast MR imaging: multicenter study. Radiology.
2006;238:42-53.
22. American College of Radiology. ACR Practice Guideline for the Performance of Contrast Enhanced Magnetic Resonance Imaging (MRI) of the
Breast (revision). 2008.
23. Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA
Cancer J Clin. 2007;57:75-89.
24. Heywang-Kobrunner SH, Schlegel A, Beck R, et al. Contrast-enhanced
MRI of the breast after limited surgery and radiation therapy. J Comput
Assist Tomogr. 1993;17:891-900.
25. Li J, Dershaw DD, Lee CH, Joo S, Morris EA. Breast MRI after
conservation therapy: usual findings in routine follow-up examinations. AJR
Am J Roentgenol. 2010;195:799-807.
26. Drukteinis JS, Gombos EC, Raza S, et al. MR imaging assessment of
the breast after breast conservation therapy: distinguishing benign from
malignant lesions. Radiographics. 2012;32:219-234.
27. Punglia RS, Hassett MJ. Using lifetime risk estimates to recommend
magnetic resonance imaging screening for breast cancer survivors. J Clin
Oncol. 2010;28:4108-4110.
28. Eidelman Y, Liebling RW, Buchbinder S, et al. Mammography in the
evaluation of masses in breasts reconstructed with TRAM flaps. Ann Plast
Surg. 1998;41:229-233.
29. Helvie MA, Bailey JE, Roubidoux MA, et al. Mammographic screening
of TRAM flap breast reconstructions for detection of nonpalpable recurrent
cancer. Radiology. 2002;224:211-216.
30. Devon RK, Rosen MA, Mies C, et al. Breast reconstruction with a
transverse rectus abdominis myocutaneous flap: spectrum of normal and
abnormal MR imaging findings. Radiographics. 2004;24:1287-1299.
31. Lee JM, Georgian-Smith D, Gazelle GS, et al. Detecting nonpalpable
recurrent breast cancer: the role of routine mammographic screening of
transverse rectus abdominis myocutaneous flap reconstructions. Radiology.
2008;248:398-405.

Advanced Imaging Techniques for the


Detection of Breast Cancer
By Maxine Jochelson, MD

Overview: Mammography is the only breast imaging examination that has been shown to reduce breast cancer mortality.
Population-based sensitivity is 75% to 80%, but sensitivity in
high-risk women with dense breasts is only in the range of
50%. Breast ultrasound and contrast-enhanced breast magnetic resonance imaging (MRI) have become additional standard modalities used in the diagnosis of breast cancer. In
high-risk women, ultrasound is known to detect approximately
four additional cancers per 1,000 women. MRI is exquisitely
sensitive for the detection of breast cancer. In high-risk
women, it finds an additional four to five cancers per 100
women. However, both ultrasound and MRI are also known to
lead to a large number of additional benign biopsies and

AMMOGRAPHY IS the only breast imaging examination shown to reduce breast cancer mortality, with
a population-based sensitivity of 75% to 80%. Current
screening guidelines for normal-risk women (15% lifetime
risk) recommend starting screening at 40 and continuing
until life expectancy is less than 5 years. Women at higher
risks (intermediate 15% to 20% and high 20%) begin
screening at an earlier age, generally 10 years earlier than
the youngest family member presented with her breast
cancer. Sensitivity of mammography in high-risk women
with dense breasts is only in the range of 50%. Both
ultrasound and MRI are standard examinations used to
improve on mammographic sensitivity; each has its own
flaws. New technologies have been and continue to be
developed to improve the breast cancer detection rate. These
include improvements on the standard techniques (mammography, ultrasound, and MRI) as well as new platforms
for breast imaging developed from body imaging tools, which
include CT and radionuclide breast imaging. This article
will review the most salient newer breast imaging technologies, as well as their potential roles.
Mammography and Mammography-Based Techniques

Digital mammography (FFDM) has almost entirely replaced analog (film-screen) mammography. It has been
shown to be more sensitive in women younger than 50 with
dense breast tissue.1 However, overall sensitivity remains
the same as with analog. The advent of digital mammography has enabled more advanced techniques, which are
added to the digital platform. These include digital breast
tomosynthesis (DBT) and contrast-enhanced spectral mammography (CESM).
Tomosynthesis

In 2011, DBT was called the most exciting new technology


in breast imaging. It is U.S. Food and Drug Administration
(FDA)-approved for performance with a screening digital
mammogram. In 1997, it was stated that DBT allowed the
radiologist to see through the structured noise of normal
breast tissue to improve the detection and characterization of early-stage breast cancer.2 By seeing through this
noise, additional lesions may be detected, and better margin
analysis can be performed. Additionally, the radiologist can

short-term follow-up examinations. Many new breast imaging


tools have improved and are being developed to improve on
our current ability to diagnose early-stage breast cancer.
These can be divided into two groups. The first group is those
that are advances in current techniques, which include digital
breast tomosynthesis and contrast-enhanced mammography
and ultrasound with elastography or microbubbles. The other
group includes new breast imaging platforms such as breast
computed tomography (CT) scanning and radionuclide breast
imaging. These are exciting advances. However, in this era of
cost and radiation containment, it is imperative to look at all of
them objectively to see which will provide clinically relevant
additional information.

determine that a mass was merely a confluence of shadows. Specificity is, therefore, theoretically enhanced. To date
no large prospective trials have been reported regarding the
ability of DBT to screen for cancer as a solo imaging tool.
What has been well documented is its ability to reduce the
need for callbacks.3,4 More recently, DBT images were
compared to routine spot films and found to show equivalent
mass characterization. DBT found seven additional cancers
along with five additional false-positive findings.5 The detection of clustered microcalcifications has been more problematic. Initially, detection was inferior with DBT because
of the very thin (1 mm) slices and the blurring inherent to
tomosynthesis. Spangler and colleagues showed superior
sensitivity (84% vs. 75%) and specificity (71% vs. 64%) with
FFDM, which also detected more cancers with calcifications
but the differences were not significant.6 More recently,
Destounis and colleagues compared the two techniques in
103 patients and found them equivalent.7 Gur and colleagues compared FFDM alone to FFDM combined with
DBT in 125 patients in a retrospective evaluation. There
were both more true-positives and true-negatives with DBT
with an overall 16% performance improvement (p 0.01).8
There are several limitations: 1) Radiation dose is twice
that of FFDM. The thought is that the reduction in callbacks
will reduce the effect of that additional radiation, as spot
films generate a higher dose than DBT. However, most
women who are screened do not get called back for additional views. That being said, the dose does fall within the
MQSA guidelines; 2) DBT only evaluates anatomy, while
many of the other emerging technologies also evaluate
physiology; 3) the interpretation of DBT takes much longer
than that of FFDM, limiting throughput; 4) reimbursement
is limited or absent.
This is a promising technology without a defined role
(Fig. 1). Possibilities include routine screening for everyone,
high-risk screening, and as a diagnostic tool after abnormal

From the Memorial Sloan-Kettering Cancer Center, New York, NY.


Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Maxine Jochelson, MD, Memorial Sloan-Kettering Cancer
Center, 300 E. 66th St., New York, NY 10065; email:jochelsm@mskcc.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

65

MAXINE JOCHELSON

Fig. 1. A clip from the newspaper regarding 3-day as a new


technology for screening.

screening. There are multiple ongoing studies to better


define its strengths and weaknesses and to determine its
ideal role.
Contrast-Enhanced Mammography

Contrast-enhanced breast MRI functions by both defining


anatomic abnormalities and evaluating physiologic changes
related to the development of neovascularity, which are
visualized by their rapid contrast enhancement in cancers.
MRI has proven to be exquisitely sensitive for the detection
of breast cancer, with a sensitivity range from 79% to
98%.9,10 A meta-analysis has shown that MRI also detects
mammographically occult multicentric or multifocal disease
in approximately 16% of patients with known breast cancer.9
Although breast MRI is extremely sensitive, specificity is
more limited, leading to additional workups and benign
biopsies. Additionally, it is expensive, and good quality

KEY POINTS

66

Mammography is the only breast imaging exam


known to reduce breast cancer mortality, but sensitivity is limited particularly in high-risk women with
dense breast tissue.
The digital mammography platform has allowed for
developments such as tomosynthesis and contrastenhanced mammography, which have the potential to
improve sensitivity.
Ultrasound detects additional cancers but at the cost
of many benign biopsies. Potential advances in ultrasound technology include automated whole-breast
scanning, elastography, and microbubbles.
Breast MRI remains the most sensitive examination
for the detection of early-stage breast cancer in a
high-risk screening population.
Radionuclide breast imaging is able to detect breast
cancers independent of breast density, but its high
extramammary radiation dose precludes use in
screening.

breast MRI is not universally available. Patients with pacemakers, certain aneurysm clips or other metallic hardware,
and severe claustrophobia are unable to undergo MRI.
Contrast-enhanced mammography has been developed to
potentially duplicate the capacity of MRI to detect and stage
breast cancer with the use of both anatomy and physiology.
It has been investigated both as an adjunct to mammography and an alternative to MRI.11,12 It uses the same iodinated contrast used for CT in the same doses.
Hardware and software adaptations to digital mammography units that automate a dual energy technique have
been developed. This technology, known as ContrastEnhanced Spectral Mammography (CESM), received FDA
approval in 2011. It provides two images in each view: a
low-energy image, which is below the K-edge of iodine
(33.2keV), and a high-energy image, just above. The two
images are combined and processed so that the background
breast tissue is essentially subtracted out, maximizing
the ability to see areas of enhancement (Fig. 2). There is a
20% additional radiation dose, which is the equivalent of
one extra mammographic view. The examination takes approximately 10 minutes to perform and is only slightly
longer than a mammogram to read. It is well tolerated by
patients.
Dromain and colleagues recently reported a comparison
of contrast-enhanced digital mammography (CEDM) plus
mammography with mammography alone and mammography plus ultrasound in 142 lesions in 120 patients. Sensitivity for CEDM plus mammography was 93% compared with
78% (p 0.001) for mammography alone. Specificity was
unchanged. There was improvement in sensitivity and specificity between CEDM plus mammography and ultrasound
plus mammography, but it was not significantly better.
Additionally, all 23 multifocal lesions were detected.13
Jochelson reported early results of a comparison of CEDM
with breast MRI in 26 patients with known breast cancer.
The two examinations each detected 25 of 26 index tumors
compared with the 22 detected by mammography alone.
MRI was more sensitive than CEDM for the detection of
additional lesions (7 vs. 5), but there were no false-positive
CEDM examinations and seven false-positive MRIs.14 Results on additional patients will be reported later this year.
The early data for CESM are promising but require
confirmation. Screening studies need to be performed. If
larger studies confirm early results, CESM could become
available as a possible poor womans MRI. Larger multiinstitutional trials are ongoing.
Ultrasound

Targeted breast ultrasound is of value in further defining


mammographic and MRI abnormalities as well as evaluating palpable lesions. Ultrasound-guided core biopsies are
an effective means of obtaining histologic diagnosis. Ultrasound is inexpensive, utilizes no radiation, and is widely
available.
The use of ultrasound for screening is more problematic.
Multiple studies, including a large ACRIN trial evaluating
the utility of ultrasound screening in high-risk patients,
have shown that ultrasound will detect additional cancers
in three to four of 1,000 patients (as compared with MRI,
which detects additional cancers in four to five of 100
patients).15,16 In doing so, a large number of additional
lesions are detected leading to short-interval follow-ups or

IMAGING TECHNIQUES FOR BREAST CANCER

Fig. 2. Three images of the left breast


from left to right: normal left mammogram; contrast-enhanced mammography showing extensive enhancement
caused by multifocal breast cancer in
the lower half of the breast; breast
MRI also showing multifocal cancer.
Contrast-enhanced mammogram corresponds well to the MRI.

biopsies with a positive predictive value (PPV) of only 9%


to 10%. Scans are operator-dependent and, therefore, less
reproducible than other modalities. A lesion not detected is
not documented.
To eradicate operator dependence, automated whole
breast ultrasound (AWBU) machines have been developed.
Images are reproducible, and there is 3D capability. Additionally, studies need not be interpreted in real time. Kelly
prospectively compared mammography alone to mammography plus AWBU in 4,419 women and showed an improved
diagnostic yield of 7.2 of 1,000 compared with 3.6 of 1,000
and equivalent PPV of 38%.17 Shin found a 92% detection
rate for lesions larger than 1.2 cm.18
Other advances have been geared toward improving the
sensitivity, specificity, and PPV. Color Doppler detects tumor vascularity. This improves specificity of B-mode ultrasound. Microbubbles have been injected as contrast agents
to improve the performance of Doppler. Although this can
improve sensitivity, specificity has been more problematic
because of its ability to detect smaller and not necessarily
malignant vessels. Liu has shown that there is good histologic correlation when using this contrast agent. Unfortunately, this technique is labor intensive and a technically
difficult procedure to perform. It is unlikely to be useful in
every day practice.
Elastography is a tool that has been developed to improve
the specificity of breast ultrasound. Because most breast
cancers are stiff, there is theoretically less displacement
on compression. There are two types of elastography. There
is more experience with static elastography, in which the
operator compresses the lesion with the special probe and
measures displacement. Unfortunately, this is also operator
dependent, and the results have been disappointing.19 Shear
strain elastography is being studied. The waves are emitted
perpendicular to the transducer, and the speed of their
traversing the tissue is measured with faster speeds occurring in hard tissue. This is less operator dependent, and

early results indicate that this may be the better way to


measure elasticity.
Although these are interesting attempts at improving
screening ultrasound, a great deal more work is necessary.
Radionuclide Breast Imaging

Radionuclide breast imaging evaluates physiology. Sestamibi and 18-FDG detect cancers by different mechanisms of
action. Their ability to detect lesions in the breast is independent of breast density, and with 18-FDG, it is independent of hormone status.
MIBI or Gamma Imaging

In the early 1990s, incidental breast cancers were seen in


patients having sestamibi cardiac scans. At that time, attempts at dedicated breast imaging had limited sensitivity
for small lesions because of the large collimators that were
distant from the breasts. Since then, new technology has
become available, wherein high resolution detectors are
used to mildly compress the breasts, which are positioned as
they are with mammography. There are two different systems: molecular breast imaging (MBI) based on a semiconductor base and breast-specific gamma imaging (BSGI),
which uses a scintillating crystal detector. The results are
similar and will be discussed together. Patients are ideally
done between days 2 and 14 of the menstrual cycle. They
receive 740 1,110 MBq. There is a 1-minute wait. Images
are then acquired for approximately 10 minutes per view.
Two views of each breast are provided. Studies show sensitivities of 91% to 96% overall but somewhat lower for
smaller lesions: 69% for lesions less than 5 mm in one
study20 and 89% for sub-centimeter lesions.21 That study
also had a specificity of only 60%no improvement over
MRI. Detection of additional foci of cancer on staging exams
is 9% to 10%, but in doing so there are a large number of
false positives. For example, Brem reported on 159 patients

67

MAXINE JOCHELSON

in whom there were 46 additional lesions, only 14 of which


were malignant.22
Positron Emission Mammography (PEM)

ing, and assessment of treatment response in patients receiving neoadjuvant chemotherapy.


MRI and Conclusions

The sensitivity of whole-body 18-FDG PET for detection of


a primary breast cancer is lowapproximately 40%. PEM
was developed to better evaluate the breasts. The scanner
again resembles a mammography machine. Twelve images
are generated for each view of the breast, providing a sort of
3D image. PEM is performed like whole-body PET: 4 6
hours of fasting, injection of about 10 mCi of FDG, followed
by a 1-hour rest period. Each view takes 10 minutes. PEM
can also be performed after a whole-body exam without
additional tracer. Multiple studies have shown sensitivities
of more than 90% (including DCIS) even for smaller lesions.23 Specificity is also reported to be more than 90%. In
large trials comparing PEM to MRI in patients with known
breast cancer, MRI was more sensitive on a lesion level in
the ipsilateral breast, more sensitive in the contralateral
breast, but less specific.24 PEM can be performed with
different tracers.
Radionuclide imaging is less expensive than MRI, and the
scanners themselves need less space. The limiting factor for
their use in routine screening is the high dose of radiation,
particularly to extramammary tissues: 50mGy to lower
large intestine for sestamibi and 59mGy to bladder was for
PEM. Vendors of both technologies are reporting promising
preliminary results using half the dose, but even those doses
may be too high to be used in yearly screening. Other
potential uses include preoperative staging, problem solv-

Breast MRI is the gold standard breast imaging test


against which all other new technologies are compared,
particularly in terms of sensitivity, which is more than 95%.
The absence of radiation is a major asset. Initial inability to
diagnose DCIS and low specificity has been limiting. Both
have improved over the years, but the perception of poor
specificity remains. MRI is clearly the ideal way to screen
women at high risk for breast cancer, but is too expensive to
be used in larger populations, and good quality MRI is not
universally available. As newer technologies become available, however, there are many lessons from the initial
experience with breast MRI that should be applied: 1) not all
MRI scanners/scans are equal, and although most of the
technologies discussed here are easier to perform, equipment performance standards should be defined. 2) There is
always a learning curve in the interpretation of new technologies. Minimal training requirements should be set. 3) A
vocabulary with standard terminology to describe abnormalities and what they mean (such as the BIRADS system)
should be developed. 4) In this era of needed cost and
radiation containment, we cannot do every test on every
woman. It is imperative that in addition to determining
sensitivity, specificity, and other factors, we also learn in
which situations these new technologies can do the most
good.

Authors Disclosure of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Maxine Jochelson*
*No relevant relationships to disclose.

REFERENCES
1. Pisano ED, Gatsonis C, Hendrick E, et al. Diagnostic performance of
digital versus film mammography for breast-cancer screening. N Engl J Med.
2005;353:1773-1783.
2. Niklason LT, Christian BT, Niklason LE, et al. Digital tomosynthesis in
breast imaging. Radiology. 1997;205:399-406.
3. Kopans D, Moore R. Digital breast tomosynthesis (DBT) NCI 3000women trial. RSNA. 2009.
4. Poplack SP, Tosteson TD, Kogel CA, Nagy HM. Digital breast tomosynthesis: Initial experience in 98 women with abnormal digital screening
mammography. AJR Am J Roentgenol. 2007;189:616-623.
5. Noroozian M, Hadjiiski L, Rahnama-Moghadam S, et al. Digital breast
tomosynthesis is comparable to mammographic spot views for mass characterization. Radiology. 2012;262:61-68.
6. Spangler ML, Zuley ML, Sumkin JH, et al. Detection and classification
of calcifications on digital breast tomosynthesis and 2D digital mammography: A comparison. AJR Am J Roentgenol. 2011;196:320-324.
7. Destounis S, Murphy P, Seifert P, et al. Clinical experience with digital
breast tomosynthesis in the characterization and visualization of breast
microcalcifications. Amer J Radiol. 2011;196:A1-A3.
8. Gur D, Bandos AI, Rockette HE, et al. Localized detection and classification of abnormalities on FFDM and tomosynthesis examinations rated
under an FROC paradigm. AJR Am J Roentgenol. 2011;196:737-741.
9. Morris EA, Liberman L, Ballon DJ, et al. MRI of occult breast carcinoma
in a high-risk population. AJR Am J Roentgenol. 2003;181:619-626.
10. Berg WA. Rationale for a trial of screening breast ultrasound: American College of Radiology Imaging Network (ACRIN) 6666. AJR Am J
Roentgenol. 2003;180:1225-1228.
11. Dromain C, Thibault F, Adler G. Dual energy contrast-enhanced digital

68

mammography: Preliminary Clinical Results 94th Scientific Assembly of the


RSNA 2007 Annual Meeting Program. 2007;326.
12. Diekmann F, Marx C, Jong R, et al. Diagnostic accuracy of contrastenhanced digital mammography as an adjunct to mammography. ECR. 2007.
13. Dromain C, Thibault F, Muller S, et al. Dual-energy contrast-enhanced
digital mammography: Initial clinical results. Eur Radiol. 2011;21:565-574.
14. Jochelson M, Sung J, Dershaw DD, Heerdt A. Bilateral-Dual Energy
Contrast-enhanced Digital Mammography: Initial Experience. Presented at
96th Annual RSNA Scientific Assembly and Annual Meeting; November 2010;
Chicago, IL.
15. Berg WA, Blume JD, Cormack JB, et al. Combined screening with
ultrasound and mammography vs mammography alone in women at elevated
risk of breast cancer. JAMA. 2008;299:2151-2163.
16. Kolb TM, Lichy J, Newhouse JH. Occult cancer in women with dense
breasts: Detection with screening US-diagnostic yield and tumor characteristics. Radiology. 1998;207:191-199.
17. Kelly KM, Dean J, Comulada WS, Lee SJ. Breast cancer detection
using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol. 2010;20:734-742.
18. Shin HJ, Kim HH, Cha JH, et al. Automated ultrasound of the breast
for diagnosis: Interobserver agreement on lesion detection and characterization. AJR Am J Roentgenol. 2011;197:747-754.
19. Kohr J, Sung, J, Malak, S, et al. Impact of elastography on assessing
the likelihood of malignancy of ultrasound lesions. Poster presented at RSNA
97th Annual Meeting; 2011; Chicago, IL.
20. Hruska CB, Boughey JC, Phillips SW, et al. Scientific Impact Recognition Award: Molecular breast imaging: A review of the Mayo Clinic experience. Am J Surg. 2008;196:470-476.

IMAGING TECHNIQUES FOR BREAST CANCER


21. Brem RF, Floerke AC, Rapelyea JA, et al. Breast-specific gamma
imaging as an adjunct imaging modality for the diagnosis of breast cancer.
Radiology. 2008;247:651-657.
22. Brem RF, Shahan C, Rapleyea JA, et al. Detection of occult foci of
breast cancer using breast-specific gamma imaging in women with one
mammographic or clinically suspicious breast lesion. Acad Radiol. 2010;17:
735-743.

23. Berg WA, Weinberg IN, Narayanan D, et al. High-resolution fluorodeoxyglucose positron emission tomography with compression (positron emission mammography) is highly accurate in depicting primary breast cancer.
Breast J. 2006;12:309-323.
24. Berg WA, Madsen KS, Schilling K, et al. Breast cancer: Comparative
effectiveness of positron emission mammography and MR imaging in presurgical planning for the ipsilateral breast. Radiology. 2011;258:59-72.

69

UPDATE OF THE OXFORD OVERVIEW: NEW


INSIGHTS AND PERSPECTIVES IN THE ERA OF
PERSONALIZED MEDICINE
CHAIR
Harold J. Burstein, MD, PhD
Dana-Farber Cancer Institute
Boston, MA
SPEAKERS
Jonas Bergh, MD, PhD
Karolinska Institutet, University Hospital
Stockholm, Sweden
Kathleen I. Pritchard, MD
Sunnybrook Health Sciences Center
Toronto, ON, Canada

Update of the Oxford Overview: New


Insight and Perspectives in the Era of
Personalized Medicine
By Kathleen I. Pritchard, MD, Jonas Bergh, MD, PhD, and Harold J. Burstein MD, PhD

Overview: There is great appreciation for the heterogeneity


of breast cancers, particularly of hormone-receptor positive
breast cancers. A goal of modern oncology managing such
heterogeneity is to determine how to individualize therapy
based on the specific pathological and biological features of a
given tumor. Two distinctive clinical literatures exist to guide
treatment of hormone-receptor-positive breast cancer. The
Oxford Overview, a seminal meta-analysis effort, has recently
been updated, and suggests that nearly all patients with
ER-positive tumors benefit from adjuvant endocrine therapy.

HE OXFORD Overview of the Early Breast Cancer


Trialists Collaborative Group (EBCTCG) dates back to
1984 when investigators responsible for trials of systemic
adjuvant systemic therapy from all around the globe met
initially, not in Oxford, but at Heathrow Airport to examine
the first meta-analysis of adjuvant systemic therapy trials.
The Overview has always involved collaboration between
the Oxford Secretariat led by Sir Richard Peto and a
consortium of investigators. A series of distinguished past
chairs have included I. Craig Henderson, MD, a prominent
breast cancer medical oncologist initially from Harvard
University and later the University of California San Francisco Helen Diller Family Comprehensive Center, and
William C. Wood, MD, then Chief of Surgery at Emory
University. The EBCTCG is currently chaired by Kathy
Pritchard, MD, of Toronto and Martine Piccart, MD, PhD,
of Brussels. The Steering Committee and Executive of the
EBCTCG both of which include members of the Oxford
Secretariat and clinical investigators (the Trialists) extensively meet, teleconference, and e-mail to bring analyses
and publications to fruition. Between 2005 and 2011,
data collection and analyses have resulted in five major
publications.1-5
The Overview concept dating back to 1984 has not
changed. Collaboration between physicians and biostatisticians based in Oxford and around the world was sought,
built, and sustained. Data were initially collected from all
randomized trials of systemic adjuvant and, later, localregional therapy. The Overview methodology involves the
collection of individual patient data, which includes a wide
variety of items such as dates of randomization and treatment allocation. Patients can be stratified by age, node
status, and other criteria and the log-rank statistics from
each trial are combined to give an overall estimate of the
effect of different treatments either in the whole patient
population or in various stratified subsets.
Outcomes include recurrence, which can be adjusted to
include or exclude contralateral breast cancers and deaths.
Deaths from unknown causes are usually included with
deaths from breast cancer unless specifically stated otherwise. Recurrences can be divided into local and/or distant
with and without contralateral breast cancers. The
EBCTCG has also been interested in collecting information
on deaths from cardiac events, stroke, and other cancers.

In addition, the overview finds that nearly all subsets of


patients with ER-positive tumors also benefit from modern
adjuvant chemotherapy regimens. Meanwhile, retrospective
subset analyses of specific trials or populations suggests that
the benefits of chemotherapy are not so uniform, and in
particular that molecular diagnostics assays can identify patients who do not warrant chemotherapy. This article will
highlight recent data and controversies in personalizing adjuvant breast cancer therapy.

In 1984, the Oxford Overview showed unequivocally for


the first time that tamoxifen improved survival and that
cyclophosphamide, methotrexate, and 5-fluorouracil (CMF)
chemotherapy improved survival. It was also shown that
ovarian ablation, which had been mainly tested in small
underpowered trials with nonsignificant results, did, in and
of itself, improve overall survival, particularly in women
whose tumors had positive estrogen receptors (ER). By 1990,
it became clear that 5 years of tamoxifen was better than 1
or 2 years and that tamoxifen effects were greater in women
with ER-positive cancers. It was first shown in 1990 that
tamoxifen reduced the rate of contralateral breast cancer
and that chemotherapy was effective in both older and
younger women.
By 1995, the huge effect of 5 years of tamoxifen was
clearly demonstrated, and it was obvious from both direct
and indirect comparisons within the Overview that 5 years
of tamoxifen was superior to shorter durations of treatment.
It was seen for the first time that tamoxifen prevented
contralateral breast cancers only in women whose initial
tumors were ER positive. That year, the Overview also
demonstrated that anthracycline-containing regimens, at
least when given in higher dosages, were better than CMFtype chemotherapy.
By 2000, the Overview was able to report on long-term
results, such as 15-year outcomes with chemotherapy, demonstrating sustained benefit in older and in younger women.
There was great controversy at this time suggesting that,
particularly in the CMF trials, the effects of chemotherapy
might be greater in women with ER-negative tumors than in
those with ER-positive tumors, a controversy which continues to this day. In 2000, it was also clearly seen that the
15-year effects of 5 years of tamoxifen were sustained and
of great magnitude. The ATLAS, ATtOM, and a few other
small trials were combined and opened the door to the
suggestion that 5 years of tamoxifen might not be optimal
and that longer tamoxifen might further reduce disease-free

From the Odette Cancer Center, McMaster University, Hamilton, ON, Karolinska
Institutet, Stockholm, Sweden, and the Dana-Farber Cancer Institute, Boston, MA.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Harold J. Burstein, Dana-Farber Cancer Institute, 450
Brookline Avenue, Boston, MA 02215; email: hburstein@partners.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

71

PRITCHARD, BERGH, AND BURSTEIN

Fig. 1. Effects of approximately 5 years


of tamoxifen on the 15-year probabilities
of recurrence and of breast cancer mortality for ER-positive disease.
Abbreviations; ER, estrogen receptor;
RR, recurrence rate; SE, standard error;
(O-E)/V, (observed-expected)/variance.
Reprinted from The Lancet, 378, Early
Breast Cancer Trialists Collaborative
Group, Davies C, Godwin J, et al. Relevance
of breast cancer hormone receptors and
other factors to the efficacy of adjuvant
tamoxifen: Patient-level meta-analysis of
randomised trials, 771784, 2011, with
permission from Elsevier.

recurrence. This remains an important and unresolved


question. It was also clear that ovarian ablation and/or
suppression was effective but not significantly so when
added to chemotherapy, perhaps because of chemotherapyinduced amenorrhea.
In 2005, structural changes were required in the Overview
process. The Trialists formed a new steering committee and
organized subcommittees, many of which continue today to
work very effectively. Many new trials were added and there
were many additional years of follow-up for all major questions. However, data from many major trials, particularly
those of taxanes, were missing in 2005.
In 2006, the Trialists and their subcommittees met and
a series of priorities were set. These included investigations
of the type of anthracycline-based regimen; all taxane trials;
aromatase inhibitors; trastuzumab; and chemoendocrine
therapy, particularly in relation to the ER-positive compared with ER-negative issue in pre- and postmenopausal
women. These meetings led five important publications on
tamoxifen, chemotherapy, and loco-regional therapy.1-5
Nearly 30 years since its inception, the Overview remains
highly relevant and informative. In comparison to individual
trials even huge trials tallying thousands of patients as
has become common in early-stage breast cancerthe Overview has several methodologic virtues that make it a unique
data resource. In particular, the Overview is important for
(1) having all the worldwide data; (2) avoiding publication

KEY POINTS

72

The Oxford Overview suggests benefits for adjuvant


endocrine therapy for all patients with ER positive
breast cancer.
The Oxford Overview suggests benefits for anthracycline- and taxane-based adjuvant chemotherapy
regardless of nodal, ER, or PR status.
Molecular diagnostic assays may identify ER-positive
tumors that may not warrant chemotherapy.
Reconciling the historic overview and newer personalized approaches to early breast cancer is a
compelling clinical challenge.

bias; (3) giving average effect sizes; and (4) clarifying the
timeframes of effects through large sample size and longterm follow-up.
Recent Notable Findings from the Overview
Endocrine Therapy

In the main tamoxifen Overview, more than 54,500


women were studied in trials of tamoxifen compared with
no tamoxifen and more than 45,000 in trials of longer
compared with shorter tamoxifen. The effects of 5 years of
tamoxifen on breast cancer recurrence and mortality are
shown in Fig. 1.
Fundamentally, tamoxifen has long and strong sustained
effects on local recurrence, contralateral breast cancer, and
distant and multiple recurrences. Tamoxifen benefits as
measured by proportional risk reduction are similar regardless of age, stage, grade, or tumor size and with and without
background chemotherapy.
Figure 2 examines the effect of ER and progesterone
receptor (PgR) expression on the benefits with tamoxifen.
Tamoxifen is similarly effective in patients with ER-positive
disease regardless of PgR expression. Patients with ERnegative but PgR-positive tumors do not get benefit from
tamoxifen, nor do patients with ER- and PgR-negative
tumors.
Figure 3 explores the relationship of quantitative levels of
ER with the benefits of tamoxifen. It demonstrates that
higher ER levels are associated with stronger effects of
tamoxifen.
Figure 4 shows the effects of tamoxifen over time. They
are large in years 0 to 1, 2 to 4 and 5 to 10 in terms of
recurrence, but by year 10 and beyond, the effects no longer
increase although the previous gains are not lost. In mortality however, the benefits come out a little later in years 2 to
4 and then years 5 to 9 and they persist into the 10 to
15year follow-up. Thus, there is a carryover effect on
recurrence of 5 years of tamoxifen that goes on to at least 10
years and in mortality that goes on to at least 15 years.
The Overview has been pivotal in demonstrating the
benefits of endocrine therapy for ER-positive breast cancer.
Five years of tamoxifen in ER-positive disease reduces
recurrences by a relative risk of 38%, breast cancer deaths
by approximately 30%, and all deaths by approximately

UPDATE OF THE OXFORD OVERVIEW

Fig. 2. Relevance of measured ER and


PR status to the effects of tamoxifen on the
10-year probably of recurrence.
Abbreviations: ER, estrogen receptor; PR,
progesterone receptor; RR, recurrence rate;
SE, standard error; (O-E)/V, (observedexpected)/variance.
Reprinted from The Lancet, 378, Early
Breast Cancer Trialists Collaborative
Group, Davies C, Godwin J, et al. Relevance
of breast cancer hormone receptors and
other factors to the efficacy of adjuvant
tamoxifen: Patient-level meta-analysis of
randomised trials, 771784, 2011, with
permission from Elsevier.

22%. Contralateral breast cancer is reduced by approximately 40%. Tamoxifen for 5 years benefits all women with
ER-positive disease and benefits those with very high levels
of ER even more. To date, ER expression is the sole deter-

minant of likely benefit from tamoxifen. Endometrial cancer,


however, is increased by 2.3-fold following 5 years of tamoxifen. The rate of endometrial cancer increases as much as
4-fold with 10 years of tamoxifen.

Fig. 3. Relationship of quantitative


levels of ER with benefits of tamoxifen.
Abbreviations: O-E, observed-expected; ER, estrogen receptor; SE, standard
error.
Reprinted from The Lancet, 378, Early
Breast Cancer Trialists Collaborative
Group, Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of
adjuvant tamoxifen: Patient-level metaanalysis of randomised trials, 771784,
2011, with permission from Elsevier.

73

PRITCHARD, BERGH, AND BURSTEIN

Fig. 4. Abbreviations: ER, estrogen receptor; y, year; SE, standard error; (O-E)/V, (observed-expected)/variance.
Reprinted from The Lancet, 378, Early Breast Cancer Trialists Collaborative Group, Davies C, Godwin J, et al. Relevance of breast cancer
hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials, 771784, 2011,
with permission from Elsevier.

Radiation Therapy

Chemotherapy

The Overview has also enabled powerful analyses of the


effects of radiotherapy for early-stage breast cancer. The
proportional effects of radiotherapy after breast-conserving
surgery are substantial for both node-negative and nodepositive disease as shown in Fig. 5. There are substantial
reductions in any recurrence and improvements in breast
cancer survival with postsurgical radiotherapy after breastconserving surgery.
An important question regarding radiotherapy for breast
cancer has been whether all-cause mortality would be enhanced by radiation treatments or whether late (rare) side
effects of radiation might negate treatment benefits in
breast cancerspecific mortality. The Overview, with its
large number of trials and patients, is uniquely positioned to
address this question. Recent data (Fig. 6) indicate that
radiotherapy after breast-conserving surgery reduces breast
cancer recurrence and all-cause mortality among both nodepositive and node-negative disease. A one in four rule
applies for patients with pN0 and pN1 disease in that one
death is prevented for every four recurrences that are
prevented. These benefits are not substantially reduced by
side effects and are durable through 15 years of follow-up.

The recent overview analysis was published in The Lancet


in December 2011 and was based on the analysis of 100,000
randomly selected patients treated in different randomized
studies.5
In short, the overview contained the quinquennial update
of the following:
Nontaxane chemotherapy compared with taxanes in
44,000 patients
Different anthracycline based regimens in 6,000 patients
Anthracyclines in the comparisons compared with CMF
in 18,000 patients
Randomized studies in 32,000 patients comparing no
chemotherapy with polychemotherapy
For this EBCTCG round, the chemotherapy regimens
were, for the first time, grouped based on scheduling and
dose intensity, with particular focus on the CMF- and
anthracycline-based regimens. All outcome analyses were
done based on individual patient tumor data with as long of
follow-up as possible for each study. Individual patient data
were also included from some unpublished randomized stud-

74

UPDATE OF THE OXFORD OVERVIEW

Fig. 5. Effect of radiotherapy after


breast-conserving surgery on 10-year risk
of any (loco-regional or distant) first recurrence on 15-year risk of breast cancer
death in women with pathologically verified node status.
Abbreviations: SE, standard error; RR, recurrence rate; BCS, breast-conserving surgery; RT, radiotherapy.
Reprinted from The Lancet, 378, Early
Breast Cancer Trialists Collaborative
Group, Darby S, McGale P, et al. Effect of
radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year
breast cancer death: Meta-analysis of individual patient data for 10,801 women in
17 randomized trials, 17071716, 2011,
with permission from Elsevier.

ies, thereby reducing the potential risks of publication bias


of studies with a positive outcome, the latter being published earlier. Data were analyzed for recurrence, breast
cancerspecific survival, and overall mortality.

A summary of major findings includes the following results:


The use of taxanes added a statistically significant
reduced risk of breast cancer death by 14% (2.7% absolute

Fig. 6. Effect of radiotherapy after breast-conserving surgery on 10-year risk of any (loco-regional or distant) first recurrence on 15-year
risks of breast cancer death and death from any cause in 10,801 women (67% with pathologically node-negative disease) in 17 trials.3
Abbreviations: SE, standard error; RR, recurrence rate; BCS, breast-conserving surgery; RT, radiotherapy.
Reprinted from The Lancet, 378, Early Breast Cancer Trialists Collaborative Group, Darby S, McGale P, et al. Effect of radiotherapy after
breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women
in 17 randomized trials, 17071716, 2011, with permission from Elsevier.

75

PRITCHARD, BERGH, AND BURSTEIN

Fig. 7. Studies comparing the add-on effect by taxanes, most AC x 4. Demonstration


of the outcome (breast cancer survival and
overall survival) when the comparator arm
contained higher doses of the nontaxane
drugs, mostly anthracyclines.
Abbreviations: AC, doxorubicin/cyclophosphamide; RR, recurrence rate; SE, standard error; (O-E)/V, (observed-expected)/
variance.
Reprinted from The Lancet, 379, Early
Breast Cancer Trialists Collaborative Group,
Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses
of long-term outcome among 100,000
women in 123 randomized trials, 432 444,
2012, with permission from Elsevier.

gain, p 0.0005, 2.2% absolute overall survival gain)


compared with anthracycline-based regimens at 8-years
follow-up. This effect was not statistically significant with
only a 6% relative effect if the anthracycline control arm was
given with a high cumulative anthracycline dose (Fig. 6).
There was no difference in schedule or taxane drug
(paclitaxel or docetaxel).
There was no difference whether endocrine therapy was
given concurrently or in sequence with chemotherapy.
There were no age-related effects by the delivered
chemotherapies, taxane, or anthracycline-based regimens.
Indeed, there was a trend suggesting greater chemotherapy
effect in the age 55 to 69 group than in younger women.
The anthracycline and taxane regimens had similar
antitumoral effects irrespective of patient age, tumor ER
status, whether tamoxifen was given, the combination of ER
by HER2, or the interaction of ER and grade. (Fig. 7).

76

Four cycles of doxorubicin and cyclophosphamide produced a similar result as six courses of standard CMF at 10
years follow-up. Anthracycline regimens with higher doses,
however, reduced the breast cancer mortality by about 4%
at 10 years (a relative improvement of 22%, p 0.004)
compared with CMF. The overall mortality was improved by
the same extent.
In comparison with no chemotherapy, CMF-like regimens and anthracycline-based regimens reduced overall
mortality by 6% at 10 years. No subgroup could be readily
identified that did not benefit from chemotherapy. The
CMF-based studies revealed a less distinct message; the
effect seemed less obvious for the elderly (irrespective of
ER status). This could be because of a combination of factors:
lower compliance in those studies run decades ago; no access
to modern antiemetic regimens; a lack of supportive care
measurement; and less patient motivation to accept toxicity

UPDATE OF THE OXFORD OVERVIEW

Fig. 8. Breast cancer mortality for anthracyclines compared with no adjuvant chemotherapy. Outcomes for different cumulative anthracyclines doses, age groups, node status, ER status. and the combination of ER status and histopathologic grade. All forest plots reveal a very similar
pattern of the same relative magnitude of chemotherapy.
Abbreviations: ER, estrogen receptor; CAF, cyclophosphamide/doxorubicin/fluorouracil; SE, standard error; 4AC/EC, four cycles of doxorubicin/cyclophosphamide or epirubicin/cyclophosphamide; NS, nodal status.
Reprinted from The Lancet, 379, Early Breast Cancer Trialists Collaborative Group, Peto R, Davies C, et al. Comparisons between different
polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomized trials,
432 444, 2012, with permission from Elsevier.

77

PRITCHARD, BERGH, AND BURSTEIN

since an eventual benefit by adjuvant therapies was not


known at the time these studies were done.
The Era of Personalized Breast Cancer Treatment

During the last decade, there have been major attempts


to tailor adjuvant chemotherapy and, to a lesser degree,
the choices for adjuvant endocrine therapy, based on consideration of the unique biologic features of breast cancers. This
effort has grown from recognition of major breast cancer
subsets defined by widely used histopathologic markers
(ER, PgR, and human epidermal growth factor receptor 2
[HER2]) as well as traditional pathology (grade, proliferation)
and molecular diagnostics (intrinsic subsets/OncotypeDX
characteristics).6 These schemes of prognostication and
therapy prediction separate breast cancer into distinct subgroups, with different management, based principally on
tumor histopathology, abetted by detailed insights from
gene expression profiling of tumors.
A number of retrospective analyses from prospective,
randomized trials have suggested that the proportional
benefits of chemotherapy are not, in fact, the same for all
kinds of breast cancer.6-9 In addition, previous studies have
also revealed that chemotherapyin particular CMF-based
therapiesmay have no or little value to patients with high
ERs levels and that the major antitumoral effect for the
premenopausal patients may be because of induction of
amenorrhea.10 These subset analyses have suggested that
the clinical benefit of chemotherapy is most dramatic in
tumors with low or no ER expression (including triplenegative cancers), overexpression of HER2, higher grade,
and higher proliferative scores. Conversely, endocrine therapies are most effective in tumors with higher levels of ER
expression, lower levels of HER2, lower grade, and lower
proliferative scores. Retrospective subset analyses of specific
phase III studies have frequently found that the benefit of
adding taxane-based therapy is least pronounced among
cancers that are ER positive and HER2 negative (the majority of most breast cancers), although these data must now
be seen in the global context of the Overview findings to the
contrary. However, consistent with the findings in single
adjuvant trials, neoadjuvant studies have suggested that
complete pathologic response to chemotherapy is far less
common in tumors that are ER positive. Molecular assays
have emerged that appear to predict the likelihood of chemotherapy benefit, particularly in addition to adjuvant
endocrine therapy. Tumors classified as having a luminal A
intrinsic subtype or a low recurrence score on the OncotypeDX assay, tend to derive minimal benefit from the
addition of chemotherapy to endocrine therapy. It is unclear
whether this is because the relative gain by chemotherapy is
the same, but with an absolute gain that is too small to affect
outcomes among patients with low-risk disease, or whether
there truly is no benefit with chemotherapy. These assays
correlate well if imperfectly with other tumor features such
as grade, proliferation, and quantitative levels of ER and
HER2, fitting with subset hypotheses about the importance
of those pathologic features.
Finally, the advent of anti-HER2 therapy in the adjuvant
setting with trastuzumab has radically altered the natural
history of HER2-positive breast cancers. These tumors,
which traditionally had a less favorable prognosis, now
appear to have as good a prognosis as HER2-negative
tumors. The use of trastuzumab for HER2-positive cancers

78

and the additional use of adjuvant endocrine therapy for


ER-positive cancers has meant that issues of endocrine
therapy or not or chemotherapy or not are less compelling
now than decades ago. The persistent question has become:
are there sufficient data to tailor treatments based on
specific biomarker subsets, or do all patients need the same
treatments?
Can We Reconcile the Overview and the Individual
Treatment Paradigms?

We now confront the paradox of the Overview. In large


measure, the Overview argues for adjuvant chemotherapy
for all women, regardless of tumor biology or stage. This
blanket observation seems at odds with the growing literature that suggests that individual tumorsand thus individual patientsrespond differently to chemotherapy and
endocrine therapy. Can these observations be reconciled?
The reason why the EBCTCG analysis demonstrates relatively similar antitumoral effects in all the different subgroups is so far not understood. There are two particular
strengths of the Overview that should not be forgotten.
First, the Overview is an enormous data repository that
dwarfs in the number of events and the duration of follow-up
of the available data from any given study. This gives the
Overview power to see effects that might be missed in
smaller, retrospective efforts. Of note, the previously published reports on selectivity of the chemotherapy effects are
the result of subgroup analysis on materials with much less
statistical power and in some studies lacking inclusion of all
randomly selected patients and overlapping 95% confidence
intervals for some of the interesting findings.
Secondly, by including data from almost all adjuvant
trials, the Overview minimizes the temptation to focus on
positive, published studies, a bias particularly notable in the
literature on biomarker subsets where negative studies
are all but unpublishable. These are important considerations that should give clinicians pause before dismissing
the Overview findings.
At the same time, there are features of the Overview
design that may overstate the benefits of chemotherapy. The
Overview reports on proportional risk reduction and related
absolute differences in outcome. However, for most patients,
the absolute gains are the driving force for decisions on
chemotherapy. Differences in absolute benefit from chemotherapy clearly vary based on tumor stage and on the
residual degree of risk that remains despite adjuvant endocrine therapy. In addition, the Overview has not been able to
capture adequate information on chemotherapy-induced
amenorrhea so as to tease out the effects of chemotherapy on
ovarian function in women with ER-positive tumors, though
chemotherapy benefit is notably similar regardless of age
and ER status.5
More critically, perhaps, is that differences in treatment
effect may hinge on consideration of multiple variables that
the Overview has not as yet grappled with in detail. It could
simply be because the EBCTCG data just describes mean
effects for all the different subgroups without enabling the
identification of distinct subgroups with claimed different
biology and outcome. The characterization of subsets of
ER-positive cancers, in particular, by molecular assays suggests that simultaneous consideration of ER levels, HER2
expression, and grade/proliferation is important for classifying cancers and determining treatment benefit. As yet, the

UPDATE OF THE OXFORD OVERVIEW

Overview analyses looking at quantitative hormone receptor


levels or considering 2 2 analyses of ER by HER2 or ER
by grade may not be sufficiently multiplexed to figure out
which patients can avoid chemotherapy. A major limitation
with the present Overview is the lack of data on proliferation, gene expression, modern immunohistochemical measurements of receptors, quality controlled pathology
classification, and central marker review. Information on
these variables would, of course, have added value to the
EBCTCG processes and analyses, and some investigators
may claim that these shortcomings may explain some of the
results. Despite these shortcomings, the example of ER
values in the overall EBCTCG suggest very robust results in
relation to adjuvant tamoxifen, further supporting the validity of the EBCTCG findings.4
Additional methodologic details may be relevant. Several
studies that have identified selective benefit for chemotherapy have centrally reanalyzed ER or HER2 data on some
patients, a detailed pathologic step not preformed in the
EBCTCG database.8,10 Similarly, the Overview used a surrogate strategy for high proliferation/higher OncotypeDx
scores by using grade as reported by local laboratories (in
particular, poorly differentiated cancers) that have not been
confirmed. Furthermore, the EBCTCG demonstration of
similar effects of chemotherapies, independent of studied
subgroups, could merely be a reflection of an inherent
common biology of breast cancer with a similar type of

sensitivity to the commonly used cytostatics. However, this


seems counterintuitive based on present extensive knowledge of breast cancer biology in relation to outcome and
therapy strategies, but it has happened before in the era of
science that conclusions made with the best intentions have
required modification.
A possible explanation to the general findings of a similar
relative magnitude in anti breast cancer effects in the
adjuvant setting by taxanes and anthracyclines could be
that all epithelial breast cancers seem to share so far
unidentified gene cassettes associated with a similar sensitivity to chemotherapy. This could, to some extent, be
potentially substantiated by ongoing studies on human
breast cancer stem cells from primary cultures, which indicate a common phenotype for most breast cancer stem cells
in relation to a specific receptor status, despite the fact that
cancers per se have different tumor and receptor characteristics (Johan Hartman, Irma Fredriksson, Jonas Bergh,
verbal communications, March 1, 2012).
At its heart, the task of reconciling the invaluable data
from the ongoing Oxford Overview with the emerging data
from subset studies using novel markers remains the fundamental challenge for adjuvant therapy for breast cancer.
Ongoing collaboration and research will be critical for helping clinicians and patients understand these different but
important clinical datasets and solving the riddle of the
Overview paradox.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Kathleen I. Pritchard

GlaxoSmithKline;
Novartis; Ortho
Biotech; Pfizer;
Roche; Sanofi;
YM BioSciences

AstraZeneca;
GlaxoSmithKline;
Novartis; Pfizer;
Roche; Sanofi

Jonas Bergh

Affibody; Amgen;
AstraZeneca;
Bayer;
GlaxoSmithKline;
i3innovus; Onyx;
Pfizer; Sanofi;
Tapestry
Pharmaceuticals

AstraZeneca;
Pfizer; Roche;
Sanofi

Research
Funding

Expert
Testimony

Other
Remuneration

AstraZeneca;
Novartis; Pfizer;
Sanofi

Merck; Pfizer;
Roche

AstraZeneca;
Roche

Harold J. Burstein*
*No relevant relationships to disclose.

REFERENCES
1. Early Breast Cancer Trialists Collaborative Group. Adjuvant polychemotherapy in estrogen-receptor-poor breast cancer: Meta-analysis of individual patient data from randomized trials. Lancet. 2008;371:29-40.
2. Early Breast Cancer Trialists Collaborative Group. Overview of the
randomized trials of radiotherapy in ductal carcinoma in situ (DCIS) of the
breast. J Natl Cancer Inst Monogr. 2010;41:162-177.
3. Early Breast Cancer Trialists Collaborative Group. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast
cancer death: Meta-analysis of individual patient data for 10,801 women in 17
randomized trials. Lancet. 2011;378:1707-1716.
4. Early Breast Cancer Trialists Collaborative Group. Relevance of breast
cancer hormone receptors and other factors to the efficacy of adjuvant
tamoxifen: Patient-level meta-analysis of randomised trials. Lancet. 2011;
378:771-784.
5. Early Breast Cancer Trialists Collaborative Group. Comparisons between different polychemotherapy regimens for early breast cancer: Metaanalyses of long-term outcome among 100,000 women in 123 randomized
trials. Lancet. 2012;379:432-444.

6. Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypesdealing with the diversity of breast cancer: Highlights of the St. Gallen
International Expert Consensus on the Primary Therapy of Early Breast
Cancer 2011. Ann Oncol. 2011;22:1736-1747.
7. Paik S, Tang G, Shak S, et al. Gene expression and benefit of
chemotherapy in women with node-negative, estrogen receptor-positive
breast cancer. J Clin Oncol. 2006;24:3726-3734.
8. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel
in node-positive breast cancer. N Engl J Med. 2007;357:1496-1506.
9. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status
and outcomes of modern chemotherapy for patients with node-positive breast
cancer. JAMA. 2006;295:1658-1667.
10. Karlsson P, Sun Z, Braun D, et al. Long-term results of International
Breast Cancer Study Group Trial VIII: Adjuvant chemotherapy plus goserelin
compared with either therapy alone for premenopausal patients with nodenegative breast cancer. Ann Oncol. 2011;22:2216-2226.

79

GENE PATENTING: EFFECTS ON BIOTECHNOLOGY


AND ONCOLOGY
CHAIR
Kenneth Offitt, MD, MPH
Memorial Sloan-Kettering Cancer Center
New York, NY
SPEAKERS
Roger D. Klein, MD, JD
Blood Center of Wisconsin
Milwaukee, WI
Hans Sauer, PhD, JD
Biotechnology Industry Organization
Houston, TX

Gene Patents and Personalized Medicine


By Roger D. Klein, MD, JD

Overview: The use of genetic information to design and guide


therapies and to develop novel diagnostic procedures creates
important patent issues. Patents on human gene sequences
have likely helped stimulate the introduction of new biologics;
however, their role and that of patents on genotype-phenotype

HE PRACTICE of personalized medicine has been


described as giving the right drug, to the right patient,
at the right dose, at the right time. Central to the concept of
personalized patient management is knowledge and application of somatic and heritable molecular pathologic (molecular genetic) changes associated with disease susceptibility,
prognosis, therapeutic responsiveness, and susceptibility to
side effects. Although we are far from achieving truly individually designed care for most patients, in oncology the era
of targeted therapies linked to measurable biomarkers has
arrived. Diagnostic tests have long been important in cancer
management, but the high sensitivity, specificity, and direct
relationship to therapy of many nucleic acid-based analyses
adds enormously to their utility.
Because they have been rationally designed to directly
influence biochemical pathways implicated in malignant
progression, targeted cancer therapies potentially offer patients greater benefits with less morbidity than most currently used chemotherapeutic agents. Moreover, by allowing
for prospective selection of individuals most likely to benefit
from a given therapy, molecular pathology-guided approaches benefit patients by rescuing antineoplastic agents,
the efficacy of which is confined to select populations. Without the ability to specifically identify potential responders,
such drugs may mistakenly be abandoned. Finally, personalized medicine encourages cost-effective use of expensive
therapies by restricting administration to patients most
likely to benefit and least likely to suffer harms from them.

Gene Patents and Personalized Medicine

The use of molecular pathologic information to develop


and prescribe therapies raises important new patent issues.
In the United States, patents confer on the patent holder
the right to exclude others from making, using, or selling an
invention for 20 years from the filing date. Under the Patent
Act, patentable inventions must be novel, nonobvious, and
useful.1 Patent claims define an inventions features much
as a deed delineates the boundaries of a plot of land. Patent
applications are submitted to the U.S. Patent and Trademark Office (USPTO) where they are rejected or allowed and
issued. Importantly, [p]rocesses, machines, manufactures,
and compositions of matter can be patented,2 but patents
may not be obtained on products of nature or, under the
natural phenomenon doctrine, laws of nature, natural
phenomena, and abstract ideas.3
Patents have been integral to the discovery and commercialization of drugs and biologics. The product exclusivity
patents confer has been instrumental in ensuring that
manufacturers can raise sufficient capital to identify, test,
obtain regulatory approval for, and bring to market new
therapeutic agents. Absent enforceable patent rights for
new drugs, investment dollars would likely be redeployed to

correlations in diagnostic testing is highly controversial.


Genotype-phenotype associations are at the heart of personalized medicine. The intellectual property rules by which these
biologic relationships are governed have profound implications for the growth of individualized medicine.

areas with a more favorable risk-reward balance. So clear


are the positive incentives patents provide the pharmaceutical industry, even patent system critics have acknowledged them.4 Similarly, the stimulatory effects of patent
protection on pharmaceutical development may extend to
patents granted on human genes, when patented genes are
cloned to produce biologic therapies and vaccines.5
By contrast, patents on relationships between genetic
variants and clinical phenotypes are controversial. Such
patents have been widely criticized and their legitimacy
challenged, whether the patents directly claim genotypephenotype associations or gene sequences themselves.5,6
Because genotype-phenotype associations are the center of
personalized medicine, the intellectual property rules by
which these biologic relationships are governed have profound implications for its growth.
Clinical implementation of molecular pathology procedures is substantially less costly than the discovery, development, and commercialization of in vivo pharmaceuticals.
Manufacturers typically invest hundreds of millions of dollars over a prolonged period of time to bring a drug or
biologic to market. Drug candidates must be extensively
tested in preclinical and clinical studies before U.S. Food
and Drug Administration (FDA) approval. Unlike therapeutics, most molecular pathology procedures are designed,
developed, and validated by individual diagnostic laboratories at limited expense. The wide availability of automated
nucleic acid extractors, thermal cyclers, and DNA sequencing instruments combined with broad licensing of standard
molecular methods and the free accessibility of online gene
sequence databases has rendered development straightforward for many molecular pathology procedures.
Laboratory quality is ensured by the Clinical Laboratory
Improvement Amendments, accreditation by the College of
American Pathologists and other professional societies, and
individual state requirements. Most molecular pathology
services do not undergo FDA clearance or approval, although laboratories serving New York patients submit tests
to the states Clinical Laboratory Evaluation Program for
pre-implementation review. The small minority of molecular
pathology procedures manufactured and sold as kits to
clinical laboratories must be cleared or approved by the
FDA. However, this process is much less burdensome and
orders of magnitude less expensive for in vitro diagnostic
kits than for drugs.

From the Medical College of Wisconsin, Milwaukee, WI.


Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Roger D. Klein, MD, JD, 27500 Cedar Road #808, Beachwood,
OH 44122; email: roger.klein@aya.yale.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

81

ROGER D. KLEIN

The majority of gene-related discoveries have been made


by federally funded academic researchers, for whom patents
are unlikely to have provided primary or even significant
motivation.7 Further, given the relative ease by which
molecular pathology procedures are introduced into practice, patents are unnecessary for the clinical implementation
of molecular pathologic discoveries. Rather, enforcement of
gene patents in the diagnostic realm results in the elimination of already existing services and dissuades laboratories
from adding new ones.8 The resultant elimination of competition is likely to result in higher prices, decreased quality,
reduced innovation, and diminished patient access to these
important medical services. Moreover, loss of academic
providers will adversely affect training and related clinical
research.
Greater interest in companion diagnostic development by
the pharmaceutical industry may alter the preceding dynamics. Control of companion diagnostics could allow drug
manufacturers to ensure assay standardization, enforce
specific quality requirements, and provide additional
sources of revenue. Companion diagnostics could serve as
vehicles by which companies preserve market share for
linked drugs, assuming they avoid patent misuse or antitrust violations. Under this model, gene-related patents may
create incentives for marker discovery and in vitro diagnostic commercialization. However, such patents could prove a
double-edged sword by creating holdout problems for drug
vendors who do not own the underlying molecular pathologic
relationships.
Thousands of U.S. patents have been issued on human
gene sequences and genotype-phenotype associations, but
their legal status remains uncertain. Several cases presently
making their way through the courts may clarify and add
reason to the law in this area.
Recent Legal Developments

In Mayo Collaborative Servs. v. Prometheus Labs., Inc.,9


Prometheus sued Mayo Clinic in the District Court for the

KEY POINTS

82

Personalized medicine in the form of targeted drug


therapies is already making important contributions
to oncology care.
Patents on human gene sequences have likely helped
stimulate the introduction of novel biologics and
pharmaceutical agents.
Conversely, patents on human gene sequences and
genotype-phenotype correlations appear to reduce
the availability of and patient access to already
existing diagnostic services, while increasing costs
and decreasing innovation in the development of
diagnostic methods.
The intellectual property rules by which patents on
human genes and genotype-phenotype associations
are governed will have a profound impact on the
advancement of personalized cancer care.
Several key legal cases now before the courts may add
clarity and guidance to the law governing this area.

Southern District of California for infringement of a process


patent covering the postadministration correlation between
thiopurine drug activity and side effects, and blood levels of
the metabolites 6-methyl mercaptopurine (6-MMP) and
6-thioguanine (6-TG). The patent claims at issue include
administering a drug, determining the level of a metabolite of the drug, and correlating this level with therapeutic
efficacy or side effects.
The district court found as a matter of law that the patent,
which essentially claims the reference range for the drugs,
covered an unpatentable natural phenomenon. The Court of
Appeals for the Federal Circuit (CAFC), the national patent
appeals court, reversed the lower court, finding that the
patent covers a treatment method. Further, the CAFC held
that the in vivo metabolism of thiopurine agents constituted
a transformation of matter, consistent with a patentable
process on an application of a natural phenomenon as
opposed to a patent on the phenomenon itself.
The Prometheus Labs case was appealed to and accepted
by the U.S. Supreme Court. Oral arguments were held
before the Court on December 7, 2011. Of note, during oral
arguments, the attorney for Prometheus Labs acknowledged
that it had patented a fact they identified, and that
physicians can infringe the patent merely by thinking about
the biologic relationship between metabolite levels and patient response. However, because the case involved an exogenously administered drug rather than a genetic variant
intrinsic to a patient, and the CAFC considered the patent
a therapeutic method patent, and Prometheus defended
its validity on this basis, the implications for genotypephenotype association patents are unclear.
In a case addressing legal standards for patent obviousness, KSR Intl Co. v. Teleflex Inc., 550 U.S. 398 (2007),
Teleflex sued KSR for infringement of a patent that claimed
the combination of an adjustable brake pedal and an electronic sensor. The district court found the patent obvious,
but the CAFC reversed the lower court decision. The Supreme Court in turn reversed the CAFC, ruling that the
patent was obvious. The CAFC, the high court stated, had
applied overly restrictive criteria in finding the patent
nonobvious. Importantly, the Supreme Court held that
obviousness to try a problem-solving approach can render
a patent obvious if there is a demonstrated need for a
discovery and a finite number of identified, predictable
solutions.
Many if not most patented genes were initially mapped
to a chromosomal region before discovery. Moreover, many
genes are involved in sequential biochemical pathways in
which disease-related changes were known before specific
genetic variations were identified. Therefore, for many of
these discoveries, it was arguably obvious to look for variants in the potentially responsible genes among the finite
number of available solutions. As a result, under KSR Intl
Co. v. Teleflex Inc. (KSR) many gene-related patents may be
subject to challenge on obviousness grounds. In an early
application of the KSR ruling, the USPTO refused to award
a patent on the gene sequence of the natural killer cell
activationinducing ligand. Although the sequence had not
been previously described, the USPTO found it obvious in
light of the prior art. The CAFC upheld the USPTOs
decision.10
Finally, in Association for Molecular Pathology v. United
States Patent and Trademark Office, a lawsuit sponsored

GENE PATENTS AND EFFECTS ON PERSONALIZED CANCER CARE

by the American Civil Liberties Union, a number of medical


and professional societies, health care providers, and patients with breast cancer sued Myriad Genetics and the
USPTO. The plaintiffs seek to invalidate key claims of
patents covering wild-type and mutated sequences of the
BRCA1 and BRCA2 genes and associations between those
sequences and the predisposition to breast and/or ovarian
cancer. In addition to arguing that the patents claim unpatentable natural products and natural phenomena, the plaintiffs asserted that they violate Article I, section 8, clause 8
and the First Amendment to the U.S. Constitution.
On March 29, 2010, in a landmark decision, the court held
that both composition of matter claims on the human
BRCA1 and BRCA2 gene sequences, and process claims
covering the correlations between mutations in these genes
and a predisposition to breast cancer are invalid as a matter
of law. These patent claims, the court ruled, were directed
toward unpatentable subject matter.10

On July 29, 2011, although upholding the district courts


finding of invalidity of the genotype-phenotype correlation
claims, the CAFC held that human gene sequences are
patent-eligible subject matter, reversing ruling of the lower
court. The plaintiffs have appealed the case to the Supreme
Court.
Conclusion

Genes as chemicals have an important role to play in


therapeutic development. However, ready access to the
information contained within patients genes is also critical
to the advancement of personalized medicine. Therefore, a
prudent course for the courts when addressing gene-related
patents is to strike a balance, upholding their validity when
the patents protect drug development, while denying their
enforceability when the patents create the potential for
genetic testing monopolies.

Authors Disclosure of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Roger D. Klein*
*No relevant relationships to disclose.

REFERENCES
1. 35 U.S.C. 101-103 (2006).
2. 35 U.S.C. 101 (2006).
3. Diamond v. Diehr. 450 U.S. 175, 185 (1981).
4. Bessen J, Meurer MJ. Patent Failure: How Judges, Bureaucrats, and
Lawyers Put Innovators at Risk. Princeton, NJ: Princeton University Press; 2008.
5. Klein RD. Gene patents and genetic testing in the United States. Nat
Biotechnol. 2007;25:989-990.
6. Secretarys Advisory Committee on Genetics, Health, and Society. Revised Draft Report on Gene Patents and Licensing Practices and Their Impact
on Patient Access to Genetic Tests (2010). http://oba.od.nih.gov/SACGHS/
sacghs_documents.html. Accessed February 10, 2010.

7. Klein RD, Mahoney MJ. LabCorp v Metabolite Laboratories: the Supreme Court listens, but declines to speak. J Law Med Ethics. 2008;36:141149.
8. Cho MK, Illangasekare S, Weaver MA, et al. Effects of patents and
licenses on the provision of clinical genetic testing services. J Mol. Diagn.
2003;5:3-8.
9. In v. Mayo Collaborative Servs. Prometheus Labs., Inc. 581 F. 3d 1136
(Fed. Circ. 2009), cert. granted (No. 10-1150).
10. In re Kubin, 561 F. 3d 1351 (Fed. Cir. 2009).
11. Assn for Molecular Pathology v. U.S. Patent and Trademark Office. 653
F. 3d 1329 (Fed. Cir. 2011), petition for cert. filed.

83

BREAST CANCER CHEMOPREVENTION:


IF NOT NOW, WHEN?
CHAIR
Abenaa M. Brewster, MD, MHS
University of Texas M. D. Anderson Cancer Center
Houston, TX
SPEAKERS
Nancy E. Davidson, MD
University of Pittsburgh Cancer Center
Pittsburgh, PA
Worta McCaskill-Stevens, MD, MS
National Cancer Institute
Bethesda, MD

Chemoprevention for Breast Cancer:


Overcoming Barriers to Treatment
By Abenaa M. Brewster, MD, MHS, Nancy E. Davidson, MD, and
Worta McCaskill-Stevens, MD, MS

Overview: Evidence from placebo-controlled, randomized


clinical trials supports the use of chemoprevention in women
at high risk for developing breast cancer, and two agents
tamoxifen and raloxifeneare U.S. Food and Drug Administration (FDA)-approved for the indication. Despite clinical
guidelines that recommend physicians counsel high-risk
women about the use of chemoprevention and the estimated
2.4 million women in the United States who meet eligibility
criteria for net benefit, the uptake of breast cancer chemoprevention has been exceedingly low. Assessments of the risks
and benefits of chemoprevention are aided by the availability
of models that can be used to estimate of the risk benefit
ratio. However, many physicians remain unaware of these

EVERAL RANDOMIZED clinical trials have provided


evidence for the chemoprevention of invasive breast
cancer by selective estrogen receptor modulators (SERMs).
The Breast Cancer Prevention Trial (BCPT) randomly selected 13,388 women age 35 or older with a 5-year predicted
risk for breast cancer of 1.66% or higher to receive either
tamoxifen or placebo.1 At a mean follow-up of 4 years, there
was a 49% reduction in the risk of developing invasive breast
carcinoma and a 50% reduction in the risk of noninvasive
breast cancer among women who were assigned to the
tamoxifen arm. The absolute risk reduction was 21.4 cases
per 1,000 women over 5 years. The benefit of tamoxifen was
limited to estrogen receptorpositive tumors, and the greatest risk reduction (86%) was observed in women with a
history of atypical hyperplasia. However, tamoxifen was also
associated with a 2.5-fold increased risk of endometrial
carcinoma and an increased risk of stroke, deep venous
thrombosis, pulmonary embolus, and cataracts.1 The results
of the Study of Tamoxifen and Raloxifene (STAR) demonstrated that raloxifene was as effective as tamoxifen in
reducing the risk of breast cancer in postmenopausal women
at increased risk of breast cancer with less adverse events of
thromboembolic events, endometrial cancer, and cataracts.2
Similar risks for ischemic heart disease, fractures, and
stroke were found for both drugs. There was a nonstatistically significant higher risk of noninvasive breast cancer
from raloxifene, which diminished at longer follow-up.2
Additional evidence for the efficacy of SERMs is derived
from the European randomized trials of tamoxifen compared
with placebo, which have demonstrated a more modest
benefit of tamoxifen for reducing the risk of invasive breast
cancer.3
The significant reduction in contralateral breast cancer
seen in the adjuvant aromatase inhibitor treatment trials
and the potentially serious toxicities associated with SERMs
led to the investigation of aromatase inhibitors for the
primary prevention of breast cancer. Goss et al published
the first results of a randomized placebo-controlled trial
designed to investigate exemestane for the primary prevention of invasive breast cancer. The National Cancer Institute
of Canada Clinical Trials Group MAP.3 randomly selected
4,560 postmenopausal women to receive exemestane or

resources to determine patient eligibility for chemoprevention


and lack the time to provide informed counseling to their
patients. The barriers for patients acceptance of chemoprevention treatment include fear of side effects and the perception that chemoprevention will not substantially lower their
risk of developing breast cancer. Despite these challenges,
there are substantial opportunities to increase the utilization
of chemoprevention. These strategies include education, dissemination of user-friendly risk benefit models, and the support of research efforts focused on identifying biomarkers that
can more accurately select women most likely to develop
breast cancer and predict responsiveness of treatment.

placebo. The inclusion criteria were similar to the BCPT and


STAR trials and included a 5-year predicted risk for breast
cancer of 1.66% or higher, history of atypia, or lobular
carcinoma in situ (LCIS). Women with ductal cancer in situ
were also eligible but represented a small portion of the
study participants (2.5%). At a median follow-up time of 35
months, exemestane was found to significantly reduce the
annual risk of invasive breast cancer by 65% (p 0.002).4
Arthritis (p 0.01) and hot flashes (p 0.001) were more
common in the exemestane treatment group, but there was
no statistically significant difference between the groups
in rates of new diagnoses of osteoporosis or cardiovascular
disease. Another phase III trial, IBIS-II, has randomly
selected 6,640 high-risk women to receive either placebo or
anastrozole and the results are eagerly awaited.
Evaluating RiskBenefit Indices for Chemoprevention

The FDA-approved indication to reduce the incidence of


invasive breast cancer for tamoxifen includes both premenopausal and postmenopausal women. However, raloxifene
which was FDA approved in 2007is indicated for postmenopausal women with osteoporosis or at high risk of
breast cancer based on the Gail model 5-year projected risk
of 1.66% or higher. Adverse events that are associated with
these agents raise concerns among women and physicians
about the benefits and risks, especially in women at high
risk of developing breast cancer who are otherwise healthy.
In addition to chronic diseases that accompany increasing
age, the risks of endometrial cancer, venous thromboembolic
events, bone fractures, and cataracts complicate the counseling for tamoxifen and raloxifene.
In 1998, the National Cancer Institute convened a workshop to determine the best ways of communicating the
results of the BCPT. The primary goal of this workshop was

From the University of Texas M. D. Anderson Cancer Center, Houston, TX; University of
Pittsburgh Cancer Institute, Pittsburgh, PA; and National Cancer Institute, Bethesda, MD.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Abenaa Brewster, MD, MHS, University of Texas M. D.
Anderson Cancer Center, 1155 Herman P. Pressler, PO Box 301439, Houston, TX 77230;
email: abrewster@mdanderson.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

85

BREWSTER, DAVIDSON, AND STEVENS

to develop a tool to identify those women whose benefits


from the use of tamoxifen outweighs the risks in reducing
the incidence of breast cancer. Of particular interest was the
need to explore the influence of tamoxifen on those health
outcomes that disproportionately affect different populations. Such a tool was developed by Gail et al, which weighed
the benefits and risk of other health outcomes in the absence
of tamoxifen and the effects of tamoxifen on other health
outcomes.5 The benefits and risks for the use of tamoxifen
were described in the format of tables by race, age, presence
or absence of a uterus, and the projected 5-year risk of
invasive breast cancer. Net benefits increased with increasing risk and decreased with age and in postmenopausal
women with an intact uterus. Younger women with elevated
risks of breast cancer had the best net benefit for tamoxifen
use. Importantly, this study showed that the adverse events
varied by age and race, preferences by the women, and
varied weights for specific events were critical complements
for weighing risk and benefits of tamoxifen.
Limitations of the 1999 Gail et al data included the lack
of incidence rates for stroke and venous thromboembolic
events from populations other than the non-Hispanic white
population and the uncertainty of applying the estimated
benefits and risks to all populations. A comparison of the
benefits and risks of tamoxifen and raloxifene for postmenopausal women to assist in communication was identified as
a research and clinical need. In addition, the availability of

KEY POINTS

86

Evidence from randomized, placebo-controlled clinical trials supports the use of chemoprevention for
reducing the risk of primary invasive breast cancer,
and there are three options: tamoxifen, raloxifene,
and exemestane.
Risk benefit models have great potential for decision
making about chemoprevention in high-risk clinical
practices and primary care practices if used in combination with a full assessment of the womans health
and preferences.
Guidelines for the prescription of tamoxifen and
raloxifene are provided by the United States Preventive Services Task Force, American Society of Clinical
Oncology, the Canadian Task Force on Preventive
Health Care, and the National Comprehensive Cancer Network.
Only a small portion of women who are eligible for
chemoprevention receive treatment, and the barriers
to uptake include lack of education about breast
cancer, inadequate physician training in risk assessment, lack of time to provide counseling, concerns
about side effects, cost, and misconceptions about
actual and perceived risks and benefits of treatment.
An active area of cancer prevention research is the
identification of biomarkers and clinical features to
improve the selection of women most likely to benefit
from breast cancer chemoprevention and to predict
and monitor treatment responsiveness.

improved incidence rates for invasive cancer for Hispanic


women from the Surveillance, Epidemiology, and End Results (SEER), modifications to the Gail model prediction tool
for the black population, and baseline incidence rates for
other health outcomes from the Womens Health Initiative
could enrich a risk benefit analysis of tamoxifen and raloxifene.
Freedman et al evaluated the probability of having a
health event in 5 years in the absence and presence of
tamoxifen and raloxifene.6 Risks and benefits were defined
as life-threatening (invasive breast cancer, hip fractures,
endometrial cancer, stroke, and pulmonary emboli) and
severe events (in situ breast cancer and deep vein thrombosis). An index of expected number of life-threatening events
without chemoprevention in 10,000 women minus the expected number of life-threatening events if tamoxifen and
raloxifene were used was presented in color-coded tables.
The authors used a complex statistical modeling approach to
simulate weighted outcomes to provide levels of evidence for
risk estimation. Strong evidence of a positive net benefit of
tamoxifen or raloxifene compared with no treatment was
deemed to exist if the net benefit was positive in 90% or
greater of replications in Bayesian boot-strap testing for
variability. Freedman et al showed that raloxifene results in
a better risk benefit profile for black, Hispanic, and nonHispanic white postmenopausal women with a uterus when
compared with tamoxifen. Similar benefits for postmenopausal black and non-Hispanic white women without a
uterus were seen for tamoxifen and raloxifene.
There are several limitations of the tables presented by
Freedman et al. Since the Gail model performs poorly at
predicting risk of breast cancer among women at higher risk
levels, generalization of the results to these women is
limited. In addition, the benefit of raloxifene over tamoxifen
may continue to diminish with longer-term follow-up and
the time line of the analysis was limited to 5 years.7 Despite
these limitations, risk benefit models have great potential
of assisting cancer care providers in high-risk clinical practices and primary care practices if used in combination with
a full assessment of the womans health and preferences.
Guidelines for Breast Cancer Chemoprevention

In 2002, the United States Preventive Services Task Force


(USPSTF) issued a recommendation statement that women
who are at both high risk of developing breast cancer and
low risk for adverse events should be counseled about
chemoprevention for breast carcinoma.8 Chemoprevention
was not recommended for women at low or average risk for
whom the adverse health events associated with tamoxifen
or raloxifene may outweigh the benefits. Although no set
definition of high risk was specified, the USPSTF referred
to the entry eligibility for the BCPT, which was a predicted
5-year risk of greater than 1.67% defined using the Gail
model.1 This guideline for the prescription of tamoxifen and
raloxifene has been supported by the American Society of
Clinical Oncology (ASCO), the Canadian Task Force on
Preventive Health Care, and the National Comprehensive
Cancer Network (NCCN).9-11 Based on the results of the
MAP.3 trial, exemestane was included as one of the choices
for breast cancer chemoprevention by the NCCN panel of
experts. Their recommendation for exemestane was limited
to postmenopausal women age 35 or older with a Gail model
5-year predicted risk higher than 1.66% or a history of LCIS.

CHEMOPREVENTION FOR BREAST CANCER

There are no data directly comparing the benefits and risks


of exemestane with those of tamoxifen and raloxifene and it
is not currently FDA approved for primary breast cancer
risk reduction.
Uptake of Breast Cancer Chemoprevention in the
United States

Despite clinical guidelines recommending tamoxifen or


raloxifene for the risk reduction of primary breast cancer,
the majority of eligible women elect not to use chemoprevention. It is estimated that approximately 10 million women
(16%) would be eligible for chemoprevention and approximately 2.4 million would have a positive risk benefit profile
for tamoxifen treatment.12 Unfortunately the uptake of
breast chemoprevention has been substantially less than
predicted. Waters et al used data from the National Health
Interview Survey between 2000 and 2005 to estimate the
number of women taking tamoxifen for chemoprevention.13
In 2000, two years after the FDA approved tamoxifen for
breast cancer chemoprevention, only 0.2% of women ages 40
to 79 had taken tamoxifen to prevent a diagnosis of breast
cancer. In 2005, 0.08% of women had taken tamoxifen,
which represented a 50% decrease in the number of women
receiving tamoxifen from 120,000 in 2000 to 60,000 in
2005.13 Armstrong et al surveyed 350 primary care physicians between 2002 and 2004 and found that only 27% had
prescribed tamoxifen for breast cancer prevention in the
previous year, which was higher than would have been
predicted based on the prevalence of women reporting taking the medication.14 There are no available data available
on the uptake of raloxifene, however, the general perception
is that public acceptance remains low for reasons that
remain unclear given its lower toxicity profile compared
with tamoxifen.15
Physician Barriers to Prescribing Breast Cancer
Chemoprevention

It is well recognized that women are more likely to accept


preventive services if recommended by their physicians.16-18
The reluctance of physicians to prescribe tamoxifen or raloxifene is therefore likely to be a major reason for the low
uptake of chemoprevention. Since primary care physicians
(PCPs) serve as the gatekeepers for implementing screening
recommendations and usually have the first interaction with
women at increased risk of developing breast cancer, studies
investigating physicians attitudes and acceptance of chemoprevention have focused on this group of health care providers.
The PCP role in the preventive care setting is to assess a
womans risk of developing breast cancer and provide a
recommendation for a risk-reduction option. How a PCP
views a womans risk of developing breast cancer has been
shown to be an important predictor of whether a prescription of tamoxifen will be offered.19,20 Tchou et al found that
women with a histologic diagnosis of atypical hyperplasia
or LCIS and women with a Gail model 5-year predicted risk
of 5.0% or greater were more likely to be offered tamoxifen
than women at lower risk.19 In a random sample of 822
Californian PCPs, Haas et al presented hypothetical patient scenarios to assess how a womans breast cancer risk
would influence her physicians recommendations for riskreduction options.20 Although 80% of PCPs would recom-

mend mammography screening and counseling for high-risk


women on lifestyle modifications, a minority endorsed the
use of tamoxifen. Some of the physician-perceived barriers
to risk-reduction counseling included not sufficiently
trained in counseling techniques and not sufficiently informed about risk-reduction options. Lack of time with
patients was the most frequently cited barrier, and 13% of
physicians reported insufficient reimbursement as an impediment to counseling.21 Interestingly, physicians concern
about the side effects of chemoprevention has not been
reported to be a significant deterrent to prescribing tamoxifen or raloxifene.14 However, more PCPs report prescribing
raloxifene (30%) compared with tamoxifen (10%) for primary
breast cancer risk reduction, which is not surprising since
Freedman et al showed that raloxifene results in a better
risk benefit profile for women with a uterus when compared
with tamoxifen.6,21 A good understanding of how to determine a womans eligibility for tamoxifen and ability to
determine whether the benefits of treatment outweigh the
risks is a significant predictor of whether a PCP prescribes
tamoxifen. Unfortunately in two surveys of PCPs conducted
by Armstrong et al and Sabatino et al, only 15% and 9% of
PCPs, respectively, felt capable of making this clinical assessment, which highlights the challenges faced by PCPs in
using and interpreting the risk benefit models that have
been developed.14,22 Contrary to the experience of PCPs, a
survey of 851 oncologists revealed that 73% discussed breast
cancer chemoprevention with their patients.23 The high
percentage of oncologists who discuss chemoprevention recommendations compared with PCPs may reflect differences
in the receipt of formal and informal training in cancer
prevention and encounters with women in the high-risk
clinical setting who are highly motivated to reduce their risk
of developing breast cancer.
Patient Barriers to Accepting Breast Cancer
Chemoprevention

Few women who meet eligibility criteria based on an


assessment of the risks and benefits of chemoprevention
treatment elect to initiate treatment. Ropka et al conducted
a meta-analysis of studies that evaluated real or hypothetical decisions made by women about breast cancer chemoprevention. The mean uptake of tamoxifen for the five
studies that reported real decision rates was 14.8% (range,
0.5% to 51.2%) and 24% (range, 5.7% to 60%) for the studies
reporting hypothetical decisions.24
The most commonly cited reason for not taking tamoxifen
is fear of the side effect of endometrial cancer, thromboembolic disease, and menopausal symptoms.16,25,26 In a study
of 43 women who were eligible to take tamoxifen for primary
prevention, the most feared side effects were endometrial
cancer and thromboembolic disease, and the majority of
women tended to overestimate their risk of developing these
side effects even after a presentation of the balance of risks
and benefits.25 When asked to estimate the risk of developing a side effect associated with tamoxifen, the majority
perceived that the risk would be 40% or greater. A survey of
29 women interviewed in a family practice setting revealed
additional concerns about nausea and vomiting, symptoms
mostly attributed to chemotherapy. In this study, the authors proposed that the name chemoprevention might
itself act as a barrier to patient acceptance because it is often
confused with chemotherapy.26

87

BREWSTER, DAVIDSON, AND STEVENS

Previous studies have shown that women tend to overestimate their risk of developing breast cancer and women
with a higher perceived risk of breast cancer are more likely
to be accepting of chemoprevention.16,27 Many women, however, have the perception that chemoprevention will not
substantially lower their risk of developing breast cancer
even after receiving information about the 50% risk reduction associated with tamoxifen treatment.28,29 Acceptance
of chemoprevention treatment has been shown to be significantly higher among women with a history of atypical
hyperplasia or LCIS compared with patients at risk on the
basis of other factors (56% vs. 28%, p 0.0001).19
Additional barriers that contribute to the reluctance of
women to use chemoprevention are related to physician
difficulty in accurately selecting individuals most likely to
develop breast cancer and the lack of a biomarker that can
be used to monitor the effect of the drug on risk. Unlike the
monitoring of cardiovascular risk factors (e.g., cholesterol
and blood pressure), which provide a measurable target for
assessing the efficacy of cholesterol or hypertension lowering
agents, there is no available reliable biomarker to measure
the preventive effect of chemoprevention that may serve to
motivate patients to accept treatment.15 Salant et al interviewed women seen at a high-risk clinic, of which the
majority were black, and found that the women understood
risk not as a numerical probability or chronic disease state
but as an immediate physical sign or symptom warranting
medical intervention. Therefore, despite meeting criteria for
being high-risk using the Gail model, many women did not
feel at high risk and therefore were not interested in
taking breast cancer chemoprevention treatment.30 This
finding has implications for the support of research efforts
aimed at identifying biomarkers and clinical features that
identify high-risk states and individualize the risk prediction of invasive breast cancer as a means of improving the
uptake of chemoprevention treatment.31
Among low-income women, acceptance of chemoprevention is dependent also on how much it costs and whether the
cost is covered by health insurance.28,30 At least three
studies have found that education and lower income are
inversely associated with breast cancer chemoprevention.27,32,33 These studies did not report on the accuracy of
the womens understanding of the risks and benefits of the
chemoprevention treatments, which is an important consideration since a greater understanding of the risk benefit
profile of chemoprevention has been demonstrated to result
in decreased patient acceptance of chemoprevention treatment.24 To overcome the significant patient-related barriers
to the uptake of chemoprevention, a comprehensive strategy
is needed that educates women about breast cancer and
their competing health risks and incorporates easily accessible decision aids that accurately convey the risks and
benefits of chemoprevention treatment.
Strategies to Improve the Uptake of Breast Cancer
Chemoprevention

Several investigators have explored the use of educational


or decision-making aids to increase the uptake of breast
cancer chemoprevention.34,35 The goal of the decision aids is
to facilitate a discussion between the patient and provider
about breast cancer chemoprevention and help guide informed decisions.36 Key components of the decision aids

88

have included education about breast cancer, an assessment


of the patients risk of breast cancer using the Gail or Claus
risk assessment models, integration of the patients risk of
breast cancer within the context of population risk, and an
assessment of the change in risks and benefits that would be
expected with tamoxifen or raloxifene treatment.34-36 In two
studies that have evaluated patient willingness to take
chemoprevention after receiving a decision aid, the uptake
rates have been disappointingly low (range, 4% to 6%).34,35
In a randomized trial designed to test whether a decision aid
intervention increased a womans interest in chemoprevention, among the 6% of high-risk women who received the
decision aid and said that they were likely to take the drug,
less than 1% had initiated therapy after the intervention.35
The challenges for PCPs considering prescribing breast
cancer chemoprevention are identifying women eligible for
treatment based on an acceptable risk benefit profile and
communicating the net benefit estimate using a balanced
approach that allows the patient to consider her personal
preferences. Increased PCP awareness of the online Gail
risk model and access to the risk benefit tools for tamoxifen
that were published in 1999 and updated in 2011 to include
raloxifene are needed to facilitate this process. It has been
advocated that the risk benefit models for breast cancer
chemoprevention should be more interactive and available
online, accessible to both physicians and patients.37 In
addition, the risk benefit models should incorporate additional variables, such as 5-year and lifetime mortality,
comorbidities including menopausal symptoms, and competing health risks that are essential to an informed decisionmaking discussion about whether to use chemoprevention
treatment.37,38 To increase awareness and education about
cancer preventive and control strategies, the ASCO Cancer
Prevention Committee is in the process of developing curricular material to disseminate to the educational programs
of a spectrum of disciplines, including family practice and
internal medicine. A recent breast cancer consensus statement recommended that to advance efforts for breast cancer
prevention, the term chemoprevention should be replaced
with the term preventive therapy to remove its inappropriate association with chemotherapy.39
A major hurdle in promoting breast cancer chemoprevention to the general population is the recognition that many
women who receive chemoprevention treatment will never
have developed breast cancer anyway. Because of the poor
discriminatory accuracy of the Gail risk model in determining individual level risk of breast cancer, many women and
their physicians remain uncertain about the benefits of
treatment and concerned about the potential serious toxicities and side effects that may affect quality of life. In
addition, advocacy groups including the Breast Cancer National Coalition are skeptical of chemoprevention and express concern about the lack of data on the long term
side-effects of the chemoprevention drugs.40 Strategies to
refine risk and predict responsiveness to chemoprevention
treatment are being explored and include random periareolar fine-needle aspiration to evaluate for cellular atypia in
otherwise normal breast tissue, breast density as a surrogate marker for monitoring response to treatment, and
single nucleotide polymorphisms associated with increased
susceptibility.36,39

CHEMOPREVENTION FOR BREAST CANCER


Conclusion

Breast cancer is the most common malignancy among


women in the United States affecting approximately
225,000 women annually. Evidence from randomized,
placebo-controlled clinical trials supports the use of chemoprevention for reducing the risk of primary invasive breast
cancer, and there are three options: tamoxifen, raloxifene,
and exemestane. Risk benefit models indicate that raloxifene results in a better risk benefit profile for black, Hispanic, and non-Hispanic white postmenopausal women with
a uterus when compared with tamoxifen. Similar benefits
for postmenopausal black and non-Hispanic white women
without a uterus are seen for tamoxifen and raloxifene. Only
a small portion of women who are eligible for chemopreven-

tion receive treatment, and the barriers to uptake include


lack of education about breast cancer, inadequate physician
training in risk assessment, lack of time to provide counseling, concerns about side effects, cost, and misconceptions
about actual and perceived risks and benefits of treatment.
Strategies to close this gap have focused on educating
women about breast cancer and their competing health risks
as well as developing easily accessible decision aids and risk
assessment models that accurately convey the risks and
benefits of chemoprevention treatment. An active area of
research is the identification of biomarkers and clinical
features to improve the selection of women most likely to
benefit from chemoprevention and to predict and monitor
responsiveness of treatment.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Abenaa M. Brewster*
Nancy E. Davidson

GlaxoSmithKline
(U)

Breast Cancer
Research
Foundation; NIH

Worta McCaskill-Stevens*
*No relevant relationships to disclose.

REFERENCES
1. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention
of breast cancer: report of the National Surgical Adjuvant Breast and Bowel
Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388.
2. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National
Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila).
2010;3:696-706.
3. Nelson HD, Fu R, Griffin JC, et al. Systematic review: comparative
effectiveness of medications to reduce risk for primary breast cancer. Ann
Intern Med. 2009;151:703-715.
4. Goss PE, Ingle JN, Ales-Martinez JE, et al. Exemestane for breastcancer prevention in postmenopausal women. N Engl J Med. 2011;364:23812391.
5. Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits
of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst.
1999;91:1829-1846.
6. Freedman AN, Yu B, Gail MH, et al. Benefit/risk assessment for breast
cancer chemoprevention with raloxifene or tamoxifen for women age 50 years
or older. J Clin Oncol. 2011;29:2327-2333.
7. Amir E, Goodwin P. Breast cancer chemoprevention gets personal. J
Clin Oncol. 2011;29:2296-2298.
8. U.S. Preventive Services Task Force. Chemoprevention of breast cancer:
recommendations and rationale. Ann Intern Med. 2002;137:56-58.
9. Visvanathan K, Chlebowski R, Hurley P. American Society of Clinical
Oncology practice guideline update on the use of pharmacologic interventions
including tamoxifen, raloxifene, and aromatase inhibition for breast cancer
risk reduction. J Clin Oncol. 1999;27:3235-3258.
10. Levine M, Moutquin JM, Walton R, et al. Chemoprevention of breast
cancer. A joint guideline from the Canadian Task Force on Preventive Health
Care and the Canadian Breast Cancer Initiatives Steering Committee on
Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.
CMAJ. 2001;164:1681-1690.
11. National Comprehensive Cancer Network. NCCN clinical practice
guidelines in oncology: Breast cancer risk reduction, v. 3.2011. http://www.
nccn.org/professionals/physician_gls/f_guidelines.asp#detection. Accessed February 13, 2012.
12. Freedman AN, Graubard BI, Rao SR, et al. Estimates of the number of
US women who could benefit from tamoxifen for breast cancer chemoprevention. J Natl Cancer Inst. 2003;95:526-532.
13. Waters EA, Cronin KA, Graubard BI, et al. Prevalence of tamoxifen use
for breast cancer chemoprevention among U.S. women. Cancer Epidemiol
Biomarkers Prev. 2010;19:443-446.
14. Armstrong K, Quistberg DA, Micco E, et al. Prescription of tamoxifen

for breast cancer prevention by primary care physicians. Arch Intern Med.
2006;166:2260-2265.
15. Meyskens FL Jr., Curt GA, Brenner DE, et al. Regulatory approval of
cancer risk-reducing (chemopreventive) drugs: Moving what we have learned
into the clinic. Cancer Prev Res (Phila). 2011;4:311-323.
16. Bober SL, Hoke LA, Duda RB, et al. Decision-making about tamoxifen
in women at high risk for breast cancer: clinical and psychological factors.
J Clin Oncol. 2004;22:4951-4957.
17. Lerman C, Rimer B, Trock B, et al. Factors associated with repeat
adherence to breast cancer screening. Prev Med. 1990;19:279-290.
18. Kinney AY, Richards C, Vernon SW, et al. The effect of physician
recommendation on enrollment in the Breast Cancer Chemoprevention Trial.
Prev Med. 1998;27:713-719.
19. Tchou J, Hou N, Rademaker A, et al. Acceptance of tamoxifen chemoprevention by physicians and women at risk. Cancer. 2004;100:1800-1806.
20. Haas JS, Kaplan CP, Gregorich SE, et al. Do physicians tailor their
recommendations for breast cancer risk reduction based on patients risk?
J Gen Intern Med. 2004;19:302-309.
21. Kaplan CP, Haas JS, Perez-Stable EJ, et al. Factors affecting breast
cancer risk reduction practices among California physicians. Prev Med.
2005;41:7-15.
22. Sabatino SA, McCarthy EP, Phillips RS, et al. Breast cancer risk
assessment and management in primary care: provider attitudes, practices,
and barriers. Cancer Detect Prev. 2007;31:375-383.
23. Ganz PA, Kwan L, Somerfield MR, et al. The role of prevention in
oncology practice: results from a 2004 survey of American Society of Clinical
Oncology members. J Clin Oncol. 2006;24:2948-2957.
24. Ropka ME, Keim J, Philbrick JT. Patient decisions about breast cancer
chemoprevention: a systematic review and meta-analysis. J Clin Oncol.
2010;28:3090-3095.
25. Port ER, Montgomery LL, Heerdt AS, et al. Patient reluctance toward
tamoxifen use for breast cancer primary prevention. Ann Surg Oncol. 2001;
8:580-585.
26. Heisey R, Pimlott N, Clemons M, et al. Womens views on chemoprevention of breast cancer: qualitative study. Can Fam Physician. 2006;52:624625.
27. Melnikow J, Paterniti D, Azari R, et al. Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for
breast cancer risk reduction. Cancer. 2005;103:1996-2005.
28. Cyrus-David MS, Strom SS. Chemoprevention of breast cancer with
selective estrogen receptor modulators: views from broadly diverse focus
groups of women with elevated risk for breast cancer. Psychooncology.
2001;10:521-533.

89

BREWSTER, DAVIDSON, AND STEVENS


29. Fagerlin A, Zikmund-Fisher BJ, Nair V, et al. Womens decisions
regarding tamoxifen for breast cancer prevention: responses to a tailored
decision aid. Breast Cancer Res Treat. 2010;119:613-620.
30. Salant T, Ganschow PS, Olopade OI, et al. Why take it if you dont
have anything? breast cancer risk perceptions and prevention choices at a
public hospital. J Gen Intern Med. 2006;21:779-785.
31. Temple R. Cancer chemopreventionthe cardiovascular model. Cancer
Prev Res. 2011;4:307-310.
32. Fasching PA, von Minckwitz G, Fischer T, et al. The impact of breast
cancer awareness and socioeconomic status on willingness to receive breast
cancer prevention drugs. Breast Cancer Res Treat. 2007;101:95-104.
33. Tija J, Micco E, Armstrong K. Interest in breast cancer chemoprevention among older women. Breast Cancer Res Treat. 2008;108:435-453.
34. McKay A, Martin W, Latosinsky S. How should we inform women at
higher risk of breast cancer about tamoxifen? An approach with a decision
guide. Breast Cancer Res Treat. 2005;94:153-159.

90

35. Fagerlin A, Dillard AJ, Smith DM, et al. Womens interest in taking
tamoxifen and raloxifene for breast cancer prevention: response to a tailored
decision aid. Breast Cancer Res Treat. 2011;127:681-688.
36. Ozanne EM, Klemp JR, Esserman LJ. Breast cancer risk assessment
and prevention: a framework for shared decision-making consultations.
Breast J. 2006;12:103-113.
37. Ravdin PM. The lack, need, and opportunities for decision-making and
informational tools to educate primary-care physicians and women about
breast cancer chemoprevention. Cancer Prev Res (Phila). 2010;3:686-688.
38. Mulley AG, Sepucha K. Making good decisions about breast cancer
chemoprevention. Ann Intern Med. 2002;137:52-54.
39. Cuzik J, DeCensi A, Arun B. Preventive therapy for breast cancer: a
consensus statement. Lancet Oncol. 2011;12:496-503.
40. The National Breast Cancer Coalition position statement on chemoprevention. Updated June 2011. www.breastcancerdeadline2020.org/know/
assets/... /chemoprevention.pdf. Accessed March 7, 2012.

CONTROVERSIES IN PROSTATE CANCER:


PSA SCREENING, CHEMOPREVENTION, AND
TREATMENT OF EARLY DISEASE
CHAIR
Barnett S. Kramer, MD, MPH
National Cancer Institute
Rockville, MD
SPEAKERS
Gerald L. Andriole, MD
Washington University School of Medicine
St. Louis, MO
Timothy J. Wilt, MD, MPH
U. S. Department of Veterans Affairs
Minneapolis, MN

The Case for Prostate Cancer Risk Reduction


by 5-Alpha Reductase Inhibitors
By Youssef S. Tanagho, MD, MPH, and Gerald L. Andriole, MD

Overview: Prostate cancer remains a significant public


health problem. The current approach with prostate-specific
antigen (PSA)-based screening has questionable effects on
prostate cancerspecific mortality but is clearly associated
with overdiagnosis of prostate cancer, especially relatively
low-risk and low-volume tumors. Methods to decrease overdiagnosis include alterations in screening practices and, potentially, the use of 5-alpha reductase inhibitors. This article
reviews the major trials that have evaluated 5-alpha reductase
inhibitors in this setting: the Prostate Cancer Prevention Trial
(PCPT) and the Reduction by Dutasteride Prostate Cancer
Events Trial (REDUCE). Although these trials enrolled different

ROSTATE CANCER risk reduction is a potentially


valuable strategy, as current approaches with PSAbased screening, which have a potentially small effect on
prostate cancer mortality, are associated with a significant
risk of overdiagnosis of prostate cancer.1-3 Most men diagnosed with PSA-detected tumors in the United States receive aggressive treatments.4,5 These treatments often have
significant side effects and are costly in both human and
economic terms. Therefore, one plausible strategy to improve the efficacy of PSA-based screening is to consider the
use of 5-alpha reductase inhibitors, as they may reduce
overdiagnosis of prostate cancer and improve the utility of
PSA as a marker for aggressive disease,6-9 as well as reduce
adverse sequelae of BPH.
Overdiagnosis of Prostate Cancer

Welch and Black10 identified three factors that result in


overdiagnosis of prostate cancer: 1) the existence of a silent
disease reservoir; 2) the use of activities (such as screening)
that lead to its detection; and 3) tumors with a long natural
history and, hence, limited cancer-specific mortality. Prostate cancer may represent a textbook disease for overdiagnosis. Multiple studies have shown a high prevalence of this
disease on autopsy, ranging from approximately 30% of men
in their 30s to up to 80% of men in their 80s. Thus, there is
a large silent reservoir of this disease that could be clinically
detected.11-12 Second, it has been estimated that close to
70% of American men have undergone one or more PSA
tests, and evidence suggests that older men, those in their
70s and 80s, who stand to benefit the least from PSA-based
screening represent the age stratum most likely to be
screened.13 Moreover, use of relatively low PSA thresholds
as a guide to select patients for biopsy could result in the
diagnosis of prostate cancer in a high proportion of men in
their 60s to 80s.14 It has been estimated that 6 to 10 times as
many men are considered to have an abnormal PSA than are
destined to die of prostate cancer. Finally, most cases of
prostate cancer have a long natural history and a limited
cancer-specific mortality. Albertsen and colleagues15 looked
at survival among men with localized prostate cancer. Men
with Gleason score 8 to 10 disease and no comorbidities had
more than twice the chance of dying of other causes than of
prostate cancer within 10 years. Men who had one or more
significant comorbidities and Gleason score 8 to 10 disease

92

patient populations, their findings are complementary and


suggest a potential role for these agents in prostate cancer
risk reduction. Use of 5-alpha reductase inhibitors results in
an approximate 25% reduction in the detection of prostate
cancer, reduces diagnosis of high-grade prostatic intraepithelial neoplasia (PIN), and improves benign prostatic hyperplasia
(BPH)-related outcomes and the performance of PSA as a
diagnostic test for aggressive prostate cancer. Side effects
occur in a small percentage of men and consist of decreased
sexual function and libido as well as gynecomastia. The risk of
high-grade tumor development while receiving these agents is
uncertain.

were about 5 times as likely to have a nonprostate cancer


related death. A contemporary clinical trial, the Goteborg
screening study, demonstrated that in a screened population
of about 20,000 Scandinavian mena population demographically predisposed to a relatively high overall death
rate from prostate cancer only 122 died of prostate cancer
and more than 3,800 died of other causes at 14 years of
follow-up.3 Similarly, of 367 men with screen-detected, localized prostate cancers who were considered candidates for
radical prostatectomy in the observation arm of the U.S.
PIVOT trial, 31 died of prostate cancer, whereas 152 died of
other causes at a median 10-year follow-up.16
Estimates of the magnitude of overdiagnosis of prostate
cancer can be made by comparing the screened to the usual
care arms of randomized screening trials. The PLCO trial,
which enrolled men across 10 participating U.S. centers,
showed that the screened arm had a 17% (95% CI: 1122)
increased chance of diagnosis of prostate cancer compared
with the usual care arm at 7 to 10 years of follow-up.4
However, it is known that the usual care arm for PLCO was
heavily contaminated with PSA testing. If one were to
compare the usual care arm of PLCO to a matched contemporary population in the United States, the usual care arm
would have a 22% excess prostate cancer detection rate.
Furthermore, men in the usual care arm of PLCO had more
than twice as many prostate cancers discovered as would
have been otherwise anticipated for a similar group of men
in the pre-PSA era.17 In ERSPC, a multicenter European
trial, there was a 71% increase in the detection of prostate
cancer in the screened arm compared with the usual care
arm, and a 64% increase was noted in the Goteborg trial. In
most European sites, screening was performed at a 4-year
interval, whereas in Scandinavia, it generally occurred at a
2-year interval. One illustration of the effect of overdiagnosis of prostate cancer was offered by Caroll and colleagues,18
who used the Goteborg data to demonstrate that if 1,000

From the Division of Urology, Washington University School of Medicine, St. Louis, MO.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Gerald L. Andriole, MD, Division of Urologic Surgery,
Washington University in St. Louis, 4960 Childrens Place, Campus Box 8242, St. Louis,
MO 63110; email: andrioleg@wustl.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

PROSTATE CANCER RISK REDUCTION

men were followed for 14 years, screening would avert the


death of five of nine men destined to die of prostate cancer
while leading to the diagnosis of prostate cancer in 120 men.
In addition to the considerable laboratory expenses associated with PSA screening, the anxiety associated with
abnormal PSA test results and the known significant side
effects of prostate biopsyincluding sepsis and hospitalizationrepresent significant costs of prostate cancer overdiagnosis. Indeed, the largest cost associated with prostate
cancer overdiagnosis is overtreatment. In a Scandinavian
study, Fall and colleagues showed that during the first week
following the diagnosis of prostate cancer, patients experienced a 2.8-fold (95% CI: 2.53.2) increased relative risk of a
major cardiovascular event and a 8.4-fold (95% CI: 1.9 22.7)
increased risk of suicide.19 In PLCO, more than 90%
of screen-detected cancers have received aggressive therapy.4 Certainly, earlier detection and treatment of prostate
cancer in the PSA era have contributed to the decreasing
mortality of this disease. Nonetheless, the significant human and economic burden of prostate cancer overtreatment
presents a considerable challenge to current PSA-based
screening efforts.
Agents to Reduce Overdiagnosis of Prostate Cancer

Plausible approaches to prostate cancer risk reduction


include a variety of agents. The 5-alpha reductase inhibitors
and vitamin E and selenium have been the best studied.
SELECT evaluated vitamin E and selenium and failed to
show any reduction in the diagnosis of prostate cancer.20 A
more recent analysis of the data suggested that vitamin E
may actually increase the detection of prostate cancer.21
Five-alpha reductase inhibitors are a group of drugs with
antiandrogenic activity, commonly used in the treatment of
BPH. These agents exert their antiandrogenic effect by
blocking the conversion of testosterone to the active form
dihydrotestosterone (DHT); the latter acts as a potent cellular androgen that promotes prostate growth. Two isoenzymes of 5-alpha reductase are found in the human genome,
Type 1 and Type 2. Type 2 appears to be the more important
isoform in the pathophysiology of BPH, whereas both Types
1 and 2 are expressed in cancer and cancer-related (PIN)
tissue. Finasteride is a selective inhibitor of 5-alpha reductase Type 2, while dutasteride is an inhibitor of both isoenzymes. Both drugs have been linked to decreased sexual

KEY POINTS

Prostate-specific antigen (PSA)-based screening is


associated with overdiagnosis of prostate cancer.
Most prostate cancers detected in the United States
are treated aggressively.
Five-alpha reductase inhibitors decrease the detection
of low-risk prostate cancers during PSA screening.
It is uncertain whether 5-alpha reductase inhibitors
used in this setting promote aggressive prostate cancer.
Five-alpha reductase inhibitors improve the performance of PSA as a diagnostic test for aggressive
prostate cancer.

Table 1. Comparison of PCPT and REDUCE


PCPT

Design
Duration (yr)
Number of patients
Location
Age
Entry PSA
5- reductase inhibition
Negative baseline biopsy
Follow-up biopsy
Cores per study biopsy
Baseline Characteristics
Median age
Median PSA
Prostate Cancer Results
Placebo
Treated

7
18,882
United States
55
3
Type 2 only
No
7 yr FC
6

REDUCE

4
8,251
International
5080
2.510
Types 1 and 2
Yes
2 yr and 4 yr FC
10

63
1.1

63
5.7

24.4%
18.4%

21.1%
16.3%

Abbreviations: FC, for cause; PSA, prostate-specific antigen; yr, years.

function and libido as well as gynecomastia in a small subset


of men. In general, men apt to experience these side effects
do so during the first year; thereafter, rates are similar
between placebo and treated men. Most side effects are
reversible if the drug is stopped.
Five-alpha reductase inhibitors have been studied in two
large prospective randomized trials, both of which have
demonstrated a reduced incidence of prostate cancer diagnosis (see Table 1). PCPT evaluated men age 55 or older with
serum PSA values of 3 who were randomly selected to
receive placebo or 5 mg per day of finasteride and underwent
for cause and end-of-study biopsies at 7 years.22 This trial
showed a 25% (95% CI: 18.6 30.6, p 0.001) statistically
significant risk reduction in the diagnosis of prostate cancer
in men treated with finasteride. However, this study has
been criticized for three main reasons. First, there was a
very high detection rate for prostate cancer over the 7-year
course of the trial. This low-risk group of men in the
placebo arm (who had a normal rectal exam and a PSA 3)
had a 24.4% chance of a prostate cancer diagnosis after 7
years of follow-up. In contrast, average U.S. men have a 17%
lifetime risk of prostate cancer. Second, there were fewer
for cause biopsies in the finasteride arm. If the biopsy rates
had been equal between the two arms, the difference in
overall prostate cancer detection rates would have been
narrowed. Finally, a major concern of PCPT was the finding
on biopsy of more prostate cancers with a Gleason score of 7
or higher in the finasteride arm. This excess of Gleason score
7 to 10 cancer has been attributed to biases induced by
finasteridethe major ones being the increased sensitivity
of PSA and the volume bias. The latter reflects the effect of
prostate size on the ability of digital rectal exam and biopsy
to detect prostate cancer. Four independent groups have
adjusted the original data of PCPT for these biases against
finasteride. The 27% excess Gleason score 7 to 10 disease in
the finasteride arm is eliminated.23-26 It was on the basis of
these findings that ASCO and the American Urological
Association together recommended that men with a PSA of
3 or below who are undergoing screening with PSA should
be encouraged to talk to their physicians about the risks
and benefits of taking a 5-alpha reductase inhibitor.27 More
recently, the U.S. Food and Drug Administration (FDA)
used other models to adjust for bias in PCPT. One of these
models showed a persistent 1.51 (95% CI: 1.01 to 2.26)

93

TANAGHO AND ANDRIOLE

excess risk of Gleason score 8 to 10 prostate cancer in the


finasteride arm.28
The REDUCE trial enrolled men between the age of 50
and 75 who are considered to be at high risk for prostate
cancer because of an elevated PSA (between 2.5 and 10).29
Patients were required to have undergone a negative
prestudy biopsy that was centrally reviewed. Patients in the
REDUCE trial received 0.5 mg of dutasteride per day or
placebo and underwent protocol-specified biopsies at 2 years
and 4 years as well as for cause biopsies whenever indicated. During the first 2 years of the REDUCE trial, there
was statistically significant 22.4% (95% CI: 13.0 30.8, p
0.001) relative risk reduction in the diagnosis of prostate
cancer.
The design of the REDUCE trial with a planned second
biopsy at 4-year follow-up for men without cancer on either
the initial prestudy biopsy or the 2-year study-mandated
biopsy is important to consider. One would anticipate that at
randomization there would be an equal number of small
volume cancers in each arm. After the discovery of 142 more
cancers in the placebo arm and their removal from the study
following the year-2 biopsies, there were more men and more
cancers remaining in the dutasteride arm, thus giving rise to
an imbalance between the two study groups for the remaining duration of the study. Despite these imbalances, a
statistically significant 23.7% (95% CI: 9.9 35.3, p 0.001)
relative risk reduction in the detection of prostate cancer
was again noted during the second round of biopsies in
REDUCE. The finding of fewer cancer cases in the dutasteride arm despite three significant biases against dutasteride during the second round of biopsies (i.e., more cancers
waiting to be discovered, more men undergoing biopsy, and
a 35% smaller prostate) suggests that dutasteride is capable
of continually suppressing tumor growth.
There was no excess of Gleason score 7 to 10 cancers in the
dutasteride arm of REDUCE. There was, however, a numerical increase in Gleason score 8 to 10 cancers in the dutasteride arm (29 vs. 19). This excess occurred exclusively
during the second round of biopsies. During the first round,
there were 17 Gleason score 8 to 10 cancers in the dutasteride arm and 18 in the placebo arm. During the second
round of biopsies, there were 12 in the dutasteride arm and
one in the placebo arm. An explanation for this excess biopsy
Gleason score 8 to 10 during the second round of the
REDUCE trial has been offered by considering that the
excess Gleason score 5 to 7 cancers diagnosed in the placebo
group during the first round of biopsies almost certainly
included the cancers of some men in whom biopsy-detectable
Gleason score 8 to 10 cancers were actually present. Using
data from the study of Choo and colleagues that considered
men with Gleason score 4 to 7 prostate cancer who were on
active surveillance and underwent follow-up biopsy, approximately 8% of such patients were found to have Gleason
score 8 to 10 disease on follow-up biopsy. Eight percent of the
141 excess cancers detected in years 1 and 2 in the placebo
arm of REDUCE would project 11 additional Gleason score
8 to 10 tumors in the placebo arm. Thus, there was a
virtually identical number of Gleason score 8 to 10 cancers
in both arms during the entire study.
Other studies have looked at the occurrence of Gleason
score 8 to 10 cancers in men receiving dutasteride. These
include the COMBAT and the REDEEM studies. Neither of
these trials showed any increase in Gleason score 8 to 10

94

cancer in the dutasteride-driven arm after 3 to 4 years,


respectively.30,31
When one considers the raw data from the REDUCE trial
and adjusts it for the bias induced by prostate shrinkage and
increased PSA sensitivity in the dutasteride arm, the odds
of Gleason 7 to 10 cancer in the dutasteride arm actually
decreased by 38%.
In preparation for the Oncology Drugs Advisory Committee meeting in December 2010, cancers in the REDUCE trial
were reread using a modified Gleason score. The REDUCE
protocol specified that tumors would be graded using the
classic Gleason scoring system. When cancers in REDUCE
were reread using a modified Gleason scoring system, similar to the one used in PCPT, the number of Gleason score 8
to 10 cancers in the dutasteride arm rose from 29 to 32,
whereas the number in the placebo arm fell from 19 to 16.
Thus, there were twice as many Gleason score 8 to 10
cancers in the dutasteride arm when the modified Gleason
score was used. This doubling of Gleason score 8 to 10
cancers suggested a safety signal and the potential induction of Gleason score 8 to 10 cancers by dutasteride, as might
have been seen for finasteride in PCPT. Based on these
considerations, the FDA concluded that if 5-alpha reductase
inhibitors were used for prostate cancer risk reduction, one
might potentially anticipate one additional modified-score
Gleason score 8 to 10 cancer in the treated arm in order to
avert three or four lower-grade cancers. The FDA has stated
that health care professionals should be aware that 5-alpha
reductase inhibitors may increase the risk of prostate cancer
and that 5-alpha reductase inhibitors are not approved for
the prevention of prostate cancer.28
Effect of 5-Alpha Reductase Inhibitors on PSA

Multiple studies have shown that 5-alpha reductase inhibitors result in a statistically significant improvement in
the performance of PSA as a diagnostic test for prostate
cancer. These include the PLESS BPH trial,6 PCPT,7 and
the REDUCE trial.8,9 Moreover, when one looks at the
ability of PSA rise to detect clinically significant cancers, use
of the National Comprehensive Cancer Networkrecommended PSA velocity guidelines in REDUCE would have
resulted in the detection of 64% of Gleason score 7 to 10
cancers in the placebo arm, whereas 75% of Gleason score 7
to 10 cancers in the dutasteride arm exhibited a PSA rise off
nadir. These data highlight the importance of monitoring
PSA in men on 5-alpha reductase inhibitors. Most patients
experience about a 50% reduction in PSA by 6 to 12 months;
any rise from nadir should warrant a biopsy.
Conclusion

In summary, PSA-based screening is associated with


considerable overdiagnosis of prostate cancer, which, in
turn, results in a significant burden of overtreatment. Fivealpha reductase inhibitors decrease the detection of low-risk
prostate cancers during PSA screening, while at the same
time improving the performance of PSA as a diagnostic test
for aggressive prostate cancer. Five-alpha reductase inhibitors may, therefore, play an important role in focusing
prostate cancer screening efforts on the more lethal forms of
prostate cancer. Nevertheless, there remains an element of
uncertainty regarding a potential role for 5-alpha reductase
inhibitors used in this setting in promoting aggressive
prostate cancer.

PROSTATE CANCER RISK REDUCTION

Authors Disclosures of Potential Conflicts of Interest

Author
Youssef S. Tanagho*
Gerald L. Andriole

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Amarex; Amgen;
Augmenix;
Bayer; BristolMyers Squibb;
Cambridge Endo;
Caris MPI;
GlaxoSmithKline;
Janssen
Biotech; Myriad
Genetics; OrthoClinical
Diagnostics;
STEBA Biotech;
Viking Medical

Envisioneering

Honoraria
Amgen; Bayer;
Bristol-Myers
Squibb; Caris;
GlaxoSmithKline;
Janssen
Biotech; Myriad
Genetics; OrthoClinical
Diagnostics;
STEBA Biotech

Research
Funding

Expert
Testimony

Other
Remuneration

Caris;
GlaxoSmithKline;
STEBA Biotech

*No relevant relationships to disclose.

REFERENCES
1. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer
screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer
Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer
Inst. 2012;104:125-132.
2. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostatecancer mortality in a randomized European study. N Engl J Med. 2009;360:
1320-1328.
3. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the
Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725-732.
4. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from
a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:13101319.
5. Cooperberg MR, Broering JM, and Carroll PR. Time trends and local
variation in primary treatment of localized prostate cancer. J Clin Oncol.
2010;28:1117-1123.
6. Andriole GL, Guess HA, Epstein JI, et al. Treatment with finasteride
preserves usefulness of prostate-specific antigen in the detection of prostate
cancer: results of a randomized, double-blind, placebo-controlled clinical trial.
PLESS Study Group. Proscar Long-term Efficacy and Safety Study. Urology.
1998;52:195-202.
7. Thompson IM, Chi C, Ankerst DP, et al. Effect of finasteride on the
sensitivity of PSA for detecting prostate cancer. J Natl Cancer Inst. 2006;98:
1128-1133.
8. Andriole GL, Bostwick D, Brawley OW, et al. The effect of dutasteride on
the usefulness of prostate specific antigen for the diagnosis of high grade and
clinically relevant prostate cancer in men with a previous negative biopsy:
results from the REDUCE study. J Urol. 2011;185:126-131.
9. Marberger M, Freedland SJ, Andriole GL, et al. Usefulness of prostatespecific antigen (PSA) rise as a marker of prostate cancer in men treated with
dutasteride: Lessons from the REDUCE study. BJU Int. Epub 2011 Jun 23.
10. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst.
2010;102:605-613.
11. Sakr WA, Grignon DJ, Haas BP, et al. Age and racial distribution of
prostatic intraepithelial neoplasia. Eur Urol. 1996;30:138-144.
12. Powell IJ, Bock CH, Ruterbusch JJ, et al. Evidence supports a faster
growth rate and/or earlier transformation to clinically significant prostate
cancer in black than in white American men, and influences racial progression and mortality disparity. J Urol. 2010;183:1792-1796.
13. Drazer MW, Huo D, Schonberg MA, et al. Population-based patterns
and predictors of prostate-specific antigen screening among older men in the
United States. J Clin Oncol. 2011;29:1736-1743.
14. Welch HG, Schwartz LM, and Woloshin S. Prostate-specific antigen
levels in the United States: implications of various definitions for abnormal.
J Natl Cancer Inst. 2005;97:1132-1137.
15. Albertsen PC, Moore DF, Shih W, et al. Impact of comorbidity on
survival among men with localized prostate cancer. J Clin Oncol. 2011;29:
1335-1341.
16. Wilt TJ. The VA/NCI/AHRQ CSP#407: Prostate cancer Intervention
Versus Observation Trial (PIVOT): main results from a randomized trial

comparing radical prostatectomy to watchful waiting in men with clinically


localized prostate cancer. In: American Urological Association 2011 Annual
Meeting; 2011 May 17.
17. Pinsky PF, Blacka A, Kramer BS, et al. Assessing contamination and
compliance in the prostate component of the Prostate, Lung, Colorectal and
Ovarian (PLCO) Cancer Screening. Clin Trials. 2010;4:303-311.
18. Carroll PR, Whitson JM, Cooperberg MR. Serum prostate-specific
antigen for the early detection of prostate cancer: always, never, or only
sometimes? J Clin Oncol. 2011;29:345-347.
19. Fall K, Fang F, Mucci LA, et al. Immediate risk for cardiovascular
events and suicide following a prostate cancer diagnosis: prospective cohort
study. PLoS Med. 2009;6:1-8.
20. Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and
vitamin E on risk of prostate cancer and other cancers: the Selenium and
Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301:39-51. Epub
2008 Dec 9.
21. Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of
prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial
(SELECT). JAMA. 2011;306:1549-1556.
22. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of
finasteride on the development of prostate cancer. N Engl J Med. 2003;349:
215-224.
23. Cohen YC, Liu KS, Heyden NL, et al. Detection bias due to the effect of
finasteride on prostate volume: a modeling approach for analysis of the
Prostate Cancer Prevention Trial. J Natl Cancer Inst. 2007;99:1366-1374.
24. Pinsky PF, Parnes H, and Ford L. Estimating rates of true high-grade
disease in the Prostate Cancer Prevention Trial. Cancer Prev Res (Phila).
2008;1:182-186.
25. Redman MW, Tangen CM, Goodman PJ, et al. Finasteride does not
increase the risk of high-grade prostate cancer: a bias-adjusted modeling
approach. Cancer Prev Res (Phila). 2008;1:174-181.
26. Kaplan SA, Roehrborn CG, Meehan AG, et al. PCPT: Evidence that
finasteride reduces risk of most frequently detected intermediate- and highgrade (Gleason score 6 and 7) cancer. Urology. 2009;73:935-939.
27. Kramer BS, Hagerty KL, Justman S, et al. Use of 5- reductase
inhibitors for prostate cancer chemoprevention: American Society of Clinical
Oncology/American Urological Association 2008 Clinical Practice Guideline.
J Clin Oncol. 2009;27:1502-1516.
28. Theoret MR, Ning YM, Zhang JJ, et al. The risks and benefits of 5-
reductase inhibitors for prostate cancer prevention. N Engl J Med. 2011;365:
97-99.
29. Andriole GL, Bostwick DG, Brawley OW, et al. Effect of dutasteride on
the risk of prostate cancer. N Engl J Med. 2010;352:1192-1202.
30. Roehrborn CG, Andriole GL, Wilson TH, et al. Effect of dutasteride on
prostate biopsy rates and the diagnosis of prostate cancer in men with lower
urinary tract symptoms and enlarged prostates in the combination of Avodart
and Tamsulosin trial. Eur Urol. 2011;59:244-249.
31. Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in localised
prostate cancer management: the REDEEM randomised, double-blind,
placebo-controlled trial. Lancet. Epub 2012 Jan 23.

95

Screening for Prostate Cancer with ProstateS p e c i fi c A n t i g e n : W h a t s t h e E v i d e n c e ?


By Pamela M. Marcus, PhD, and Barnett S. Kramer, MD, MPH

Overview: In October 2011, the U.S. Preventive Services Task


Force (USPSTF, or Task Force) released draft recommendations on prostate cancer screening with prostate-specific
antigen (PSA), concluding that PSA-based screening results
in small or no reduction in prostate cancerspecific mortality
and is associated with harms related to subsequent evaluation
and treatments, some of which may be unnecessary. This
statement was accompanied by a grade D recommendation,
which indicates that in the Task Forces judgment there is
moderate or high certainty that the service has no net benefit
or that the harms outweigh the benefits. The Task Force, an
independent panel of nonfederal (U.S.) experts in prevention
and evidence-based medicine, conducts systematic evidence
reviews of preventive health care services and makes recommendations about preventive services in primary care. Task
Force recommendations do not set U.S. federal policy but can

HE USPSTF IS an independent panel of nonfederal


(U.S.) primary care providers and scientists with expertise in prevention and evidence-based medicine. The Task
Force conducts systematic evidence reviews of preventive
health care services and makes recommendations about
preventive services in primary care. Task Force recommendations do not set U.S. federal policy but can and do
influence clinical practice as well as health care coverage
and reimbursement. Therefore, they are important and
often controversial, particularly when the recommendation
questions a common medical intervention. Under the Task
Forces purview is cancer screening, a prevention strategy
that has, over the years, proven to be contentious and
emotionally charged.
In October 2011, the Task Force released a draft of
recommendations on prostate cancer screening with PSA.1
They concluded that PSA-based screening results in small
or no reduction in prostate cancerspecific mortality and is
associated with harms related to subsequent evaluation and
treatments, some of which may be unnecessary. This statement was accompanied by a grade D recommendation,
which indicates that in the Task Forces judgment there is
moderate or high certainty that the service has no net
benefit or that the harms outweigh the benefits. As of this
writing, the recommendations are still in draft form, and the
Task Force is assessing a large number of comments sent to
them during the public comment period. Whatever the
ultimate conclusions of the Task Force, prostate cancer
screening with PSA will remain a Medicare benefit for men
of all ages and risk factor profiles.
Screening for prostate cancer with PSA is an example of
mass screening. A mass cancer screening program strives to
screen asymptomatic persons with certain characteristics
(usually based on age) and reduce the rate of disease-specific
mortality in the population being screened. For a mass
cancer screening program to be of value, mortality from the
target cancer must be reduced, but harms associated with
the screening process and downstream events triggered by
screening cannot outweigh the benefit. Persons who are
screened have no symptoms of the disease in question and
therefore are healthy with regard to that illness. It is

96

and do influence reimbursement and clinical practice. In this


article, we will present evidence the Task Force considered
when making its decision, including two highly influential
randomized controlled trials (RCTs) of prostate cancer
screening, the European Randomized Study of Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal and Ovarian
Cancer Screening Trial (PLCO). The two trials arrived at
different conclusions about the efficacy of routine prostate
cancer screening, but similar conclusions about the accompaniment of clinically relevant harms with prostate cancer
screening, including overdiagnosis (screen detection of cancers that never would be diagnosed in the absence of screening). We also will present other available evidence on benefits
and harms of PSA-based screening and consider that evidence
and the findings of ERSPC and PLCO in conjunction with one
another.

difficult to make healthy individuals any healthier, especially with an intervention like cancer screening, which puts
large numbers of people in harms way. Therefore, there
should be strong evidence of benefit from cancer screening
before mass screening programs are implemented.
In this article, we discuss the evidence that led to the Task
Forces decision to recommend against routine prostate
cancer screening with PSA. We first present prostate cancer
statistics for the United States. Before presenting the evidence that influenced the Task Forces recommendation, we
provide an overview of cancer screening, as such knowledge
is necessary for proper evaluation of evidence. For a thorough treatment of the topic, please see Prorok and colleagues.2
Prostate Cancer in the United States

Prostate cancer is the most frequently diagnosed nonskin


cancer and the second-leading cause of cancer death in U.S.
men. More than 240,000 cases are expected to be diagnosed
in 2012 and more than 28,000 men are expected to die of the
disease.3 Early prostate cancer is treatable but usually has
no symptoms; advanced prostate cancer, on the other hand,
is symptomatic but not curable. More than 90% of prostate
cancers in the United States are detected at a treatable
stage, however, and the 5-year relative survival for those
cancers approaches 100%. Because treatments often lead to
urinary and erectile dysfunction, some clinicians have adopted a watchful waiting or active surveillance strategy
rather than an initial surgical one for older patients and
those who appear to have less aggressive tumors.
Historically, prostate cancer incidence rates began to rise
rapidly in the mid- to late 1980s, continued to do so until the

From the Division of Cancer Control and Population Sciences, National Cancer Institute,
Bethesda, MD.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Pamela M. Marcus, PhD, Division of Cancer Control and
Population Sciences, National Cancer Institute, 6130 Executive Blvd., Room 4106,
Bethesda, MD 20892-7344; email: marcusp@mail.nih.gov.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

PSA SCREENING: HARMS WITHOUT CLEAR BENEFIT

mid-1990s, and then started to fall. This trend is thought by


many to be primarily attributable to changes in use of PSA
screening rather than radical changes in risk factors or
classification schemes for invasiveness of disease. In the
early 1990s, at the height of PSA screening, the age-adjusted
prostate cancer incidence rate was in excess of 200 per
100,000 man-years, but in 2008 (the most recent data
available), it was about 150 per 100,000 man-years.4 Prostate cancer mortality peaked in 1993 at about 39 per 100,000
man-years but in 2008 had fallen to about 23 per 100,000
man-years.4
Cancer Screening

Cancer screening refers to the routine testing of persons


who are asymptomatic for cancer of a particular organ. The
goal of screening is to decrease the risk of death from a given
cancer by detecting the cancer at a time when treatment can
lead to cure. A reduction in disease-specific mortality with
screening, relative to established care without that exam,

KEY POINTS

A 2010 meta-analysis of prostate-specific antigens


(PSAs) effect on prostate cancer mortality that included five randomized controlled trials (including
the two largest, the European Randomized Study of
Prostate Cancer and the Prostate, Lung, Colorectal
and Ovarian Cancer Screening Trial) generated a
summary risk ratio of 0.88 (95% CI: 0.711.09),
indicating no statistically significant benefit of PSA
screening.
If PSA screening does reduce prostate cancer mortality, the reduction is likely to be small.
The harms associated with prostate cancer screening
(false-positive exams), diagnostic evaluation of positive exams (e.g., hematospermia, hematuria, sepsis),
treatment of prostate cancer (e.g., urinary incontinence and impotence), and overdiagnosis (screen detection of cancers that never would be diagnosed in
the absence of screening) are well-established and clinically relevant, and should be considered in concert with
any benefit of PSA screening that might exist.
In October 2011, the U.S. Preventive Services Task
Force (USPSTF) released a draft statement advising
against prostate cancer screening with PSA and assigned a grade D recommendation, which states
that in the Task Forces judgment there is moderate
or high certainty that the service has no net benefit or
that the harms outweigh the benefits. Nevertheless,
prostate cancer screening with PSA will remain a
Medicare benefit for men of all ages and risk profiles.
The USPSTF recommendation reflects two core concepts in the field of cancer prevention and screening:
1) it is difficult to make healthy persons even healthier; and 2) strong evidence of benefit should exist
before routinely administering a clinical intervention
to healthy persons if that measure is likely to incur
harm.

Table 1. The Potential Positive and Negative Consequences


of Cancer Screening
Positive
Reduced risk of death from the target cancer
Provides some reassurance to those who are concerned that they may have
cancer
Negative
False reassurance if cancer is present, which may lead to disregard of symptoms
Harms of the screening test (e.g., perforation from endoscopy)
False-positive exams, including the need to undergo diagnostic evaluation and
experience any harms that accompany it
Earlier detection of cancer that does not lead to a change in outcome
Identification of overdiagnosed* cancers, with accompanying unnecessary,
potentially harmful diagnostic evaluation and treatment
* Cancers that never would have been diagnosed in the absence of screening.

indicates that screening works. RCTs are used to determine


whether screening reduces cancer mortality, as that study
design provides the most definitive evidence. Other study
designs, such as case-control studies or comparisons of
temporal trends in screening and mortality, are subject to
powerful confounding because of the inability to control for
factors that are related to both screening and death due to
the disease of interest. Metrics such as an increase in 5-year
survival, number of cases detected, and number of earlystage cases are insufficient on their own to demonstrate a
benefit of screening as a result of the presence of certain
methodologic biases.
There are both positive and negative consequences of
cancer screening (Table 1). Screening may benefit patients
by reducing the risk of death from the target cancer, relative
to what it would be in the absence of that screening exam. A
negative screening exam can provide some reassurance to
those who are concerned that they may have cancer, although occasionally the reassurance is false and may lead to
disregard of cancer symptoms. Screening, however, can lead
to substantial harm. Medical misadventures may occur as
part of the screening exam itself. Many positive screening
exams will be false positives, which lead to unnecessary
anxiety as well as diagnostic evaluation that may be accompanied by harm. Screening can result in earlier detection of
a cancer that does not lead to a change in date of death; in
this instance, the patient spends more of his or her life as a
patient with cancer, but life expectancy and cause of death
are unchanged. Screening also can result in the detection of
overdiagnosed cancers, cancers that never would have been
diagnosed in the absence of screening. Patients with overdiagnosed cancers receive unnecessary treatment, experience
unnecessary treatment-related morbidity, and can even die
prematurely as a result of unnecessary treatment (e.g.,
lethal cancers induced by radiotherapy, postoperative death,
and heart disease or leukemia caused by chemotherapy).
The U.K. National Screening Committee has compiled a
list of criteria for appraising the viability, effectiveness, and
appropriateness of a screening program5 (www.screening.
nhs.uk/criteria/fileid9287). We have identified and adapted
the most relevant criteria to prostate cancer screening with
PSA, and the 13 we consider most relevant are listed in
Table 2. Among those criteria are at least five that either are
known not to be true for PSA screening or whose veracity is
uncertain: the natural history of the detected lesions is not
fully understood, PSA screening appears not to preferentially detect lesions that are most likely to progress, there is

97

MARCUS AND KRAMER


Table 2. Criteria for Implementation of a Screening Program
Applied to Prostate Cancer Screening*
Criteria for Screening
An important health problem
Recognizable latent or early asymptomatic stage
Available suitable test with agreed-upon cutoff values
Test acceptable to the population
Natural history of the detected lesions understood
Preferential detection of lesions likely to progress
Available, accepted treatment
Available facilities for diagnosis and treatment
Agreed-upon policy on whom to treat
Strong evidence (RCTs) of mortality/morbidity reduction
Benefits proven to outweigh harms
Quality assurance standards in place (including monitoring)
Affordable (cost-effectiveness)
* Adapted from www.screening.nhs.uk/criteria/fileid9287.

no standard clinical policy on whom to treat, strong evidence


(RCTs) of mortality/morbidity reduction does not exist, and
benefits have not been proven to outweigh harms.
Evaluation of PSA Screening for Prostate Cancer:
Prostate Cancer Mortality

Five RCTs of PSA prostate cancer screening (either alone


or in conjunction with another modality) have reported
prostate cancer mortality results.6 A 2010 meta-analysis of
those studies generated a summary risk ratio of 0.88 (95%
CI: 0.711.09), indicating no statistically significant benefit
of PSA screening.6 The meta-analysis included ERSPC7 and
PLCO,8 the two largest and most influential RCTs of prostate cancer screening. ERSPC, which randomly selected in
excess of 180,000 men ages 50 to 74 from 1991 to 2003,
reported a 20% prostate cancer relative mortality reduction
(95% CI: 0.67 0.98) with screening using the core group of
men ages 55 to 69 (more than 160,000), although the
prostate cancer mortality reduction was not statistically
significant in the entire study population (rate ratio: 0.85,
95% CI: 0.731.00). PLCO, which randomly selected almost
77,000 men ages 55 to 74 from 1993 to 2001, reported a
nonsignificant 9% (95% CI: 0.87 to 1.36) increase in prostate
mortality with screening after 13 years of follow-up. Both
trials, however, demonstrated clinically important levels of
harm associated with diagnostic evaluation of positive
screens and treatment of screen-detected prostate cancers.
Neither ERSPC nor PLCO was perfect. As to be expected,
researchers with an a priori belief that prostate cancer
screening is warranted believe that ERSPCs shortcomings
are not fatal, but those who take a more negative view of
prostate cancer screening feel that PLCO is the stronger of
the two trials. Those who make their decisions based on
systematic evidence reviews, such as the Task Force, look at
the evidence base as a whole and conclude that although a
small benefit of PSA screening may be possible, the harms
that can follow may outweigh that potentially small benefit.
ERPSC was a multicenter trial: Finland, Switzerland,
Italy, the Netherlands, Belgium, Switzerland, Spain, Portugal, and France participated, although data from the latter
two countries were excluded from the initially published
analyses. Given the unique characteristics of health care in
each country, intervention arm participants had different
experiences and access to different diagnostic evaluation
procedures and treatments. The screening interval varied by

98

country (2 to 7 years), as did the use of additional modalities


and the PSA value that defined a positive screen. In the
Netherlands, Belgium, Switzerland, and Spain, randomization occurred after informed consent was received, but in
Finland, Switzerland, and Italy, potential subjects were
identified using population registries and randomly selected, and then those selected for screening were asked to
provide written informed consent, thus raising the question
of whether two equivalent arms were produced. A substantial number of men randomly selected for the control arm
were unaware of their participation in the trial, so they were
less likely to receive cutting-edge treatment, in particular,
radical prostatectomy, because they had no relationship
with the screening centers, which were academic centers. It
has been demonstrated that participants in the screened
arm were more likely to receive therapy with curative
intent. Therefore, it is unclear whether screening led to a
reduction in mortality or whether differences in the treatment were responsible.
PLCOs randomization was more likely than ERSPCs to
have produced equivalent screening arms, as all participants signed their informed consent forms before they were
randomly selected. Furthermore, all 10 PLCO centers used
the same criterion to define a positive PSA screen, and
control participants knew they were in the trial and had a
relationship with the specialty medical center where the
intervention arm participants were screened. PLCOs
Achilles heel was a high rate of PSA screening in the
control arm. The trial had been designed to have 90%
statistical power to detect a 20% reduction in prostate
cancer mortality in the presence of no more than 20%
noncompliance (i.e., screening) in the control arm, but actual
noncompliance, measured annually, was between 40% and
54% at particular screening years. Given that rate of noncompliance, PLCOs statistical power was 90% for a mortality reduction no smaller than 40%, which may be unrealistic
for PSA screening.
Evaluation of PSA Screening for Prostate Cancer:
Harms

Although ERSPC and PLCO came to different conclusions


about whether PSA screening could reduce prostate cancer
mortality, they both did come to the conclusion that screening could lead to nontrivial levels of adverse events due to
diagnostic evaluation and treatment. They also both indicate
that overdiagnosis occurs with prostate cancer screening.
PSA screening itself, which requires a blood draw, has
infrequent side effects, and the ones that do resultinfection at the draw site, vasovagal reaction, discomfortare
considered to be minor. However, adverse events associated
with prostatic biopsy are of more concern. In PLCO, almost
13% of men had at least one false-positive PSA exam and of
those, more than 5% had a biopsy dictated by that exam9; at
the Netherlands ERSPC site, 50% of men who had a biopsy
as a result of a positive exam had hematospermia, 23% had
hematuria, and 4% had fever.10 In addition, there are
reports of a recent and consistent increase in urosepsis with
resistant organisms for men undergoing PSA-motivated
prostatic biopsy. Surveillance, Epidemiology, and End Results (SEER)-Medicare data indicate that the rate of hospitalization for biopsy-related infection within 30 days of that
biopsy has quadrupled, from about 0.25% before 2001 to
more than 1% in 2007.11 Hospitalizations also occur for

PSA SCREENING: HARMS WITHOUT CLEAR BENEFIT

Fig. 1. Prostate cancer in the United States, 1975 to


2008: new cases and deaths.

noninfectious biopsy-related complications, but not to the


same degree. A similar pattern for biopsy-related hospitalizations was observed in Ontario, Canada, during the 2000s.13
The complications associated with prostate cancer treatment are unpleasant and life-altering. Urinary incontinence
and erectile dysfunction occur as a result of treatment,
although the percentage of men whose morbidities are
attributable solely to treatment likely varies by patient
characteristics, treatment received, the definition of incontinence and erectile dysfunction employed, whether the
diagnosis is self-assigned, and the prevalence of these morbidities in the study population before screening, and thus is
difficult to pinpoint. Nevertheless, those receiving prostatectomy have been shown in research settings to have a 2- to
11-fold increase in risk of urinary incontinence and a 1.2- to
2.1-fold increase in risk of erectile dysfunction, relative to
men who are treated with watchful waiting.1 In the Task
Forces 2011 review,1 the smallest and largest absolute
percentile differences for urinary incontinence following
prostatectomy compared with watchful waiting were nine
(19% vs. 10%) and 40 (44% vs. 4%). For erectile dysfunction,
the figures were 21 (89% vs. 68%) and 36 (81% vs. 45%). In
a community-based (U.S.) study of experiences of men diagnosed with prostate cancer in 1994 and 1995 who had
radical prostatectomy, 87% of men reported that they had
total urinary control prior to their surgery as compared with
less than 40% at 6, 12, 24, and 60 months postsurgery.14
Eighty-one percent reported that they had erections firm
enough for intercourse before their surgery, as compared
with less than 30% at the same postsurgery time points.14
Radiation therapy may confer a lower relative risk of incontinence and erectile dysfunction, but androgen deprivation
therapy may increase the risk of the latter.15 Postoperative
deaths or cardiovascular events occur about 0.5% of the
time, although rates are age-dependent.
Men with overdiagnosed prostate cancers are harmed the
most by PSA screening. In the case of overdiagnosis, any
expense, inconvenience, discomfort, sexual dysfunction,
morbidity, hospitalization, or death that results from diagnostic evaluation for a positive screen and treatment of a
diagnosed cancer is entirely unnecessary. Figure 1 provides
convincing evidence of overdiagnosis: the number of prostate
cancer cases in the United States was substantially higher
in 2008 than it was in the early 1970s, but the prostate

cancer mortality rates between the early 1970s and 2008


were not very different. This increase in risk correlates with
two changes in medical practice: an increase in transurethral resection of the prostate (which could serendipitously
detect prostate cancers when performed for other reasons)
beginning in the 1970s and the adoption of PSA in the late
1980s. A true epidemic of prostate cancer cannot explain
this rise in incidence because the rise was unaccompanied by
extreme shifts in risk factor prevalence or the identification
of a new, widespread exposure that strongly increased risk;
even if it had, not all cancers would have been curable.
Additional data supporting the existence of overdiagnosis
come from a comparison of prostate cancer incidence and
mortality in Connecticut and the Seattle-Puget Sound
area,16 two areas that differed with regard to the uptake of
PSA screening in the 1980s and 1990s. Connecticut, where
PSA screening was less common, had consistently lower
prostate cancer incidence rates from 1987 through 2001, but
prostate cancer mortality rates were very similar, with
Seattle data showing a possible, although not statistically
significant, increase in prostate cancer mortality for men
ages 75 to 79. A nearly identical reduction in the prostate
cancer mortality rate in both regions over time has been
observed; if PSA screening was reducing mortality in addition to reductions due to treatment, the reduction for Seattle
would have been even more pronounced.
Microsimulation methods have been used to estimate the
percentage of prostate cancers that are considered to be
overdiagnosed disease. Using ERSPC data, Draisma and
colleagues estimated that among men screened annually
from age 55 to 67, 50% of screen-detected cases would be
overdiagnosed cases.17 Using SEER data, overdiagnosis
ranged from 23% to 42% of all screen-detected cases.18
Modeling using PLCO data is not yet available, but an
excess of cases existed in the intervention arm in every
study, including after 13 years of follow-up.8 Two years after
the last screen (i.e., the end of study year 7), the excess of
479 cases indicates that overdiagnosis could have accounted
for about 17% of cases in the screened arm. That figure is an
underestimate, as contamination occurred in the control
arm. Although it is unclear whether the extent of overdiagnosis is moderate or extreme, it is clear that it exists with
PSA screening.

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MARCUS AND KRAMER


Conclusion

One could argue that neither ERSPC nor PLCO findings


can be considered definitive, as the shortcomings of those
trials provide an unreliable measure of PSAs actual benefit.
In fact, the Physician Data Query Prevention and Screening
Editorial Board concluded that the evidence for PSA screening is insufficient to determine whether that practice results
in a mortality reduction. But board members concluded as
well that based on solid evidence, screening with PSA
and/or digital rectal exam detects some prostate cancers
that would never have caused important clinical problems
and leads to some degree of overtreatment, and that based
on solid evidence, current prostate cancer treatments, in-

cluding radical prostatectomy and radiation therapy, result


in permanent side effects in many men.19
The harms associated with PSA screening for prostate
cancer are well-established; the benefit of screening, however, is not and therefore remains theoretical. Given that a
central principle of medicine is first, do no harm, the
medical community must recognize that routine PSA screening may run counter to that principle. Rather than simply
advocating the practice both in the office and in the public
arena, health care providers must engage in informed decision making with men, as the U.S. Centers for Disease
Control and Prevention currently supports,20 to make sure
they are aware of the potential benefits, harms, and remaining uncertainties.

Authors Disclosures of Potential Conflicts of Interest

Author
Pamela M. Marcus*
Barnett S. Kramer*

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

*No relevant relationships to disclose.

REFERENCES
1. Chou R, Croswell JM, Dana T, et al. Screening for prostate cancer: a
review of the evidence for the U.S. Preventive Services Task Force. Ann Intern
Med. 2011;155:762-771.
2. Prorok PC, Kramer BS, Gohagan JK. Screening theory and study design:
the basics. In Kramer BS, Gohagan JK, Prorok PC (eds). Cancer Screening:
Theory and Practice. New York: Marcel Dekker, 1999;29-53.
3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer
J Clin. 2012;62:10-29. Epub 2012 Jan 4.
4. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics
Review 1975-2008. http://seer.cancer.gov/csr/1975_2008/. Accessed January
30, 2012.
5. UK National Screening Committee. Programme Appraisal Criteria.
http://www.screening.nhs.uk/criteria/fileid9287. Accessed January 30, 2012.
6. Djulbegovic M, Beyth RJ, Neuberger MM, et al. Screening for prostate
cancer: systematic review and meta-analysis of randomised controlled trials.
BMJ. 2010 Sep 14;341:c4543.
7. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostatecancer mortality in a randomized European study. N Engl J Med. 2009;360:
1320-1328.
8. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Prostate cancer
screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer
Screening Trial: Mortality results after 13 years of follow-up. J Natl Cancer
Inst. 2012;104:125-132.
9. Croswell JM, Kramer BS, Kreimer AR, et al. Cumulative incidence of
false-positive results in repeated, multimodal cancer screening. Am Fam Med.
2009;7:212-222.
10. Ilic D, OConnor D, Green S, et al. Screening for prostate cancer.
Cochrane Database Syst Rev. 2006 Jul 19;3:CD004720.
11. Loeb S, Carter HB, Berndt SI, et al. Complications after prostate biopsy:
data from SEER-Medicare. J Urol. 2011;186:1830-1834. Epub 2011 Sep 23.

100

12. Welch HG. Should I be tested for cancer? Maybe not and heres why.
Berkeley and Los Angeles, CA, University of California Press, 2004.
13. Nam RK, Saskin R, Lee Y, et al. Increasing hospital admission rates for
urological complications after transrectal ultrasound guided prostate biopsy.
J Urol. 2010;183:963-969.
14. Penson DF, McLerran D, Feng Z, et al. 5-year urinary and sexual
outcomes after radical prostatectomy: results from the Prostate Cancer
Outcomes Study. J Urol. 2005;173:1701-1705.
15. Potosky AL, Davis WW, Hoffman RM, et al. Five-year outcomes after
prostatectomy or radiotherapy for prostate cancer: the Prostate Cancer
Outcomes Study. J Natl Cancer Inst. 2004;96:1358-1367.
16. Lu-Yao G, Albertsen PC, Stanford JL, Stukel TA, Walter-Corkery E,
Barry MJ. Screening, treatment, and prostate cancer mortality in the Seattle
area and Connecticut: fifteen-year follow-up. J Gen Intern Med. 2008;23:18091814.
17. Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to
prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst. 2003;95:868878.
18. Draisma G, Etzioni R, Tsodikov A, et al. Lead time and overdiagnosis in
Prostate-Specific Antigen screening: importance of methods and context.
J Natl Cancer Inst. 2009;101:374-383.
19. Department of Health and Human Services, National Institutes of
Health, National Cancer Institute. Prostate cancer screening. http://www.
cancer.gov/cancertopics/pdq/screening/prostate/HealthProfessional. Accessed
March 5, 2012.
20. Department of Health and Human Services, Centers for Disease
Control and Prevention. Prostate cancer screening: a decision guide. http://
www.cdc.gov/cancer/prostate/pdf/prosguide.pdf. Accessed March 5, 2012.

GLIOBLASTOMA: TAKING THE STANDARD OF CARE


TO THE CUTTING EDGE
CHAIR
Mark R. Gilbert, MD
University of Texas M. D. Anderson Cancer Center
Houston, TX
SPEAKERS
Daniel J. Brat, MD, PhD
Emory University
Atlanta, GA
Howard Colman, MD, PhD
University of Utah
Salt Lake City, UT

Glioblastoma: Biology, Genetics, and Behavior


By Daniel J. Brat, MD, PhD

Overview: Glioblastoma (GBM) is a highly malignant, rapidly


progressive astrocytoma that is distinguished pathologically
from lower-grade tumors by necrosis and microvascular hyperplasia. The global pattern of growth changes dramatically
with the development of GBM histology and is characterized
by hypoxia-driven peripheral expansion from a growing necrotic core. Necrotic foci present centrally in GBM and are
typically surrounded by pseudopalisading cellsa configuration that is relatively unique and long recognized as an
ominous prognostic feature. Theses pseudopalisades are severely hypoxic, overexpress hypoxia inducible factor-1 (HIF-1),
and secrete proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin 8 (IL-8). The microvascular hyperplasia that emerges in response promotes
peripheral tumor expansion. Recent evidence suggests that
pseudopalisades represent a wave of tumor cells actively
migrating away from central hypoxia that arises following a

LIOBLASTOMA (GBM; World Health Organization


[WHO] grade 4) is the highest grade astrocytoma and
has a dismal prognosis.1 Mean survival following the most
advanced treatment, including neurosurgery, radiotherapy,
and chemotherapy is only 60 to 70 weeks.2 When patients
receive only surgical resection, but are not treated with
adjuvant therapy, mean survival is a mere 14 weeks, underscoring the tremendous natural growth properties of these
tumors. Lower-grade infiltrative astrocytomas (i.e., WHO
grade 2 and 3 astrocytomas) are also ultimately fatal, but
have substantially slower growth rates and longer survivals
(3 to 8 years). Only once lower-grade tumors have progressed to GBM do they demonstrate accelerated growth
and rapid progression to death. Those GBMs that progress
from lower-grade gliomas are referred to as secondary
GBMs, whereas those GBMs that present without a lowergrade precursor are termed primary or de novo GBMs.
De novo tumors account for approximately 90% of all GBMs
and are both clinically and molecularly distinct from secondary GBMs, as will be discussed below.
Growth Patterns in Grade 23 Astrocytomas

Importantly, the biologic properties of GBM (grade 4)


are quite distinct from those of lower-grade astrocytomas
(grade 2 and 3) and suggest that it represents more than an
incremental step in malignancy. The unique neuroimaging
and pathologic features that emerge during the transition to
GBM provide the best insight into potential mechanisms
responsible for the enhanced growth. By magnetic resonance
imaging (MRI), grade 2 and 3 astrocytomas show hyperintense T2-weighted (or fluid attenuated inversion recovery
[FLAIR]) signal abnormalities, reflecting vasogenic edema
generated in response to diffuse infiltration by individual
tumor cells. Lower-grade tumors expand the involved brain,
but show mild or no contrast enhancement, suggesting an
intact blood-brain barrier and a lack of tumor necrosis.
Radial growth rates are modest, with annual increases in
diameter of 2 to 4 mm/yr.3 Histologic sections of grade 23
tumors reflect the imaging properties: neoplastic cells are
seen diffusely infiltrating between neuronal and glial processes, leading to architectural distortion and edema.4-5 As

102

vascular insult. Vaso-occlusive and prothrombotic mechanisms in GBM could readily explain the presence of pseudopalisading necrosis in tissue sections, the rapid peripheral
expansion on neuroimaging, and the dramatic shift to an
accelerated rate of clinical progression as a result of hypoxiainduced angiogenesis. The genetic alterations that coincide
with progression to GBM include amplification of epidermal
growth factor receptor (EGFR), deletion of CDKN2A, and
mutation or deletion of PTEN. Other diagnostic and prognostic
tests used in neuro-oncology include assessment of 1p/19q,
MGMT promoter methylation, IDH1, and p53. More recently,
the Cancer Genome Atlas data have indicated that there are
four robust transcriptional classes of GBM, referred to as
proneural, neural, classical, and mesenchymal. These classes
have genetic associations and may pave the road for future
development of targeted therapies.

astrocytomas progress from the lower end of grade 2 to the


upper end of grade 3, the degree of nuclear anaplasia
increases and the proliferative capacity creeps upward,
resulting in a more densely cellular tumor with greater
malignant potential. Thus, grade 23 astrocytomas represent a continuum of gradually increasing tumor grade and
biologic potential, with clinical behavior generally correlating with the properties of individual tumor cells.
Changes in Tumor Growth from Grade 23
Astrocytomas to Glioblastoma

Tumor dynamics are fundamentally altered in GBM in


comparison to grade 23 astrocytomas. Radial growth rates
for GBM can accelerate to values nearly 10 times greater
than those in grade 2 astrocytomas.3 MRI of GBM typically
reveals a central, contrast-enhancing component (rimenhancing mass) emerging from within the infiltrative
astrocytoma and rapidly expanding outward, causing a
much larger T2-weighted signal abnormality in the tumors
periphery.
Studies of cellular proliferation strongly suggest a fundamental difference in driving biologic forces between the
grade 23 astrocytomas and glioblastoma.6 The most reliable marker of proliferation is the Ki-67/MIB-1 antibody,
which identifies nuclei of cells in the G1, S, G2, and M
phases of the cell cycle, but is not expressed in the resting
phase, G0. In one study of proliferation in diffuse astrocytomas of grades 2, 3, and 4, Giannini and colleagues found that
MIB-1 index was highly correlated with survival on multivariate analysis among grade 2 and 3 astrocytomas. However, when GBMs (grade 4) were included in the analysis,
proliferation was no longer an independent marker of prog-

From the Department of Pathology and Laboratory Medicine, Winship Cancer Institute,
Emory University School of Medicine, Atlanta, GA.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Daniel J. Brat, MD, PhD, Department of Pathology and
Laboratory Medicine, Emory University Hospital, H-176, 1364 Clifton Rd. NE, Atlanta, GA
30322; email: dbrat@emory.edu
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

GLIOBLASTOMA: BIOLOGY, GENETICS AND BEHAVIOR

nosis.7 Similarly, the significance of MIB-1 prolifieration in


prognosticating grade 2 and 3 astrocytomas was also supported by an investigation by Hsu and colleagues, who
concluded that the MIB-1 index was useful in grade 2 and 3
tumors, but not GBM.8 When proliferation is studied in the
setting of the GBM histology alone, the prognostic significance is not evident. For example, in one study of 116 newly
diagnosed GBMs, the mean MIB-1 index was 12.5% and
varied from 0 to 76.4%. In this series, MIB-1 proliferation was
not associated with survival on either univariate or multivariate analysis.9 Thus, taking the evidence from these and other
studies together, proliferation is a biologically important,
prognostically significant driving force in grade 2 and 3 astrocytomas. However, once the disease has progressed to GBM,
biologic forces more significant than proliferation emerge.
Forces That Drive Gliobastoma Progression

What are these driving forces that emerge in GBM? The


histopathologic features that distinguish GBM from lower
grade astrocytomas are found near the contrast-enhancing
rim on MRI and include the following: 1) foci of necrosis,
usually with evidence of surrounding cellular pseudopalisades (pseudopalisading necrosis), and 2) microvascular
hyperplasia, a form of angiogenesis morphologically recognized as endothelial proliferation within newly sprouted
vessels.1 In contrast to lower-grade astrocytomas, these two
diagnostic findings of GBM are largely independent of tumor
cell properties (i.e., degree of anaplasia, proliferation, etc.),
yet carry an inordinate degree of prognostic power. Rather
than mere markers, these structures are more likely to be
mechanistically linked to the accelerated growth properties
that characterize the grade 3 to 4 transition.
An emerging model of tumor progression may explain the
development of pseudopalisades, the relationship between
pseudopalisades and angiogenesis, and the strong association between pseudopalisades and aggressive clinical behav-

KEY POINTS

The growth pattern of glioblastoma is fundamentally


distinct from lower-grade gliomas and represents
more than a small incremental change in tumor
grade.
Whereas tumor cell proliferation is prognosic in
lower-grade gliomas, hypoxia-driven mechanisms become more relevant in glioblastoma.
Vasco-occlusion and thrombosis are typical in glioblastoma and likely initiate or propagate perfusionlimited hypoxia and necrosis associated with tumor
progression.
Genetic tests that are performed for diagnostic and
prognostic purposes for glioblastoma include assessment of EGFR, PTEN, 1p/19q, MGMT promoter
methylation, IDH1, and p53.
Analysis of the Cancer Genome Atlas data has demonstrated four distinct transcriptional classes of
glioblastoma that have genomic correlates and prognostic significance: proneual, neural, classical, and
mesenchymal.

ior.10,11 This model hypothesizes a sequence that begins


with an infiltrating astocytoma of moderate to high cellularity (i.e., grade 3 astrocytoma) and continues with 1) vascular
occlusion within the tumor that is often associated with
intravascular thrombosis; 2) hypoxia in regions surrounding
vascular pathology; 3) outward migration of tumor cells
away from hypoxia, creating a peripherally moving wave
(pseudopalisade) and central necrosis; 4) secretion of
hypoxia-inducible, proangiogenic factors (VEGF, IL-8) by
pseudopalisading cells; 5) an exuberant angiogenic response
creating microvascular proliferation in regions adjacent to
central hypoxia; and 6) accelerated outward expansion of
tumor cells toward a new vasculature. The global growth
properties of GBM within the brain reflect a coalescence of
these microscopic processes and result in a peripherally
expanding tumor with a large degree of central necrosis.
Pseudopalisades Are Actively Migrating Tumor Cells

Pseudopalisading of cells around central degereneration


has been recognized for nearly a century as both a defining
feature of GBM and a morphologic finding that predicts
aggressive behavior. A commonly held belief has been that
pseudopalisades represent a rim of residual tumor cells
around a centrally degenerating clone of highly proliferative
cells. However, recent studies have refuted this and concluded that pseudopalisades represent a wave of actively
migrating tumor cells that are moving away from an area of
central hypoxia. Pseudopalisading cells are known to be
hypoxic, as demonstrated by their dramatic upregulation of
HIF-1, a nuclear transcription factor that orchestrates the
cells adaptive response to low oxygen.12 Gene expression
studies performed on microdissected pseudopalisading cells
have demonstrated upregulated gene transcripts in this
population that suggest a response to a hypoxic microenvironment, including those related to glycolysis, angiogenesis,
and cell cycle control.13 Hypoxic GBM cells in culture that
have similar upregulation of HIF-1 are more highly migratory than normoxic cells, and HIF-1 itself mediates many of
the critical promigratory mechanisms in gliomas and other
neoplastic cells.12 Moreover, hypoxic pseudopalisades express increased levels of extracellular matrix proteases
associated with invasion, including MMP-2 and uPAR.4,12
Thus, the combined evidence suggests that the pseudopalisades in GBM are formed by a population of hypoxic,
actively migrating neoplastic cells that have imposed themselves on a less mobile population, thereby creating a hypercellular zone around an evolving area of central necrosis.
Pseudopalisades Are Hypoxic Tumor Cells Migrating
Away from Vascular Pathology

The hypoxia that leads to increased tumor cell migration


to form pseudopalisades and to widespread invasiveness
could result from limitations in vascular perfusion within
the tumor (i.e., disruption of the blood supply) or from
reduced oxygen diffusion within the neoplasm, in part due to
increased metabolic demands of a growing tumor. Attenuated perfusion would lead to cell migration away from
central blood vessels that no longer provides the necessary
oxygen supply. Limitations in oxygen diffusion, on the other
hand, would cause tumor cells at greatest distance from
arterial supplies to become hypoxic and migrate toward
viable vessels. These mechanisms are not mutually exclu-

103

DANIEL J. BRAT

sive. However, a growing body of experimental and observational evidence favors the hypothesis that pseudopalisades
represent tumor cells migrating away from a dysfunctional
vasculature.12,14,15 Perhaps less appreciated, abnormal vessels can often be noted within the lumina of at least a subset
of pseudopalisades. A comprehensive survey of human GBM
specimens found that over 50% of pseudopalisades had
evidence of a central vascular lumen that was either degenerating or thrombosed.12 Thus, pseudopalisades around necrosis appear to represent hypoxic tumor cells migrating
away from vaso-occlusion and thrombosis.
Intravascular Thrombosis Accentuates and Propagates
Tumor Hypoxia

While precise initiators of vascular pathology in GBM


continue to be studied, it is becoming clear that intravascular thrombosis within these neoplasms can accentuate and
propagate tumoral hypoxia and necrosis. Intravascular
thrombosis within the tumoral tissue of GBM is a frequent
intraoperative finding by the neurosurgeon. Even more
impressively, thrombosed vessels within resected GBM
specimens can almost always be identified under the microscope (noted histologically in over 90% of GBMs).12,15 In
contrast, the frequency of microscopic thrombosis is much
lower in anaplastic astrocytoma (grade 3), a tumor that
lacks necrosis and angiogenesis. In the uncommon instance
when intravascular thrombosis is identified microscopically
in anaplastic astrocytomas (AAs, WHO grade 3), it is predictive of aggressive growth, similar to that of GBM, suggesting it may precede the necrosis and angiogenesis that
arise in GBM and are associated with a more rapid progression.15 Since the frequency of intravascular thrombosis
within neoplastic tissue is much higher in GBMs (grade 4)
than AAs (grade 3), critical pro-thrombotic events must
occur in this transition. In many instances, the intravascular thrombosis can be seen within or adjacent to the regions
of pseudopalisading necrosis, leading to the proposition that
vaso-occlusion due to thrombosis could directly initiate or
propagate hypoxia and necrosis in GBM.
Multiple factors likely contribute to intravascular thrombosis in GBM, including abnormal blood flow within a
distorted vasculature, increased interstitial edema, dysregulation of pro- and anticoagulant factors, and access of
plasma-clotting factors to tumoral tissue. Normal central
nervous system (CNS) blood vessels allow only limited
diffusion though their walls because of a highly restrictive
blood-brain barrier, which is formed primarily by endothelial tight junctions, but also has contributions from astrocytic foot plates, extracellular matrix, and endothelialpericytic interactions. This barrier becomes breached in
GBM and can be visualized radiologically by the presence of
contrast enhancement due to increased vascular permeability to contrast agents (e.g., gadolinium) and to proteins that
bind them, such as albumin. Damaged vessels appear fenestrated, show detachment of pericytes, and exhibit extracellular matrix alterations. All the factors that contribute to
increased permeability have not been defined, but VEGF
secretion by neoplastic cells is known to cause vascular
leakage.16 One result is to bring plasma coagulation factors
such as factor VII into the tissue spaces where they are
activated by binding tissue factor and result in thrombosis.

104

Angiogenesis Supports Peripheral Tumor Growth

If emerging models of GBM progression are valid, then


vascular pathology may underlie the development of hypoxia and necrosis in GBM. Although necrosis has long been
recognized as a marker of aggressive behavior in diffuse
gliomas, by itself it does not explain rapid tumor progression. Indeed, tumor cell death is the goal of most adjuvant
therapies. Instead, pseudopalisades that surround necrosis
in GBM are intimately related to microvascular hyperplasia,
a defining morphologic feature of GBM that is most often
noted in regions directly adjacent to pseudopalisades.11 This
exuberant angiogenic response attempts to lay down a new
vasculature for rapid neoplastic expansion, yet the proper
function of these distorted vessels has not been established.
The formation of new blood vessels from pre-existing ones is
tightly regulated process and follows a complex sequence in
response to pro- and antiangiogenic factors. Initial phases
require increased vascular permeability of parent vessels,
extravasation of plasma, and deposition of proangiogenic
matrix proteins. In response to the mitogenic effects of
proangiogenic cytokines, endothelial cells proliferate and
migrate along a chemotactic gradient into the extracellular
matrix. Once established, endothelial cells form tubes with a
central lumen, elaborate a basement membrane, and eventually recruit pericytes and smooth muscle cells to surround
the mature vessels.
One of the most critical proangiogenic factors produced by
pseudopalisades that is responsible for directing nearby
angiogenesis in GBM is VEGF. As noted above, pseudopalisading cells are severely hypoxic and express high levels of
hypoxia-inducible transcription factors, including HIF-1.
The VEGF gene contains a hypoxia-responsive element
(HRE) within its promoter that binds HIF-1, thereby activating transcription.17 VEGF concentrations in the cystic
fluid of human GBMs can reach levels that are 200 300-fold
higher than in serum. Inhibition of this HIF/VEGF pathway
suppresses tumor growth experimentally. Once expressed
and secreted, extracellular VEGF binds to its high affinity
receptors, VEGFR-1 and VEGFR-2, which are upregulated
on endothelial cells of high-grade gliomas, but not present in
normal brain. Receptor activation then leads to angiogenesis
in regions adjacent to pseudopalisades, eventually leading to
a vascular density in GBMs that is among the highest of all
human neoplasms.
A second proangiogenic factor that is highly upregulated
in GBMs is interleukin-8 (IL-8, CXCL8).18 Much like VEGF,
hypoxia/anoxia strongly stimulates IL-8 expression and its
expression is also found at highest levels within the pseudopalisades of GBM. Unlike VEGF, IL-8 has a more punctate distribution within pseudopalisades, and it remains
unclear if tumor cells or scattered infiltrating macrophages
are most responsible for the majority of its expression.
Hypoxic upregulation of IL-8 is not directly due to HIF
activation, but is more likely due to activation of AP-1 by
hypoxia/anoxia. The IL-8 receptors that could potentially
contribute to IL-8 mediated tumorigenic and angiogenic
responses in GBM include CXCR1 and CXCR2, both of
which are G-protein coupled.
The precise type of angiogenesis that is most evident
in GBM, microvascular hyperplasia, is characterized by
numerous enlarged, rapidly dividing endothelial cells, pericytes, and smooth muscle cells that form tufted microaggre-

GLIOBLASTOMA: BIOLOGY, GENETICS AND BEHAVIOR

gates at the leading edge of sprouting vessels. In its most


florid form, angiogenesis takes the shape of glomeruloid
bodiesa feature that is most characteristic of GBM, but is
also an independent marker of poor prognosis in other forms
of cancer.19 Since necrosis and hypoxia are located in the
GBMs core and near the contrast-enhancing rim, hypoxiainduced angiogenesis occurs further peripherally, favoring neoplastic growth outward. The permissive nature of the CNS
parenchymal matrix to diffuse infiltration by individual
glioma cells allows for this burst of peripheral expansion.4
Genetic Testing

A large and growing number of genetic alterations have


been identified in the diffuse gliomas, some of which are
used for diagnostic and prognostic purposes in neurooncology. The genetic alterations that coincide with progression to GBM include amplification of EGFR, deletion of
CDKN2A, and mutation or deletion of PTEN. Other diagnostic and prognostic tests used in neuro-oncology include
assessment of 1p/19q, MGMT promoter methylation, IDH1,
and p53.1
p53 Pathway Alteration

Alterations in the p53 tumor suppressor pathway are


frequent in infiltrative astrocytomas. The p53 pathway can
be altered mechanisms including mutation of TP53 and
deletion of the opposite allele, MDM2 gene amplification,
and p14ARF gene deletion. Point mutations in the DNAbinding region of TP53 are the most frequent source of
inactivation. The majority (50% to 60%) of lower-grade
(WHO grade 2) infiltrating astrocytomas show such TP53
mutations, suggesting it occurs early. GBMs that arise from
grade 2 and 3 astrocytomas, so-called secondary GBMs, have
similar frequencies of TP53 mutations. TP53 mutations are
less frequent (30%) in primary, or de novo, GBMs, yet the
p53 pathway is altered by other mechanisms in these
tumors. The prognostic significance of TP53 mutations and
p53 protein expression in astrocytomas has been debated.
Young age is a strong predictor of prolonged survival among
patients with astrocytomas, especially GBM. Since TP53
mutations occur more frequently in GBMs from young
patients, their significance must be separated from the
survival advantage of youth.
For glioma classification, TP53 mutations currently have
limited utility. Since p53 derived from mutant genes has a
longer cellular half-life than wild type, the protein accumulates in the nucleus. Thus, positive nuclear immunohistochemical staining for the p53 protein correlates, albeit
imperfectly, with the presence of TP53 mutations. Positive
p53 immunostaining can be occasionally helpful for distinguishing astrocytic from oligodendroglial differentiation,
since the oligodendrogliomas rarely harbor TP53 mutations.
1p/19q

There is a strong association of allelic losses on chromosomes 1p and 19q and the oligodendroglioma phenotype, and
60% to 80% of oligodendroglial neoplasms demonstrate combined 1p and 19q losses.1,6 Enthusiasm for defining genetic
subsets of oligodendrogliomas increased substantially with
the demonstration of prognostically distinct groups.20
1p and 19q losses are less frequent in other forms of
gliomas. For example, Smith and colleagues investigated the

allelic losses of 1p and 19q in 115 diffuse gliomas.21 Combined loss of 1p and 19q were seen in 11% of astrocytomas,
31% of the mixed oligoastrocytomas, and 64% of oligodendrogliomas. Thus, while most oligodendrogliomas showed
1p/19q loss, not all did. Moreover, a small percentage of
mixed gliomas and astrocytomas also showed similar deletions. More recent studies have demonstrated less frequent
1p/19q losses in diffuse astrocytomas.22
Similar studies have interrogated the prognostic significance of combined loss of 1p and 19q in diverse types of
diffuse gliomas and found them to be predictive of prolonged
overall survival only for patients with oligodendrogliomas.
Combined 1p and 19q losses are not predictive of prolonged
survival in astrocytomas or oligoastrocytomas of any
grade.22-23 However, diagnostic testing for 1p/19q is often
used in cases of diffuse gliomas that have ambiguous morphology, since 1p/19q codeletion is highly associated with
oligodedroglioma.
EGFR

Amplifications of the EGFR gene occur in approximately


40% of GBMs and 10% of anaplastic astrocytomas.1 Amplifications are much less frequent in low-grade astrocytomas
and are considered a late genetic event in the progression of
tumors to GBM. Either wild-type or mutated forms of EGFR
can be amplified. The most common EGFR amplification is a
mutated form lacking exons 27, which results in a truncated cell surface protein with constitutive tyrosine kinase
activity (EGFRvIII).
The significance of EGFR gene amplification or EGFR
protein overexpression as a prognostic marker in GBM has
been debated. Most comprehensive studies have concluded
that EGFR status is not prognostically significant in patients with GBM. However, therapies have been developed
that are directed at the overexpressed EGFR in GBMs.
Therefore, it may become critical to establish the EGFR
status of GBM as a part of the pathologic diagnosis in order
to predict pharmacologic responses to EGFR inhibitors. For
example, Mellinghoff and colleagues demonstrated that
those GBMs that have the best therapeutic response to
EGFR inhibitors are characterized by the coexpression of
EGFRvIII and PTEN.24
Losses on Chromosome 10/PTEN Mutation

Some of the most frequent genetic deletions in GBMs


involve chromosome 10 and occur as losses of the entire
chromosome or as losses of only the long or short arms. Most
interest focuses on 10q, since it is commonly implicated in
high-grade progression and is the location of PTEN. Located
at 10q23.3, PTEN is mutated in 20% to 40% of GBMs and
generally occurs in the setting of chromosome 10 allelic loss.
Both chromosome 10 losses and PTEN mutations are much
more frequent in diffuse forms of astrocytoma than oligodendrogliomas. They are also relatively late events in the
progression to GBM, since both are much more frequent in
GBMs than in AAs or grade 2 astrocytomas.
The high frequency of chromosome 10 losses in GBMs
( 80%) and the tight correlation of its loss with the GBM
phenotype might suggest that it would not be a useful
prognostic marker across tumor grades. Indeed, in studies of
high-grade astrocytomas (AAs and GBMs), loss of heterozygosity (LOH) of chromosome 10 (either 10p or 10q) has been

105

DANIEL J. BRAT

an independent predictor of poor prognosis in large part


because LOH was highly associated with AAs that had short
survivals. Some investigators have therefore suggested that
AAs with LOH of 10q may behave clinically as GBMs.
Overall, it appears that chromosome 10 losses could serve as
a marker of astrocytic differentiation in diffuse high-grade
gliomas and of poor prognosis among high-grade astrocytomas, with special relevance for predicting aggressive AAs.
MGMT

Current standard of care chemotherapy (temozolomide)


used to treat GBM acts by crosslinking DNA by alkylating at
the O6 of guanine. DNA crosslinking is reversed by the DNA
repair enzyme MGMT (O6-methylguanine-DNA methyltransferase). Thus, low levels of MGMT expression would be
expected to be associated with an enhanced response to
therapy. The expression level of MGMT is determined in
large part by the methylation status of the genes promoter.
This epigenetic silencing of MGMT occurs in 40% to 50% of
GBMs and can be assessed by its promoter methylation
status on polymerase chain reaction (PCR)-based tests of
genomic DNA. Epigenetic silencing of MGMT in tumoral
tissue is associated with response to BCNU therapy and
improved survival in patients with GBM.
A recent investigation of temozolamide for the treatment
of GBM found that epigenetic gene silencing of MGMT was
associated with a longer survival, independent of treatment.2,25 The study also demonstrated a survival advantage
among those patients treated with temozolomide and radiotherapy whose GBMs had a silenced MGMT gene. Since
temozolamide is now standard of care for the treatment of
GBM, testing for MGMT status is becoming an important
component of a complete diagnostic work-up.
IDH1

Mutations in isocitrate dehydrogenase 1 (IDH1) are frequent in grade 2 and 3 astrocytomas, oligodendrogliomas,
and oligoastrocytomas, as well as the GBMs that progress
from these lower-grade lesions (i.e., secondary GBMs).26,27
IDH2 mutations have also been noted in these same neoplasms, but at much lower frequency. Since IDH mutations
occur in diffuse gliomas with astrocytic, oligodendroglial,
and mixed histologies, it is believed that they are an early
event, preceding molecular alterations such as TP53 mutations and 1p/19q codeletion, which are associated with
astrocytic and oligodendroglial histologies, respectively.
Within all histologic types and grade of diffuse glioma, the
presence of IDH mutations is associated with prolonged
survival. In GBMs, the finding of IDH1 mutations is
strongly associated with patients with younger age and a
substantially longer survival.26,27
Importantly, over 90% of IDH1 mutations in the diffuse
gliomas occur at a specific site and are characterized by a
base exchange of guanine to adenine within codon 132,
resulting in an amino acid change from arginine to histidine

(R132H). Because of this consistent protein alteration, a


monoclonal antibody has been developed to the mutant
protein, allowing its use in paraffin-embedded specimens
(mIDH1R132H).28 The initial characterization of this antibody was performed on 186 gliomas of various histologies
and grades that had been sequenced for IDH1 mutations
and showed excellent sensitivity and specificity of the antibody for mutations. Moreover, the ability of the antibody to
detect only a minor component of the tissue as mutant may
give this method greater sensitivity than sequencing for
identifying R132H mutant gliomas.
The Cancer Genome Atlas Project

The Cancer Genome Atlas (TCGA) is a large-scale collaborative effort supported by the National Cancer Institute
and the National Human Genome Research Institute that
has provided an integrated platform for defining the molecular alterations of cancer that are associated with pathologic
and radiologic features, clinical behaviors, and response to
therapy. One of the first three malignancies targeted by the
TCGA pilot project was GBM, resulting in the identification
of specific genetic mutations, copy number variations, chromosomal translocations, gene and microRNA expression,
and DNA methylation patterns in nearly 500 tumor samples. All data is publically available for intensive correlative
analysis. The genomic component of this investigation confirmed frequent alterations in the p53 (TP53 mutations,
p14ARF deletion, MDM2 amplification), RB (CDKN2A
deletion, CDK4 amplification, RB1 deletion/mutation), and
receptor tyrosine kinase signaling pathways (EGFR,
PDGFRA, and ERBB2 amplification, PTEN and PI(3)K
mutation, NF1 deletion).29 The TCGA project also led to the
identification of four distinct molecular subtypes based on
transcriptional profiles: proneural, neural, classical, and
mesenchymal.30 These expression classes have variable associations with genomic alterations. For example, the proneural class has a high frequency of IDH1 mutations and
PDGFR amplifications; NF1 mutations and deletions are
most frequent in the mesenchymal class; and the classical
class has a high frequency of EGFR amplifications. However, these genetic associations are not absolute, and GBMs
with EGFR and PDGFR amplification, TP53 and PTEN
mutations, and CDKN2A deletions are noted in each transcriptional class. The proneural gene expression signature is
associated with improved clinical outcome. Much of this
survival advantage is due to the inclusion of tumors with
IDH mutations. This specific subset of GBMs, those within
the proneural expression class and with IDH mutations, is
tightly correlated with the CpG island methylator phenotype (G-CIMP).31 The prognostic difference among the other
three transcriptional classes in the TCGA data is not statistically significant. However, this robust transcriptional classification may lead to the identification of class-specific
therapeutic targets that are directed at underlying molecular mechanisms.

Authors Disclosure of Potential Conflicts of Interest

Author
Daniel J. Brat*
*No relevant relationships to disclose.

106

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

GLIOBLASTOMA: BIOLOGY, GENETICS AND BEHAVIOR

REFERENCES
1. Louis DN, Ohgaki H, Wiestler OD, et al. WHO Classification of Tumours
of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research; 2007.
2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med.
2005;352:987-996.
3. Swanson KR, Bridge C, Murray JD, et al. Virtual and real brain tumors:
using mathematical modeling to quantify glioma growth and invasion. J Neurol Sci. 2003;216:1-10.
4. Bellail AC, Hunter SB, Brat DJ, et al. Microregional extracellular matrix
heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell
Biol. 2004;36:1046-1069.
5. Gupta M, Djalilvand A, Brat DJ. Clarifying the diffuse gliomas: an
update on the morphologic features and markers that discriminate oligodendroglioma from astrocytoma. Am J Clin Pathol. 2005;124:755-768.
6. Brat DJ, Prayson RA, Ryken TC, et al. Diagnosis of malignant glioma:
Role of neuropathology. J Neurooncol. 2008;89:287-311.
7. Giannini C, Scheithauer BW, Burger PC, et al. Cellular proliferation in
pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol. 1999;58:46-53.
8. Hsu DW, Louis DN, Efird JT, et al. Use of MIB-1 (Ki-67) immunoreactivity in differentiating grade II and grade III gliomas. J Neuropathol Exp
Neurol. 1997;56:857-65.
9. Moskowitz SI, Jin T, Prayson RA. Role of MIB1 in predicting survival in
patients with glioblastomas. J Neurooncol. 2006;76:193-200.
10. Brat DJ, Van Meir EG. Vaso-occlusive and prothrombotic mechanisms
associated with tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest. 2004;84:397-405.
11. Rong Y, Durden DL, Van Meir EG, et al. Pseudopalisading necrosis in
glioblastoma: a familiar morphologic feature that links vascular pathology,
hypoxia, and angiogenesis. J Neuropathol Exp Neurol. 2006;65:529-539.
12. Brat DJ, Castellano-Sanchez AA, Hunter SB, et al. Pseudopalisades in
glioblastoma are hypoxic, express extracellular matrix proteases, and are
formed by an actively migrating cell population. Cancer Res. 2004;64:920-927.
13. Dong S, Nutt CL, Betensky RA, et al. Histology-based expression
profiling yields novel prognostic markers in human glioblastoma. J Neuropathol Exp Neurol. 2005;64:948-955.
14. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science.
1999;284:1994-1998.
15. Tehrani M, Friedman T, Olson JJ, et al. Intravascular thrombosis in
central nervous system malignancies: a potential role in astrocytoma progression to glioblastoma. Brain Pathol. 2008;18:164-171.
16. Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular
permeability factor that promotes accumulation of ascites fluid. Science.
1983;219:983-985.

17. Plate KH. Mechanisms of angiogenesis in the brain. J Neuropathol Exp


Neurol. 1999;58:313-320.
18. Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its
receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncol. 2005;7:
122-133.
19. Straume O, Chappuis PO, Salvesen HB, et al. Prognostic importance of
glomeruloid microvascular proliferation indicates an aggressive angiogenic
phenotype in human cancers. Cancer Res. 2002;62:6808-6811.
20. Cairncross G, Berkey B, Shaw E, et al. Phase III trial of chemotherapy
plus radiotherapy compared with radiotherapy alone for pure and mixed
anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group
Trial 9402. J Clin Oncol. 2006;24:2707-2714.
21. Smith JS, Alderete B, Minn Y, et al. Localization of common deletion
regions on 1p and 19q in human gliomas and their association with histological subtype. Oncogene. 1999;18:4144-4152.
22. Perry A, Fuller CE, Banerjee R, et al. Ancillary FISH analysis for 1p
and 19q status: preliminary observations in 287 gliomas and oligodendroglioma mimics. Front Biosci. 2003;8:a1-a9.
23. Brat DJ, Seiferheld WF, Perry A, et al. Analysis of 1p, 19q, 9p, and 10q
as prognostic markers for high-grade astrocytomas using fluorescence in situ
hybridization on tissue microarrays from Radiation Therapy Oncology Group
trials. Neuro-oncol. 2004;6:96-103.
24. Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of
the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med.
2005;353:2012-2024.
25. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and
benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:9971003.
26. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of
human glioblastoma multiforme. Science. 2008;321:1807-1812.
27. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas.
N Engl J Med. 2009;360:765-773.
28. Capper D, Weissert S, Balss J, et al. Characterization of R132H
mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol.
2010;20:245-254.
29. The Cancer Genome Atlas Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature.
2008;455:1061-1068.
30. Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic
analysis identifies clinically relevant subtypes of glioblastoma characterized
by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:
98-110.
31. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG
island methylator phenotype that defines a distinct subgroup of glioma.
Cancer Cell. 2010;17:510-522.

107

Future Directions in Glioblastoma Therapy


By Howard Colman, MD, PhD

Overview: The standard of care for both newly diagnosed and


recurrent glioblastoma (GBM) patients has changed significantly in the past 10 years. Surgery followed by radiation and
concurrent and adjuvant temozolomide is now the wellestablished standard treatment for newly diagnosed GBM.
More recently, bevacizumab has become a mainstay of treatment for recurrent GBM. However, despite these advances and
significant improvements in patient outcomes, the management and treatment of GBM patients remains a challenging
and frustrating endeavor. Difficulties in interpretation of imaging changes after initial treatment, as well as the effects of
antiangiogenic agents like bevacizumab on MRI characteristics, can make even the determination of disease progression
complicated in multiple situations. Although a high percentage of patients benefit from antiangiogenic therapy in terms
of radiographic response and progression-free survival, the

LIOBLASTOMA (GBM) IS the most common malignant brain tumor in adults, with approximately 15,000
new GBM cases diagnosed each year in the United States.
GBM is classified by the World Health Organization (WHO)
as a grade 4 astrocytic tumor and is differentiated from
lower grade astrocytomas by the pathologic features of
pseudopalisading necrosis and microvascular proliferation,
among others.

Standard Therapy for Newly Diagnosed GBM

Radiographically, these tumors typically present as ring


enhancing masses on contrast-enhance MRI imaging, often
associated with marked infiltration and edema of surrounding brain. Standard treatment for newly diagnosed GBM
includes maximal safe resection followed by chemoradiation,
as defined by the phase III study by Stupp and colleagues.1
This standard treatment includes fractionated external
beam radiation given over 6 weeks to a dose of 60 Gy
combined with daily temozolomide at a dose of 75 mg/m2.
This initial concurrent chemoradiation phase is followed by
adjuvant temozolomide treatment at a dose of 150 mg/m2
day 1 through 5 out of 28 for the first cycle, with dose
escalation to 200 mg/m2 day 1 through 5 out of 28 for
subsequent cycles. The duration of adjuvant therapy in the
initial study was 6 months, but subsequent studies have
continued adjuvant treatment out to 12 months or more.
Although this regimen demonstrated significant improvement in median survival compared with radiation alone
(14.6 months compared with 12.1 months, p 0.001) and a
benefit in 2-year survival rates (26.5% compared with
10.4%), long-term survival for GBM patients remains disappointing. In a follow-up analysis of the initial phase III
study, 2-, 3-, and 5-year survival rates were 27.2%, 16.0%,
and 9.8%, respectively in the temozolomide chemoradiation
group.2 More recently, a phase III study comparing two dose
schedules of adjuvant temozolomide after chemoradiation
(RTOG 0525) was reported with no significant difference in
overall survival between the standard and dose-dense temozolomide groups.3 Together, these studies demonstrate that
temozolomide chemoradiation has a significant benefit in
newly diagnosed GBM compared to radiation alone (and
prior chemotherapy/radiation combinations). However, de-

108

effects of bevacizumab on prolonging overall survival remain


controversial. Furthermore, tumor progression after treatment
with antiangiogenic agents carries a particularly poor prognosis and there is a general lack of effective therapies for this
group of patients. These limitations in terms of standard
treatments contrast with a relative wealth of new information
regarding the molecular underpinnings of GBM. Data from
several large-scale efforts to molecularly profile GBM tumors
including The Cancer Genome Atlas (TCGA) project have
helped define specific molecular subtypes of GBM with distinct biology and clinical outcomes. These findings are helping
to refine our understanding of the molecular heterogeneity
and pathogenesis of these tumors and provide a basis for the
future development of rational and targeted therapies for
specific tumor subtypes.

spite this improved standard of care, the majority of patients


still die of their disease before 2 years.
The Problem of Pseudoprogression

One aspect of the management of GBM patients that


causes significant uncertainty is the issue of interpretation
of MRI imaging and disease progression. Gadoliniumenhanced MRI remains the mainstay of assessment of GBM
status. However, changes in enhancement on MRI reflect
changes in vascular permeability, and are thus an imaging
surrogate for disease status rather than a reflection of true
tumor burden. Other causes of increased vascular permeability can increase the extent and degree of enhancement on
MRI, resulting in a potentially incorrect determination of
tumor progression. This need to differentiate pseudoprogression (a radiographic increase in MRI enhancement or
edema resulting from tissue injury or inflammation without
increased tumor activity) from true tumor progression represents a clinical and diagnostic challenge, particularly in
patients who have recently completed radiation with concurrent chemotherapy.4 Pseudoprogression typically stabilizes
or improves without alteration in treatment within 3 to 6
months. Pseudoprogression rates have been reported between 9% and 31% in patients with malignant glioma after
chemoradiation, with significantly higher incidence in tumors with MGMT promoter methylation.5,6
Since conventional MRI often cannot distinguish true
progression from pseudoprogression, a lot of attention has
been focused on other advanced imaging modalities. Although MRI perfusion, MRI spectroscopy, and PET can add
diagnostic information and aid in clinical decision making,
none of these are sufficiently sensitive or specific to definitively determine the underlying etiology.7 An incorrect determination of progression in these patients can lead to

From the Department of Neurosurgery and Huntsman Cancer Institute, University of


Utah, Salt Lake City, UT.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Howard Colman, MD, PhD, 175 North Medical Drive East,
Salt Lake City, UT, 84132; email: howard.colman@hci.utah.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

FUTURE DIRECTIONS IN GBM THERAPY

premature discontinuation of an effective therapy and/or


initiation of less effective therapies. In addition, treatment
of pseudoprogression as progression with an alteration in
therapy can lead to a misinterpretation of subsequent imaging improvement as a response to the new therapy. For
these reasons, a clear understanding regarding the issues
and limitations of current imaging is crucial for clinicians
managing these patients. To help guide these decisions, the
recent recommendations by the Response Assessment in
Neuro-Oncology (RANO) Working Group are that progression can only be determined with certainty in the 12 weeks
after initial chemoradiation by pathologic confirmation or if
the majority of the new enhancement is outside the original
high-dose radiation field.8 Patients in which the determination of progression cannot be made with certainty should not
be enrolled in clinical trials during this time period, and
patients who remain clinically stable or in whom pseudoprogression is suspected should continue with their current
therapy.
Standard Therapies for Recurrent GBM

Following disease progression, historic outcomes for treatment of recurrent disease have been disappointing. In
pooled analyses of multiple clinical trials for recurrent
GBM, response rates have ranged from 4% to 7%; 6-month

KEY POINTS

Radiation therapy with concurrent temozolomide and


adjuvant temozolomide is the established standard
treatment for newly diagnosed glioblastoma (GBM).
Pseudoprogression is an important complicating factor in the interpretation of MRI imaging of GBM
patients and practitioners need to have a good awareness of this issue and familiarity with current recommendations by the Response Assessment in NeuroOncology (RANO) Working Group.
Although multiple therapeutic options exist for recurrent GBM, bevacizumab monotherapy remains the
most common standard salvage therapy. However,
bevacizumab treatment is associated with modest
effects on overall survival, difficulties in imaging
interpretation of progression, and the development of
resistance and poor prognosis at progression.
Understanding of the molecular alterations associated with distinct molecular subtypes and clinical
outcome in GBM continues to increase. Key biomarkers with prognostic and/or tumor subtype associations include proneural and mesenchymal gene
expression patterns, MGMT promoter methylation,
IDH1 mutation, and CpG island methylation phenotype (CIMP).
The efficacy and evaluation of targeted therapy in
GBM can be complicated by issues of drug permeability and difficulty in assessing biologic endpoints in
the tumor, and these aspects have to be addressed in
current and future clinical trials to increase the
likelihood of further improvements in outcome.

progression-free survival (PFS) rates ranged from 9% to


15%; and median overall survival (OS) rates ranged from
57 months.9,10 Standard treatment options for recurrent
disease are more varied than for newly diagnosed patients,
with recent United States Food and Drug Administration
(FDA) approvals adding to the number and types of standard treatment options. Reresection alone or with placement
of polifeprosan 20 with carmustine is an option for patients
with recurrence in noneloquent areas of the brain.11,12
Treatment with additional cytotoxic chemotherapy is frequently considered, with several potential choices. Retreatment with alternative schedules of temozolomide has some
efficacy, with one study suggesting improved 6-month PFS
and one-year survival in patients who had been stable for
at least several months after completing standard adjuvant
temozolomide, but with poorer outcomes in patients who
were treated with an alternative temozolomide schedule at
the time of failure on standard dose temozolomide.13 Several
other alkylating agents (CCNU, BCNU) and other cytotoxic
chemotherapies (carboplatin, irinotecan, etoposide) are also
options for initial or subsequent progressions. Evaluation of
data from the control arm using CCNU at 100 130 mg/m2
every 6 weeks from a recent phase III study demonstrated
a modest radiographic response rate (4.3%) but a relatively
good PFS-6 rate of 19%,14 which was somewhat better than
the enzastaurin (experimental) arm (11.1%, p 0.13) and
highlighted the potential activity of CCNU in this situation.
Very recently, the FDA approved a device, the NovoTTF100A system, for treatment of recurrent GBM based on a
randomized study demonstrating similar survival outcomes
in patients treated with this system compared with chemotherapy of the physicians choice.
Antiangiogenic Therapies

Glioblastoma has long been recognized as a promising


tumor for antiangiogenic treatments because of its high
vascularity. Perhaps the most significant development in
the treatment of recurrent GBM in recent years has been
the development of antiangiogenic therapies and the FDA
granting of accelerated approval in March 2009 for bevacizumab. Although this agent has altered the standard options and approach for recurrent GBM, it has also become
increasingly clear that this treatment has limitations in
terms of disease control and requires clinicians to modify
their standard interpretation of MRI imaging and determination of disease progression. This approval was based on
two independent phase II studies demonstrating activity.15,16 Both studies showed a high radiographic response
rate and an improvement in 6-month PFS with bevacizumab
treatment compared to prior historic controls treated with
cytotoxic chemotherapies and other targeted agents. In the
multicenter BRAIN study, use of bevacizumab resulted in a
radiographic response rate of 28% (95% CI 18.5%, 40.3%)
and the median duration of response was 4.2 months (95%
CI 3.0%, 5.7%).15 Bevacizumab treatment also resulted in an
increase in the percentage of patients treated with stable or
decreasing corticosteroid dosages. A second study reported
by Kreisl and colleagues demonstrated similar results with
single agent bevacizumab in which 29% of patients achieved
6 months of PFS.16 Based on these results, two phase III
studies testing the addition of bevacizumab to temozolomide
chemoradiation in newly diagnosed GBM have been completed or are in progress, with results expected within the

109

HOWARD COLMAN

next 2 to 3 years. In addition to bevacizumab, several other


agents targeting vascular endothelial growth factor (VEGF)
or its receptor have been tested in clinical trials. In general,
reported radiographic response rates and PFS rates have
been similar or lower with these agents compared with
bevacizumab.17,18 In one recent phase III study testing the
VEGF receptor inhibitor cediranib as monotherapy or with
lomustine compared with lomustine alone in recurrent GBM
found no significant difference in median PFS between these
groups.19
The Problem of Bevacizumab Failure

Although bevacizumab and other antiangiogenesis agents


have demonstrated improved radiographic response rates
and PFS rates in recurrent GBM compared to prior cytotoxic
and targeted therapies, it is less clear that these agents are
really improving OS. In addition, multiple studies to date
have failed to demonstrate a benefit of combination therapy
with bevacizumab. In the setting of bevacizumab failure,
studies of various salvage therapies have demonstrated low
radiographic response rates and 6-month PFS rates in the
0% to 2% range.20,21 This dismal prognosis indicates that
progression in the setting of antiangiogenic therapy likely
represents a change in biology of the tumor. However, the
mechanisms of resistance and strategies for optimizing
treatment at this stage of disease remain an active area of
investigation. Because of concern regarding rebound edema
with discontinuation of bevacizumab, many practitioners
tend to continue bevacizumab in this setting despite radiographic progression. Although data related to the question
of continuation or discontinuation of bevacizumab at the
time of bevacizumab progression continues to evolve, a
recent single institution meta-analysis suggested an improved outcome with continuation of bevacizumab in this
situation.22
Opportunities and Barriers for Improved
Treatment of GBM

Molecular subtypes and candidate therapeutic targets in


GBM. One of the recent therapeutic themes in oncology is
that the identification of signature molecular alterations in
particular tumors in combination with drugs that potently
and specifically target that alteration can have dramatic
effects on patient outcome. The term oncogene addiction
describes the hypothesis that tumor growth and survival is
dependent on activity of one key gene or pathway23 and can
be seen in successes of targeted therapies in specific tumor
subtypes such as imatinib for BCR-ABL-positive CML or
BRAF inhibitors for metastatic melanoma with BRAF mutations. Although similar dramatic advances in GBM have
not been observed yet, notable increases in our knowledge of
the molecular underpinnings of GBM are raising hopes for
targeted breakthroughs in therapy.
Strong data indicate that the pathologic entity defined
under the single WHO diagnosis of GBM consists of multiple
molecular subtypes of tumors. These tumors all share the
histopathologic features of GBM, but demonstrate very
distinct biology and molecular ontology. These data may
point the way to more effective or personalized treatment
based on the molecular features of an individual patients
tumor.24 In particular, several studies have identified gene
expression differences between GBM subtypes. One prominent subtype, referred to as mesenchymal, is characterized

110

by increased levels of expression of genes associated with


mesenchymal differentiation, extracellular matrix, invasion,
and angiogenesis. These mesenchymal tumors are associated with worse prognosis and may be associated with
primary GBMs. Another robust gene expression GBM
subtype identified and validated in multiple data sets is
characterized by increased expression of genes associated
with normal neural tissues or neural development, and has
been called proneural. These proneural tumors are associated with better prognosis and secondary GBMs.25-27
The recent integrated molecular analysis from The Cancer
Genome Atlas Network (TCGA) effort in GBM further found
that specific somatic mutation and DNA copy number alterations were associated with specific gene expression subtypes.27 Proneural tumors were associated with significantly
higher rates of point mutations in IDH1 (p 0.01) or p53
genes (p 0.1), and amplification of PDGRA (p 0.01). In
contrast, mesenchymal tumors were characterized by higher
rates of chromosomal deletions involving NF1 or mutations in NF1. Another gene expression subtype called Classical was associated with higher rates of amplification of
chromosome 7 (including amplification of EGFR) and loss
of chromosome 10. Since these molecular alterations are
associated with differences in clinical behavior and prognosis, these and other less-dominant molecular alterations
are potential candidates for therapies targeting particular
tumor subtypes.
Predictive and Prognostic Biomarkers in GBM

In addition to a better understanding of the molecular


pathogenesis of gliomas, the growing molecular profiling
data have led to the identification of biomarkers that are
beginning to be used to help guide patient therapy. Clinically relevant biomarkers can be roughly divided into those
that are prognostic and predictive. Prognostic markers are
associated with patient outcome or natural history of the
disease in patients without treatment or in patients receiving nontargeted therapies. Predictive biomarkers are associated with differential outcome to treatment with a specific
targeted therapy. Recent studies have identified several
molecular markers prognostic of patient outcome to standard therapy (radiation and temozolomide) in GBM. These
include MGMT promoter methylation28 and a multigene
predictor based on gene expression levels of multiple
genes.25 Mutation in the genes IDH1 and IDH2 was recently
described in low- and high-grade gliomas.29 Mutation of
IDH1 or IDH2 is observed in a small subset of GBM tumors
and is strongly associated with the proneural gene expression phenotype and better prognosis. In addition, evidence
from TCGA has also identified an epigenetically defined
tumor subset that overlaps with IDH1 mutation. This
CIMP, is analogous to prior descriptions of CIMP in colon
cancer and other tumors, although the identity of the genes
methylated in GBM is distinct from these other tumors.30
CIMP-positive tumors are positively associated with IDH1
mutation and show improved prognosis, compared to CIMPnegative tumors. Future work is required to define the
causative role of CIMP, IDH mutation, and their relation to
gene expression phenotype and gliomagenesis in GBM and
lower grade gliomas.

FUTURE DIRECTIONS IN GBM THERAPY


Challenges for the Evaluation and Efficacy of
Targeted Therapies in GBM

As in other solid tumors, there are currently a large


number of ongoing trials in GBM testing various targeted
therapies and other approaches to overcoming resistance
including those targeting DNA repair, receptor tyrosine
kinases and other signaling pathways, and pathways involved in tumor stem-cell maintenance and regulation.
Unfortunately, the use of targeted therapies in brain tumors and their evaluation in clinical trials face some additional challenges that are different than with solid tumors
elsewhere in the body. First, many small molecule inhibitors have relatively poor penetration into the brain and
cerebrospinal fluid, resulting in lower effective dose. Second,
evaluating the biologic effects of a drug on its target in
brain tumors is challenging because of its anatomic location
and increased difficulty in doing repeat biopsies during or

after treatment compared to some other systemic cancers.


Nonetheless, if experience from other solid tumors is any
indication, future successful clinical trials in recurrent
GBM will likely need to have a larger emphasis on pharmacodynamics and biologic tissue effects as important endpoints.
In summary, the dramatic increase in our understanding
of the molecular underpinnings and subtypes of glioblastoma, along with increases in the number and type of
available small molecule inhibitors, indicates that improvement in patient outcome in GBM with appropriate targeted
therapy is indeed feasible. However, the success and rapidity of these developments will hinge on successful integration of molecular and preclinical data with the more efficient
and innovative clinical trial designs in order to identify
those key pathways and drugs that will have the highest
benefit for particular GBM subtypes.

Authors Disclosure of Potential Conflicts of Interest

Author
Howard Colman

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Castle
Biosciences

REFERENCES
1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med.
2005;352:987-996.
2. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with
concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the
EORTC-NCIC trial. Lancet. 2009;10:459-466.
3. Gilbert MR, et al. M.P. RTOG 0525: A randomized phase III trial
comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd)
schedule in newly diagnosed glioblastoma (GBM). Neuro-Oncology. 2011;
13:3s (suppl; abstr 46).
4. de Wit MC, de Bruin HG, Eijkenboom W, et al. Immediate postradiotherapy changes in malignant glioma can mimic tumor progression.
Neurology. 2004;63:535-537.
5. Brandsma D, van den Bent MJ. Pseudoprogression and pseudoresponse
in the treatment of gliomas. Curr Opin Neurol Neurosurg. 2009;22:633-638.
6. Brandes AA, Franceschi E, Tosoni A, et al. MGMT promoter methylation
status can predict the incidence and outcome of pseudoprogression after
concomitant radiochemotherapy in newly diagnosed glioblastoma patients.
J Clin Oncol. 2008;26:2192-2197.
7. Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and
management of pseudoprogression in malignant gliomas. Lancet. 2008;9:453-461.
8. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology
working group. J Clin Oncol. 2010;28:1963-1972.
9. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors
in recurrent glioma patients enrolled onto phase II clinical trials. J Clin
Oncol. 1999;17:2572-2578.
10. Lamborn KR, Yung WK, Chang SM, et al. Progression-free survival: an
important end point in evaluating therapy for recurrent high-grade gliomas.
Neuro-Oncology. 2008;10:162-170.
11. Barker FG 2nd, Chang SM, Gutin PH, et al. Survival and functional
status after resection of recurrent glioblastoma multiforme. Neurosurgery.
1998;42:709-720.
12. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of
safety and efficacy of intraoperative controlled delivery by biodegradable
polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor
Treatment Group. Lancet. 1995;345:1008-1012.
13. Perry JR, Belanger K, Mason WP, et al. Phase II trial of continuous
dose-intense temozolomide in recurrent malignant glioma: RESCUE study.
J Clin Oncol. 2010;28:2051-2057.
14. Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of

enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28:1168-1174.
15. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in
combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;
27:4733-4740.
16. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent
bevacizumab followed by bevacizumab plus irinotecan at tumor progression
in recurrent glioblastoma. J Clin Oncol. 2009;27:740-745.
17. Norden AD, Drappatz J, Wen PY. Antiangiogenic therapies for highgrade glioma. Nat Rev Neurol. 2009;5:610-620.
18. Reardon DA, Turner S, Peters KB, et al. A review of VEGF/VEGFRtargeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw.
2011;9:414-427.
19. Batchelor T, Mulholland P, Nyns B, et al. The efficacy of cediranib as
monotherapy and in combination with lomustine compared to lomustine alone
in patients with recurrent glioblastoma: A phase III randomized study. Neuro
Oncol. 2010;12(suppl 4).
20. Iwamoto FM, Abrey LE, Beal K, et al. Patterns of relapse and prognosis
after bevacizumab failure in recurrent glioblastoma. Neurology. 2009;73:1200-1206.
21. Quant EC, Norden AD, Drappatz J, et al. Role of a second chemotherapy
in recurrent malignant glioma patients who progress on bevacizumab. Neuro
Oncol. 2009;11:550-555.
22. Reardon DA, Vredenburgh JJ, Desjardins A, et al. Bevacizumab (BV)
continuation following BV progression: Meta-analysis of five consecutive recurrent glioblastoma (GBM) trials. J Clin Oncol. 2011;29:45s(suppl; abstr 2030).
23. Weinstein IB, Joe A. Oncogene addiction. Cancer Res. 2008;68:3077-3080.
24. Colman H, Aldape K. Molecular predictors in glioblastoma: toward
personalized therapy. Arch Neurol. 2008;65:877-883.
25. Colman H, Zhang L, Sulman EP, et al. A multigene predictor of
outcome in glioblastoma. Neuro-Oncology. 2010;12:49-57.
26. Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of
high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157-173.
27. Verhaak RG, Hoadley KA, Purdom E, et al. Integrated genomic analysis
identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98-110.
28. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit
from temozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003.
29. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas.
N Engl J Med. 2009;360:765-773.
30. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG
island methylator phenotype that defines a distinct subgroup of glioma.
Cancer Cell. 2010;17:510-522.

111

Establishing the Standard of Care for


Patients with Newly Diagnosed and
Recurrent Glioblastoma
By Mark R. Gilbert, MD

Overview: The current standard of care for patients with


newly diagnosed glioblastoma includes maximal safe tumor
resection followed by concurrent external-beam radiation with
daily low-dose temozolomide followed by 6 to 12 months of
adjuvant temozolomide, typically by using a cycle of 5 consecutive days out of 28. Efforts to improve on these results
from the European Organisation for Research and Treatment
of Cancer (EORTC)/National Cancer Institute of Canada (NCIC)
trial using either dose-dense chemotherapy strategies or
combinations with signal transduction modulators have, to
date, been unsuccessful. Two large international randomized
trials examining the efficacy of adding bevacizumab, an antiangiogenic agent, to the standard treatment have been completed, with expectations of results within in the next 2 years.
For recurrent glioblastoma, there are no firmly established

LIOBLASTOMA IS classified as a grade 4 glioma by


using the now universally accepted WHO grading
criteria. It is the most common malignant primary brain
neoplasm, accounting for 54% of all gliomas.1 The annual
incidence in the United States is estimated to be between
3 and 4 per 100,000 of the general population. Although
glioblastoma is found in all age groups, the highest incidence
is in middle age to elderly. Although distinct pathologic
characteristics such as microvascular proliferation and necrosis are used to define the disease, recent advances in
molecular characterization demonstrate that the uniform
histologic criteria belie tremendous genetic heterogeneity.
Primary glioblastoma, developing as a glioblastoma, has
distinct molecular characteristics from the secondary glioblastoma which evolves from the progression transformation
from lower grade gliomas.2 These differences may influence
treatment decisions and in the case of mutations in the
IDH1 gene which is found almost exclusively in secondary
glioblastoma, clear implications on prognosis.3
The prognosis for patients with glioblastoma remains
poor. Overall, the 1-year survival rate in population-based
studies is less than 40%, although patients enrolled on
clinical trials do have better reported outcomes.1 Several
clinical prognostic factors have been identified, including
age, performance status, and extent of initial tumor resection.4 Several of the important clinical prognostic factors
have been combined by using recursive partitioning analysis
into a six-class system, allowing easier stratification accounting in clinical trials.5 Median survival for glioblastoma
ranges from 6 months to 18 month according to clinical
prognostic factors in the recursive partitioning analysis.
This underscores the importance of clinical factors in outcome and the potential for misinterpretation of clinical trial
outcomes if there is an imbalance of these factors. Additionally, molecular prognostic factors have been identified that
are independent of the clinical factors. These include IDH1
mutation, presence of a glioma-specific CpG Island hypermethylation phenotype (G-CIMP), a gene expression profile,
and the methylation of the promoter region of the methylguanine methyltransferase (MGMT) gene.3,6-8

112

standards of care. Although intracavitary insertion of carmustineimpregnated polymers has been approved by the U.S. Food
and Drug Administration (FDA), this strategy is not widely
used. Bevacizumab has been FDA approved for recurrent
glioblastoma, but no randomized trial has clearly demonstrated a survival benefit. Alternative dosing schedules of
temozolomide (i.e., metronomic) has modest activity even in
patients with prior temozolomide exposure. Clinical trials
testing small-molecule signal transduction modulators have
been disappointing, although most report a small response
rate, suggesting that molecularly definable tumor subpopulations may help guide treatment decisions. Successful
implementation of marker-based treatment would lead to
personalized care and the creation of individualized standards
of care.

Treatment of Newly Diagnosed Glioblastoma

The seminal work of the Brain Tumor Study Group in


the 1970s established the efficacy of external-beam radiation
for glioblastoma.9 Their studies demonstrated a more than
doubling of survival from 3 to 4 months with surgery and
corticosteroids to more than 9 months with radiation treatment. The addition of chemotherapy, typically a nitrosourea
such as lomustine or carmustine, did not substantially
improve survival compared with radiation alone. In fact, a
large meta-analysis compiling 12 randomized trials and
including more than 3,000 patients found only a 6% improvement in 1-year survival when chemotherapy was
added to surgery and conventional radiation.10
However, a new standard of care for patients with glioblastoma was established with the 2005 publication of the
results of a clinical trial performed by the European Organisation for Research and Treatment of Cancer (EORTC) and
National Cancer Institute of Canada (NCIC).11 This was a
large, randomized phase III trial that compared regional
external-beam radiation (60 Gy in 2-Gy fractions) as the
standard arm with the experimental treatment comprising
concurrent regional radiation (60 Gy in 2-Gy fractions) with
daily temozolomide (75 mg/m2 for 42 consecutive days). The
chemoradiation was then followed by six cycles of singleagent temozolomide (150 to 200 mg/m2/day for 5 consecutive
days of every 28 day cycle). The treatment schema is
provided in Fig. 1. The clinical trial demonstrated statistically significant improvements in overall survival (14.6 vs.
12.1 months), progression-free survival, and the 2-year survival rate (26.5% vs. 10%). Long-term follow-up continued to
demonstrate improved outcomes with a 5-year survival rate

From the Department of Neuro-oncology, University of Texas M. D. Anderson Cancer


Center, Houston, TX.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Mark R. Gilbert, MD, Department of Neuro-oncology,
University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX
77030; email: mrgilbert@mdanderson.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

ESTABLISHING TREATMENTS FOR GLIOBLASTOMA

Fig. 1. Treatment schema for the chemoradiation regimen from the EORTC/NCI-Canada Clinical Trial.

of 9.8% in the combined treatment patients compared with


1.9% in the radiation-only group.12
A companion laboratory correlative study to the EORTC/
NCIC trial evaluating patient outcomes on the basis of the
methylation status of the methylguanine methyltransferase
(MGMT) gene was performed by Hegi and colleagues.8
Hypermethylation of the promoter region was postulated to
decrease or eliminate gene expression and that with absent
or low intracellular MGMT, a major mechanism of repair of
alkylating agentmediated DNA damage. Therefore, in the
presence of the methylated MGMT promoter region, the
addition of temozolomide would result in a better response
rate. They were able to analyze 206 and found that 45% were
had MGMT promoter methylation. These studies did demonstrate an improved outcome for patients with tumors
harboring methylated MGMT gene promoter regions. However, although not as marked, the outcomes for patients
with unmethylated tumors experienced improvement with
the addition of temozolomide, suggesting that MGMT methylation status is clearly prognostic but not fully predictive of
treatment benefit.
These findings, correlating MGMT promoter methylation
with outcomes, suggested that the MGMT enzyme may be
an important therapeutic target and depletion of intracellular MGMT in tumor cells may enhance temozolomide
efficacy. Prolonged exposure to temozolomide has been demonstrated to decrease MGMT activity in peripheral-blood
mononuclear cells in patients receiving 21 consecutive days
of treatment.13 This approach, using a dose-dense treatment
schedule, was tested in Radiation Therapy Oncology Group

KEY POINTS

A standard of care consisting of concurrent radiation


and temozolomide followed by adjuvant temozolomide has been established for patients with newly
diagnosed glioblastoma.
Recently completed and ongoing randomized clinical
trials in newly diagnosed glioblastoma seek to enhance the current therapy by adding synergistic
therapies.
There are very few treatments established for recurrent glioblastoma despite extensive testing of many
signal transduction modulators.
Antiangiogenic therapies look promising for recurrent glioblastoma. Bevacizumab is administered frequently in this setting.
Given the molecular heterogeneity of glioblastoma,
further advances will likely require a comprehensive
effort merging tumor profiling with targeted
therapies.

(RTOG) 0525, an international collaborative phase III


trial.14 Enrollment criteria included adults older than 18
years with available tumor tissue blocks with more than
1 cm2 of tumor and Karnofsky performance score of 70 or
greater. All patients received concurrent radiation with
daily temozolomide and then were randomly assigned to
either standard adjuvant temozolomide (150 to 200 mg/m2/
day for 5 consecutive days of a 28-day cycle) or dose-dense
temozolomide (75 to 100 mg/m2/day for 21 consecutive days
of a 28-day cycle). Patients could receive treatment for up
to 12 cycles of adjuvant therapy. The study accrued 1,173
patients with 833 undergoing random assignment. The two
treatment arms were well balanced in all parameters including age, gender, performance status, extent of tumor resection and MGMT methylation status. The results, presented
at the 47th ASCO Annual Meeting (June 4 8, 2011, Chicago,
IL), demonstrated that there was no improvement in either
overall or progression-free survival with the use of the
dose-dense temozolomide schedule. Additionally, subset
analysis by MGMT methylation status did not show a
selective benefit for dose-dense treatment for tumors with
either methylated or unmethylated MGMT gene promoter
phenotype. However, this prospective study did demonstrate
that MGMT methylation status is clearly prognostic.
Other strategies have been evaluated as potential enhancers of the established efficacy of the chemoradiation regimen. A series of signal transduction modulators and other
similar agents have been evaluated, typically in single-arm
phase II trials. Agents such as erlotinib, talampanel, and
Poly ICLC have been tested with promising results compared with the historic controls provided by the EORTC
study.15,16 However, the validity of this comparison has been
questioned, and concerns regarding patient population differences and the more recent availability of effective salvage
regimens have limited interest in pursuing large-scale clinical trials.
Interest in the use of antiangiogenic strategies has generated several large-scale randomized clinical trials. Bevacizumab, a humanized monoclonal antibody targeting
vascular endothelial growth factor (VEGF) A, has demonstrated activity in patients with recurrent glioblastoma
(discussed in more detail later herein). This has led to the
development and completion of two randomized, doubleblind placebo-controlled trials for patients with newly diagnosed glioblastoma. The results of the two studies (RTOG
0825 and AvaGLIA) are expected within the next 2 years.
Additionally, data from a phase II trial adding the integrin
inhibitor cilengitide to the conventional chemoradiation regimen showed an improved outcome in newly diagnosed,
MGMT-methylated glioblastoma compared with historic
controls and led to a phase III placebo-controlled randomized trial.17 This study recently completed accrual and
outcome results are expected soon. Other studies including
randomized phase II trials evaluating mammalian target

113

MARK R. GILBERT

of rapamycin (mTOR) inhibition, VEGFR inhibition (cediranib), or poly (ADP-ribose) polymerase (PARP) inhibition
are either underway or in planning.
In summary, the pivotal clinical trial performed by the
EORTC and NCIC using radiation and temozolomide established the current standard of care for patients with newly
diagnosed glioblastoma. Efforts to improve on these results
with intensification of the chemotherapy were unsuccessful.
Clinical studies have been performed or are underway to
determine whether there are synergistic therapies that can
further enhance outcomes for this patient population and
thereby establish a new standard of care.
Treatment of Recurrent Glioblastoma

The treatment of recurrent glioblastoma remains unsatisfactory. Tumor resection for recurrent disease does not
appear to substantially affect either the 6-month progressionfree survival rate nor overall survival from the time of
progression.18 However, relief of tumor-induced mass effect
may be clinically beneficial and the confirmation of true
recurrence (rather than treatment-related necrosis or pseudoprogression) may be extremely helpful in treatment decisions.
A wide variety of approaches have been studied for recurrent glioblastoma. These include local strategies often requiring a surgical procedure and systemic chemotherapy
treatments either as single agent or in combination.
Locoregional Treatment Strategies

A variety of treatment approaches have been tested targeting the tumor directly, recognizing that spread of glioblastoma outside of the nervous system is rare. Use of a
carmustine-impregnated bioerodable polymer was tested for
recurrent disease and in a placebo-controlled randomized
trial showed a modest, but statistically significant improvement in the 6-month survival rate.19 These findings led to
FDA approval, but this treatment approach is not used
widely today.
Attempts to improve delivery of agents directly to tumor
led to the institution of convectional enhanced delivery.
Intratumoral catheters delivering small volumes of fluid
under pressure have been shown to spread widely from the
point of infusion. This method was used to deliver cintredekin besudotox (interleukin [IL]-13-PE38QQR, IL-13
pseudomona extoxin) in a series of clinical trials. Despite
strong preclinical data, there was no improvement in outcome compared with the carmustine wafer in a phase III
clinical trial.20 Alternative strategies are looking at using
convection-enhanced delivery for chemotherapies, particularly those like topotecan that do not cross the blood-brain
barrier with systemic delivery.21
Direct injection of vectors containing gene therapies has
also been evaluated. Preclinical studies using transfection of
the herpes thymidine kinase gene into tumor cells by using
a retroviral vector demonstrated high efficacy after administration of acyclovir or ganciclovir. However, clinical trials
in both recurrent and newly diagnosed glioblastoma failed
to demonstrate efficacy, potentially the consequence of
poor vector delivery by using direct injection into the walls
of the tumor cavity.22 More recently, replication-competent
viruses are being evaluated in clinical trials, potentially
reducing the problem of delivery with continued local pro-

114

duction and spread of the virus. For example, the delta-24


virus, a replication-competent adenovirus that requires amplification of the Rb pathway to replicate, is currently being
studied in a clinical trial.23
Systemic Chemotherapy

Metronomic and dose-dense temozolomide. Dose-dense temozolomide has also been investigated in patients with
recurrent glioblastoma.24 Two alternative dosing schedules,
alternating weekly schedule or 21 consecutive days of a
28-day cycle, have been used most commonly. Several phase
II trials have evaluated the 21 of 28-day regimen with
6-month progression-free survival rates ranging from 18% to
30% even in patients with prior temozolomide exposure.
Similarly, retrospective analyses of patients treated with
the week on, week off dose-dense schedule with temozolomide report a 6-month progression-free survival rate as high
as 36%. Both schedules are associated with a high rate of
lymphopenia, although this toxicity may be more pronounced with the 21 of 28-day schedule.
Metronomic schedules of temozolomide have been evaluated in a prospective clinical trial.25 Temozolomide was
administered at low dose (50 mg/m2/day) continuously to
patients who had previously been treated with standard
dosing of temozolomide as a component of first-line treatment (as described previously herein for newly diagnosed
glioblastoma). Interestingly, patients rechallenged after
early failure ( 6 months of adjuvant temozolomide) or after
a treatment-free interval experienced 6-month progressionfree survival rates of 27% and 36%, respectively. Patients
with treatment failure during adjuvant treatment but more
than six cycles fared poorly. These results suggest that in
select subpopulations, re-treatment with temozolomide may
be effective.
Resistance modulation with PARP inhibitors. There is
increasing interest in exploring inhibitors of PARP as a
novel strategy to enhance the efficacy of temozolomide and
address the recent finding that recurrent glioblastomas
acquire either MSH6 mismatch geneinactivating mutations or hypermethylation of the promoter region leading to
reduced expression.26 Several PARP inhibitors are in early
clinical trials, typically in combination with a variety of
temozolomide dosing schedules. The dose-limiting toxicity
is likely to be myelosuppression, supporting the need for
pharmcodynamic studies confirming maximal synergy of
PARP inhibition with temozolomide-induced tumor DNA
damage.
Nitrosoureas and other chemotherapy agents. Nitrosoureas such as carmustine and lomustine were the standard treatment for recurrent malignant gliomas but their
use steadily declined with the introduction of temozolomide,
which is better tolerated and rarely causes cumulative
myelotoxicity. There has been a recent resurgence of nitrosourea use after the report of a 6-month progression-free
survival rate of 19% in patients with prior temozolomide
exposure.27 Other chemotherapy agents such as irinotecan,
carboplatin, cisplatin and procarbazine are used but the
response rates in recurrent disease have been modest.
Targeted agents. As discussed previously, glioblastoma
has been classified into two types primarily on the basis of
genetic features. Although there is some similarity in genetic alterations, such as loss of phosphotase and tensin
homolog on chromosome 10 (PTEN), loss of cyclin-dependent

ESTABLISHING TREATMENTS FOR GLIOBLASTOMA


Table 1. Single-Agent Targeted Therapies for Recurrent Glioblastoma

Agent

Erlotinib
Gefitinib
Imatinib
Pazopanib
Vorinostat
Tipifarnib
Temsirolimus
Enzastaurin

Study

van den Bent


Rich30
Raymond31
Iwamoto32
Galanis33
Cloughesy34
Galanis35
Chang36
Wick27
Kreisl37

29

Year

Target

2009
2004
2008
2010
2009
2006
2005
2005
2010
2010

EGFR
EGFR
C-ABL, C-KIT, PDGFR
VEGFR, PDGFR
HDAC
Farnesyltransferase

Trial
Phase

No. of
Patients

6-Month
Progression-Free
Survival (%)

II
II
II
II
II
II
II

110
53
51
35
66
67
65
41
174
72

11
13; 14
16
3
15
12
8
3
11
7

mTOR
III
I/II

PKC

Abbreviations: EGFR, epidermal growth factor receptor; C-ABL, a non-receptor protein tyrosine kinase; C-KIT, a cell surface protein that binds stem cell factor;
C-MET, met proto-oncogene; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor; HDAC, histone deacetylase; mTOR,
mammalian target of rapamycin; PKC, protein kinase C.

kinase inhibitor p16INK4A and amplification of CDK 4,


primary glioblastoma typically has higher incidence of epidermal growth factor receptor (EGFR) amplification with
inactivation of PTEN and p16 tumor suppression genes. In
contrast, secondary glioblastoma multiforme is characterized by mutation of TP53 gene and more recently, almost
exclusively demonstrate mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes.
Epidermal growth factor (EGF) and its receptor EGFR,
platelet-derived growth factor (PDGF) A and B and their
receptors PDGFR and , VEGF and its receptor (VEGFR),
insulin-like growth factor (IGF)-1 and IGF receptor (IGFR),
transforming growth factor (TGF)-, fibroblast growth factor
(FGF), and hepatocyte growth factor (HGF) are thought to
be critical to the pathogenesis and survival of glioblastoma.
Activation of these tyrosine kinase receptors triggers three
major downstream pathways: mitogen-activated protein
kinase (MAPK); phosphoinositide 3 kinase (PI3K)/Akt; and
phospholipase C (PLC) and protein kinase C (PKC). These
signaling pathways regulate cell proliferation and differentiation and prevent apoptosis, and are therefore logical
targets of treatment for glioblastoma.
Unfortunately, despite these molecular findings in a high
percentage of glioblastoma, as indicated in Table 1, studies
with single-agent signal transduction modulators demonstrated only modest results at best. In particular, even in the
presence of amplification or mutation of EGFR, treatment
with a potent EGFR inhibitor such as erlotinib did not result
in a high response rate. Subsequent analyses suggested that
response to erlotinib occurred only when the downstream
component of the pathway was not already constitutively
activated as indicated by the presence of a functional PTEN
gene regulating Akt.28 These results underscore the complex
nature of signal transduction modulation strategies with
pathway overlap and downstream effectors. Attempts and
combination regimens of signal transduction modulators has
been complicated by overlapping toxicities.
Antiangiogenic agents. One of the hallmarks of glioblastoma is prominent angiogenesis, making this component of
tumor biology a logical target. The newly formed blood
vessels are often poorly developed, with incomplete tight
junction between endothelial cells and tortuous paths with
blind loops. These features lead to peritumoral edema and
account for much of the imaging enhancement by leakage of
systemic administration of contrast material before either
computed tomography or magnetic resonance imaging. A

variety of antiangiogenic agents have been tested, as outlined in Table 2.


Bevacizumab, a humanized monoclonal antibody, works
by sequestering the circulating ligand VEGF-A, resulting in
angiogenesis inhibition. Several phase II studies have been
performed in patients with recurrent glioblastoma. Most
studies demonstrate a response rate ranging from 25% to
40% and a 6-month progression-free survival in the same
range. Importantly, nearly all patients receiving bevacizumab are able to either reduce or stop corticosteroid use.
These findings, most notably in a multicenter randomized
noncomparative phase II trial, led to the accelerated approval of bevacizumab for patients with recurrent glioblastoma.39
A variety of other antiangiogenic agents have been evaluated including aflibercept (VEGF-Trap), a decoy VEGFR
fused to the Fc portion of an immunoglobulin molecule.
However, results of a phase II trial in recurrent glioblastoma
revealed only modest activity. Cediranib is a small-molecule
tyrosine kinase inhibitor of the spectrum of VEGFR that
showed early efficacy, but a subsequent phase III trial with
lomustine failed to demonstrate added benefit from the
cediranib. Carbozantinib (XL184), a small-molecule agent
that targets both VEGFR and c-Met also showed efficacy in
early studies, but systemic toxicities often precluded extended use. Cilengitide is a novel antiangiogenic agent that
targets the v3 integrin that is required for endothelial cell
migration for neovascularization. There may be additional
tumor signal pathway effects that further enhance efficacy.
Single-agent activity has been modest, but as described
herein, synergistic efficacy with chemoradiation is being
tested in newly diagnosed glioblastoma.

Table 2. Antiangiogenic Therapies Investigated for


Recurrent Glioblastoma

Agent

Study

Cediranib
Batchelor38
Bevacizumab Friedman39
Cilengitide
Reardon40
Gilbert41
XL-184
Wen42

Year

Target

2010
2009
2008
2011
2010

pan-VEGFR
VEGF-A
v3 integrin
v5 integrin
VEGFR, C-MET

6-Month
Trial
No. of Progression-Free
Survival (%)
Phase Patients

II
II
II
II

31
85
81
26
124

26
36
15
12
21

Abbreviations: VEGFR, vascular endothelial growth factor receptor; C-MET,


met proto-oncogene; EGFR, epidermal growth factor receptor; VEGF, vascular
endothelial growth factor.

115

MARK R. GILBERT
Conclusion

A standard of care has been established for patients with


newly diagnosed glioblastoma on the basis of level 1 evidence for a randomized clinical trial. Current investigations
are exploring agents to add to the established chemoradiation regimen that would augment activity without a marked
increase in toxicity. Many of these trials are also including
molecular characterization of the tumors in an effort to
define patient subpopulations likely to benefit (or not benefit) from the new regimen, thereby enhancing the risk to
benefit for individual patients.

A similar standard does not currently exist for recurrent


glioblastoma, although antiangiogenic agents particularly
bevacizumab, demonstrate tumor response and tumor control although this is often short-lived and to date, there are
no salvage regimens after bevacizumab failure. Given the
marked molecular heterogeneity of recurrent glioblastoma,
future advances will likely require a major initiative to
perform clinical trials encompassing correlations or patient
selection on the basis of tumor characteristics. This initiative will require both an increase in resource allocation and
a widespread collaborative effort to be successful.

Authors Disclosure of Potential Conflicts of Interest

Author
Mark R. Gilbert

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Abbott
Laboratories;
Genentech;
GlaxoSmithKline;
Merck

Honoraria

Research
Funding

Genentech;
Merck

Genentech;
Merck

Expert
Testimony

Other
Remuneration

REFERENCES
1. 2005-2006 Statistical Report: Primary Brain Tumors in the United
States Statistical Report, 1998-2002 (Years Data Collected). Hinsdale, IL:
Central Brain Tumor Registry of the United States; 2006.
2. Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med.
2008;359:492-507.
3. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas.
N Engl J Med. 2009;360:765-773.
4. Weller M, Felsberg J, Hartmann C, et al. Molecular predictors of
progression-free and overall survival in patients with newly diagnosed
glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27:5743-5750.
5. Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis
of prognostic factors in three Radiation Therapy Oncology Group malignant
glioma trials. J Natl Cancer Inst. 1993;85:704-710.
6. Noushmehr H, Weisenberger DJ, Diefes K, et al: Identification of a CpG
island methylator phenotype that defines a distinct subgroup of glioma.
Cancer Cell 17:510-522.
7. Colman H, Zhang L, Sulman EP, et al. A multigene predictor of outcome
in glioblastoma. Neuro Oncol. 2010;12:49-57.
8. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit
from temozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003.
9. Walker MD, Green SB, Byar DP, et al. Randomized comparisons of
radiotherapy and nitrosoureas for the treatment of malignant glioma after
surgery. N Engl J Med. 1980;303:1323-1329.
10. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic
review and meta-analysis of individual patient data from 12 randomised
trials. Lancet. 2002;359:1011-1018.
11. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med.
2005;352:987-996.
12. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with
concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the
EORTC-NCIC trial. Lancet Oncol. 2009;10:459-466
13. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6alkylguanine-DNA alkyltransferase activity with protracted temozolomide
schedules. Br J Cancer. 2003;88:1004-1011.
14. Gilbert MR, Wang M, Aldape K, et al. RTOG 0525: a randomized phase
III trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense
(dd) schedule in newly diagnosed glioblastoma (GBM). J Clin Oncol 2011;29
(suppl; abstr 141s).
15. Prados MD, Chang SM, Butowski N, et al. Phase II study of erlotinib
plus temozolomide during and after radiation therapy in patients with newly
diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27:
579-584.
16. Grossman SA, Ye X, Piantadosi S, et al. Survival of patients with newly

116

diagnosed glioblastoma treated with radiation and temozolomide in research


studies in the United States. Clin Cancer Res. 2010;16:2443-2449.
17. Stupp R, Goldbrunner B, Neyns B, et al. Phase I/IIa trial of cilengitide
(EMD121974) and temozolomide with concomitant radiotherapy, followed
by temozolomide and cilengitide maintenance therapy in patients (pts) with
newly diagnosed glioblastoma (GBM). J Clin Oncol. 2007;25 (suppl; abstr
2000).
18. Clarke JL, Ennis MM, Yung WK, et al. Is surgery at progression a
prognostic marker for improved 6-month progression-free survival or overall
survival for patients with recurrent glioblastoma? Neuro Oncol. 2011;13:
1118-1124.
19. Brem H, Piantadosi S, Burger PC, et al. Placebo-controlled trial of
safety and efficacy of intraoperative controlled delivery by biodegradable
polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor
Treatment Group. Lancet. 1995;345:1008-1012.
20. Kunwar S, Prados MD, Chang SM, et al. Direct intracerebral delivery
of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a
report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin
Oncol. 2007;25:837-844.
21. Anderson RC, Elder JB, Brown MD, et al. Changes in the immunologic
phenotype of human malignant glioma cells after passaging in vitro. Clin
Immunol. 2002;102:84-95.
22. Rainov NG. A phase III clinical evaluation of herpes simplex virus type
1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical
resection and radiation in adults with previously untreated glioblastoma
multiforme. Hum Gene Ther. 2000;11:2389-2401.
23. Jiang H, Gomez-Manzano C, Lang FF, et al. Oncolytic adenovirus:
preclinical and clinical studies in patients with human malignant gliomas.
Curr Gene Ther. 2009;9:422-427.
24. Wick W, Platten M, Weller M. New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol. 2009;11:69-79.
25. Perry JR, Rizek P, Cashman R, et al. Temozolomide rechallenge in
recurrent malignant glioma by using a continuous temozolomide schedule:
the rescue approach. Cancer. 2008;113:2152-2157.
26. Yip S, Miao J, Cahill DP, et al. MSH6 mutations arise in glioblastomas
during temozolomide therapy and mediate temozolomide resistance. Clin
Cancer Res. 2009;15:4622-4629.
27. Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of
enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28:1168-1174.
28. Haas-Kogan DA, Prados MD, Tihan T, et al. Epidermal growth factor
receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl
Cancer Inst. 2005;97:880-887.
29. van den Bent MJ, Brandes AA, Rampling R, et al. Randomized phase II
trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27:1268-1274.

ESTABLISHING TREATMENTS FOR GLIOBLASTOMA


30. Rich JN, Reardon DA, Peery T, et al. Phase II trial of gefitinib in
recurrent glioblastoma. J Clin Oncol. 2004;22:133-142.
31. Raymond E, Brandes A, Van Oosterom A, et al. Multicentre phase II
study of imatinib mesylate in patients with recurrent glioblastoma: an
EORTC/NDDG/BTG Intergroup Study. J Clin Oncol. 2004;22 (suppl; abstr
1501).
32. Iwamoto FM, Lamborn KR, Kuhn JG, et al. A phase I/II trial of the
histone deacetylase inhibitor romidepsin for adults with recurrent malignant
glioma: North American Brain Tumor Consortium Study 03-03. Neuro Oncol.
2010;13:509-516.
33. Galanis E, Jaeckle KA, Maurer MJ, et al. Phase II trial of vorinostat in
recurrent glioblastoma multiforme: a North Central Cancer Treatment Group
study. J Clin Oncol. 2009;27:2052-2058.
34. Cloughesy TF, Wen PY, Robins HI, et al. Phase II trial of tipifarnib in
patients with recurrent malignant glioma either receiving or not receiving
enzyme-inducing antiepileptic drugs: A North American Brain Tumor Consortium Study. J Clin Oncol. 2006;24:3651-3656.
35. Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus
(CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer
Treatment Group Study. J Clin Oncol. 2005;23:5294-5304.
36. Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in

patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005;23:


357-361.
37. Kreisl TN, Kotliarova S, Butman JA, et al. A phase I/II trial of
enzastaurin in patients with recurrent high-grade gliomas. Neuro Oncol.
2010;12:181-189.
38. Batchelor TT, Duda DG, di Tomaso E, et al. Phase II study of cediranib,
an oral pan-vascular endothelial growth factor receptor tyrosine kinase
inhibitor, in patients with recurrent glioblastoma. J Clin Oncol. 2010;28:
2817-2823.
39. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in
combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;
27:4733-4740.
40. Reardon DA, Fink KL, Mikkelsen T, et al. Randomized phase II study
of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in
recurrent glioblastoma multiforme. J Clin Oncol. 2008;26:5610-5617.
41. Gilbert MR, Kuhn J, Lamborn KR, et al. Cilengitide in patients with
recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with
measures of treatment delivery. J Neurooncol. 2011;106:147-153.
42. Wen PY, Prados M, Schiff D, et al: Phase II study of XL814 (BMS
907351), an inhibitor of MET, VEGFR2 and RET in patients (pts) with
progressive glioblastoma (GB). J Clin Oncol. 2010;28 (suppl; abstr 2006).

117

IMAGING IN NEURO-ONCOLOGY: PRACTICAL


PRIMER FOR THE PRACTICING PHYSICIAN
CHAIR
Susan M. Chang, MD
University of California, San Francisco
San Francisco, CA
SPEAKERS
Whitney B. Pope, MD, PhD
University of California, Los Angeles
Los Angeles, CA
Andrew D. Norden, MD, MPH
Dana-Farber Cancer Institute
Boston, MA

Current Concepts in Brain Tumor Imaging


By Andrew D. Norden, MD, MPH, Whitney B. Pope, MD, PhD, and Susan M. Chang, MD

Overview: Magnetic resonance imaging (MRI) is the most


useful imaging tool in the evaluation of patients with brain
tumors. Most information is supplied by standard anatomic
images that were developed in the 1980s and 1990s. More
recently, functional imaging including diffusion and perfusion
MRI has been investigated as a way to generate predictive and
prognostic biomarkers for high-grade glioma evaluation, but
additional research is needed to establish the added benefits
of these indices to standard MRI. Response critieria for
high-grade gliomas have recently been updated by the Response Assessment in Neuro-Oncology (RANO) working

HE FIRST published magnetic resonance image (MRI)


was from a paper in the journal Nature by Nobel Prize
Laureate Paul Lauterbur in 1973.1 By 1981, magnetic resonance had been used for imaging the brain, demonstrated
the pathologic appearance of glioblastoma (GBM), and
compared favorably to computed tomography (CT) as the
posterior fossa was visualized with substantially less artifact. . . .2 MRI was noted to detect tumors not seen on CT as
early as 1982, and this led quickly to an explosion of articles
evaluating MRI of brain tumors and other intracranial
pathology. T1- and T2-weighted images were quickly adopted as standard imaging along with multiple planar scanning. Gadolinium-based contrast agents were introduced
around 1984,3 as were high-field strength superconducting
(1.5 Tesla) scanners.4 Another advance in brain tumor
imaging occurred in the late 1990s with the introduction of
fluid-attenuated inversion recovery (FLAIR) sequences that
generated strongly T2-weighted images although signal associated with cerebrospinal fluid (CSF) was suppressed.5
Today, MRI remains the imaging modality of choice for
tumor diagnosis, characterization, and assessment of treatment response.
Conventional MRI in Neuro-Oncology

MRI has traditionally been used to evaluate tumor location, size and extent, mass effect, involvement of critical
structures such as adjacent blood vessels, and compromise of
the blood-brain barrier (which results in contrast enhancement). The typical MR scan for a patient with glioma
includes sagittal T1, axial T1, T2, FLAIR and postcontrast
axial and coronal T1-weighted images. Recently pulse sequences sensitive to physiology, rather than just anatomy,
are being more commonly used (see following). Changes in
enhancing tumor size based on bidimensional measurements of postcontrast T1-weighted images are the basis for
both the Macdonald and later RANO criteria for evaluating
tumor response.6 Conversely, nonenhancing tumor is assessed qualitatively in RANO, but not at all in the Macdonald criteria. Nonenhancing tumor is typified by areas of
increased T2 signal intensity associated with mass effect
and architectural distortion such as blurring of the graywhite interface.7 Edema and treatment effect including
gliosis also result in increased T2 signal, which can make
nonenhancing tumor difficult to quantify. FLAIR is more
sensitive to T2 signal abnormalities, as a result of the
nulling of CSF, thereby overcoming the limitation of partial
volume averaging in the cortical and periventricular regions

group. The new criteria account for nonenhancing tumor in


addition to the contrast-enhancing abnormalities on which
older criteria relied. This issue has recently come to the fore
with the introduction of the antiangiogenic agent bevacizumab
into standard treatment for recurrent glioblastoma. Because
of its potent antipermeability effect, contrast enhancement is
markedly reduced in patients who receive bevacizumab. The
RANO criteria also address the phenomenon of pseudoprogression, in which there may be transient MRI worsening of a
glioblastoma following concurrent radiotherapy and temozolomide.

as can be seen in standard T2 images. However, FLAIR also


reduces gray-white differentiation in comparison to typical
T2-weighted images, which can diminish the image readers
ability to distinguish the T2 changes that are a result of
tumor compared with T2 changes that are the result of
edema and/or gliosis. Thus, T2 and FLAIR images can
provide complementary information, and both should be
acquired for evaluation of patients with brain tumors.
Although relying on changes in enhancing tumor previously worked well for evaluating treatment response, the
widespread adoption of bevacizumab therapy for recurrent
GBM highlights the limitations of this approach. This limitation stems largely from bevacizumabs antipermeability
effect. GBMs are characterized by extensive abnormal vasculature with a leaky blood-brain barrier.8 As a result,
contrast material extravasates out of tumor vessels, leading
to increased signal on gadolinium-enhanced T1-weighted
images. Bevacizumab sequesters vascular endothelial
growth factor (VEGF), a potent permeability factor and
promoter of angiogenesis, and thereby acts to diminish
contrast enhancement. Therefore a reduction in contrast
enhancement following bevacizumab infusion may not necessarily reflect a cytotoxic tumor effect. Relying on the
change in contrast enhancement alone can thus misrepresent treatment response, a phenomenon known as pseudoresponse.9,10
Although the RANO criteria include FLAIR or T2 hyperintensity changes as potentially indicative of nonenhancing
tumor progression, no quantification of nonenhancing tumor
is performed. This is because of difficulties in determining
the borders of T2 abnormal regions as well as differentiating
gliosis and other treatment effects from tumor. This has
spurred interest in physiologic imaging as a way of obtaining
quantitative data on tumor burden, although to date, this
goal has not been fully realized.

From Dana-Farber Cancer Institute and Brigham and Womens Hospital, Boston, MA;
David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA;
University of California, San Francisco, Department of Neurological Surgery, San Francisco, CA.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Susan M. Chang, MD, University of California, San
Francisco, Department of Neurological Surgery, 400 Parnassus Ave., A808, San Francisco,
CA 94143-0372; email: changs@neurosurg.ucsf.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

119

NORDEN, POPE, AND CHANG


Functional Imaging in Neuro-Oncology
Magnetic Resonance Perfusion

Given the antiangiogenic effects of bevacizumab, perfusion imaging is intuitively an appealing technique for assessing the effect of drug treatment. Several methods of
obtaining perfusion data have been developed, the two most
common of which are dynamic susceptibility contrast
(DSC) imaging and dynamic contrast enhanced (DCE)
imaging. DSC is used to generate maps of relative cerebral
(or tumor) blood volume (rCBV), and relative cerebral blood
flow (rCBF), among other metrics. DCE is generally used to
measure the permeability constant Ktrans, which is a metric
of capillary leakiness. Many groups have investigated the
role of perfusion imaging in the evaluation of gliomas. For
instance, maximal rCBV has prognostic value in astrocytoma, even when controlling for tumor grade.11 A number of
studies have shown that high rCBV or increasing rCBV is
associated with a worse prognosis across tumor grades.12
Perfusion imaging has been used to assess response to
standard (radiation and cytotoxic chemotherapy) as well as
antiangiogenic treatment. For patients with GBM who receive standard therapy, the percentage change in rCBV from
pre- to post-treatment measurements is predictive of 1-year
survival.13 In patients with recurrent GBM who are treated
with antiangiogenic therapy, a vascular normalization index that is generated by combining Ktrans, microvessel

KEY POINTS

120

Magnetic resonance imaging (MRI) is the imaging


modality of choice to evaluate brain tumor location,
size and extent, mass effect, involvement of critical
structures such as adjacent blood vessels, and compromise of the blood-brain barrier.
Perfusion and diffusion magnetic resonance imaging
tools are examples of physiologic imaging modalities
that may provide quantitative data on tumor burden,
although further investigation is required to define
their roles in routine care and clinical trials.
In approximately 20% to 30% of glioblastoma cases,
the first MRI obtained after radiation therapy and
concurrent temozolomide meets the criteria for progressive disease, but subsequent follow-up scans
show lesion shrinkage or stability. This has been
termed pseudoprogression and is among the most
common causes of misdiagnosed tumor recurrence.
Because of its antipermeability effect, antiangiogenic
therapy with bevacizumab results in marked reduction of tumor enhancement, which reduces the sensitivity of magnetic resonance imaging for diagnosing
tumor recurrence.
Response critieria for high-grade gliomas have recently been updated by the Response Assessment in
Neuro-Oncology working group. The new criteria account for nonenhancing tumor in addition to the
contrast-enhancing abnormalities on which older criteria relied.

volume, and circulating collagen IV is predictive of survival,


even though it is acquired only 1 day after treatment
initiation.14 Yet many studies that assess treatment response to bevacizumab therapy have not been particularly
successful in relating changes in CBV or CBF to outcomes.15,16 Thus challenges continue in the application of
perfusion indices as a biomarker of treatment response in
this setting. The use of perfusion as an early response (1-day
posttreatment initiation marker14) could have a clinical
effect, however.
Perfusion imaging has also been applied to the issue of
differentiating true from pseudoprogression. In general,
true progression has higher perfusion than radiationinduced changes, although there can be overlap in
values.17-20 Standardized protocols may help improve the
use of perfusion imaging in multicenter trials, but overall
accuracy also must be increased to have the desired clinical
affect.
Magnetic Resonance Diffusion

Diffusion-weighting imaging (DWI) is another potential


physiology-based magnetic resonance biomarker for the
evaluation of gliomas. Based on the movement of water
molecules, diffusion data are typically reported as the
apparent diffusion coefficient (ADC); decreased water motion corresponds to lower ADC values. Since water molecules are generally more motion-restricted intracellularly
compared to extracellularly, necrosis and cell death or
lysis can result in increased ADC. Similarly, edema increases ADC by expanding the interstitial, extracellular
fluid volume, which also allows for freer movement of
water molecules. Conversely, lower ADC is associated
with increased cell density.23 Because of these properties,
DWI has the potential to indicate treatment response in
gliomas.
Functional diffusion maps (fDMs) are used to assess
the voxel-wise changes in ADC measured in the same
patient over time.21-24 This can increase the sensitivity in
detecting subtle changes in tumor cell density. Initially
fDMs were used to predict response to cytotoxic chemotherapy and radiotherapy within the contrast-enhancing tumor
bed,22-24 but recent studies have demonstrated their effective use outside regions of contrast enhancement21,25,26 and
as tools for studying the effects of antiangiogenic treatment.27,28
Another approach to using diffusion imaging data is to
construct histograms of ADC values. ADC histogram analysis has been investigated as a predictive biomarker of
bevacizumab treatment response in the setting of recurrent
GBM.29 For this application, tumors with low ADC values
before initiation of bevacizumab were more likely to progress by 6 months compared with tumors with high ADC
values. These results have since been confirmed in a retrospective analysis of a large multicenter trial.30 However,
prospectively validated biomarkers for response to antiangiogenesis treatment are not currently available for clinical
use.
Imaging of Recurrent Gliomas

The Macdonald criteria defined progressive disease, or


recurrence, as . . . 25% increase in size of enhancing

CONCEPTS IN BRAIN TUMOR IMAGING

tumor or any new tumor on CT or MRI scans, or neurologically worse, and steroids stable or increased.31 Although
these were the best available criteria for nearly 20 years,
their focus on enhancing tumor limited their usefulness
because low-grade diffuse gliomas typically lack an enhancing component and high-grade gliomas often contain nonenhancing elements. Furthermore, processes other than tumor
frequently influence the extent of contrast enhancement.
Examples include treatment-induced inflammation or
necrosis, postoperative changes, seizures, and infarction.
Medications may also affect contrast enhancement. Corticosteroids, for example, perhaps the most commonly used class
of medication in neuro-oncology, are known to reduce contrast enhancement in a large portion of patients with gliomas.32
False Positives

A number of phenomena may lead to an inaccurate diagnosis of tumor recurrence on posttreatment MRI scans.
Since publication of a large, randomized trial in 2005,
standard-of-care therapy for GBM includes involved-field
radiation therapy with concurrent and adjuvant temozolomide.33 Most neuro-oncologists obtain an initial posttreatment MRI scan 4 weeks following the radiation therapy
phase. In approximately 20% to 30% of cases, this MRI
meets the criteria for progressive disease, but without
further treatment other than adjuvant temozolomide, subsequent follow-up scans show lesion shrinkage or stability.34,35 This has been termed pseudoprogression and is
among the most common causes of misdiagnosed tumor
recurrence.
Knowledge of this phenomenon has changed practice for
many neuro-oncologists, who now accept the first postradiation MRI scan as a new baseline; so long as a patient is
not highly symptomatic from apparent progression, a
reasonable approach is to proceed with one-to-three cycles
of adjuvant temozolomide before deciding whether the
changes reflect pseudoprogression or true progression. In
general, pseudoprogression that is related to radiation
therapy occurs within 3 months following treatment, but
cases have been described as late as 6 months following
treatment. For patients who develop severe or symptomatic worsening in this window of time, surgery may be
required. Although the pathologic substrate of pseudoprogression remains to be determined with certainty, in one
article seven patients underwent surgical resection for pseudoprogression and subsequent histopathology showed only
necrosis.36
Given an increasing recognition of pseudoprogression in
the temozolomide treatment era and the knowledge that
temozolomide has radiosensitizing properties, many have
suggested that combining temozolomide with radiation therapy increases the risk of pseudoprogression compared with
radiation therapy alone.36 However, the rates of pseudoprogression reported in recent studies34,35 are similar to the
rates reported before the widespread use of temozolomide.37
Another potentially important risk factor for pseudoprogression is the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Recent data
demonstrate that MGMT promoter methylation status is
predictive of response to temozolomide and a favorable
prognosis in patients with GBM.38 This finding is intuitive

because MGMT is an endogenous DNA repair enzyme that


mediates resistance to alkylating chemotherapeutics like
temozolomide. In a study of 103 patients newly diagnosed
with GBM, pseudoprogression was diagnosed in 32 (31%)
patients. Ninety-one percent of subjects whose tumors had
methylated MGMT promoters developed pseudoprogression
as compared with 41% of patients whose tumors had unmethylated MGMT promoters, and the difference was statistically significant.35 Also of interest is that overall
survival was higher in patients whose tumors developed
pseudoprogression. The findings suggest that pseudoprogression may occur when concurrent radiation therapy and
temozolomide are particularly active against residual tumor, although this remains to be confirmed in prospective
studies.
Pseudoprogression is problematic from the perspective of
clinical trial end points in addition to the clinical challenges
it creates. Accrual of patients whose tumors spontaneously
respond falsely elevates response rates and prolongs
progression-free survival in clinical trials for recurrent disease. For this reason, the recently adopted RANO criteria
(Table 1) stipulate that progression cannot be diagnosed
within the first 12 weeks after radiation therapy unless the
majority of new enhancement is outside the radiation field
or there is histopathologic confirmation of tumor progression.6
Treatments other than radiation therapy are less common
causes of misdiagnosed progression. It is well known, for
example, that enhancement at the margin of an operative
cavity often develops 48 to 72 hours after surgery and may
persist for weeks or months. In some cases, perioperative
infarction may result in new enhancement that is visually
indistinguishable from tumor recurrence. In a study of 50
GBM resections, diffusion-weighted MRI sequences showed
restricted diffusion consistent with infarction in 35 (70%)
cases. Of these, 15 (43%) showed enhancement that might
have been confused with recurrent disease.39 Finally, local
therapies may provoke MRI changes that are suspicious for
recurrence. Examples include carmustine wafers and experimental therapies administered by direct intracerebral injection or convection-enhanced delivery.
False Negatives

As noted above, the Macdonald criteria were not designed


to assess nonenhancing tumors. This is problematic because
the majority of low-grade gliomas and an important minority of high-grade gliomas do not enhance, particularly in
older adults.40 Furthermore, nonenhancing elements are
present in almost all enhancing high-grade gliomas. Another challenge in assessing nonenhancing tumor is that
these abnormalities typically appear hyperintense on T2- or
FLAIR sequences and cannot be readily distinguished from
edema, gliosis, toxic leukoencephalopathy, microangiopathy, or radiation-induced white matter disease.
Unfortunately, the widespread use of antiangiogenic
therapy has only compounded the problem. The prototypic
antiangiogenic agent is bevacizumab, a humanized monoclonal antibody against VEGF that received accelerated
United States Food and Drug Administration approval
for recurrent high-grade glioma in 2009. Although bevacizumab is responsible for high radiographic response rates
and marked prolongation of progression-free survival,41,42

121

NORDEN, POPE, AND CHANG


Table 1. RANO Criteria for Response Assessment Incorporating MRI and Clinical Factors
Complete response

Partial response

Stable disease

Progressive disease

Requires all of the following: complete disappearance of all enhancing measurable and nonmeasurable disease sustained for at least 4
wk; no new lesions; stable or improved nonenhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on physiologic
replacement doses only); and stable or improved clinically. Note: Patients with nonmeasurable disease only cannot have a complete
response; the best response possible is stable disease
Requires all of the following: 50% decrease compared with baseline in the sum of products of perpendicular diameters of all
measurable enhancing lesions sustained for at least 4 wk; no progression of nonmeasurable disease; no new lesions; stable or
improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; the corticosteroid
dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan; and stable or improved clinically.
Note: Patients with nonmeasurable disease only cannot have a partial response; the best response possible is stable disease
Requires all of the following: does not qualify for complete response, partial response, or progression; stable nonenhancing (T2/FLAIR)
lesions on same or lower dose of corticosteroids compared with baseline scan. In the event that the corticosteroid dose was increased
for new symptoms and signs without confirmation of disease progression on neuroimaging, and subsequent follow-up imaging shows
that this increase in corticosteroids was required because of disease progression, the last scan considered to show stable disease will
be the scan obtained when the corticosteroid dose was equivalent to the baseline dose
Defined by any of the following: 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with
the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of
corticosteroids*; significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared with
baseline scan or best response after initiation of therapy* not caused by comorbid events (eg, radiation therapy, demyelination,
ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any new lesion; clear clinical deterioration not
attributable to other causes apart from the tumor (eg, seizures, medication adverse effects, complications of therapy, cerebrovascular
events, infection, and so on) or changes in corticosteroid dose; failure to return for evaluation as a result of death or deteriorating
condition; or clear progression of nonmeasurable disease

Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery.


All measurable and nonmeasurable lesions must be assessed using the same techniques as at baseline.
* Stable doses of corticosteroids include patients not on corticosteroids.
Reprinted with permission. 6 2010 by American Society of Clinical Oncology.

the results of ongoing studies are needed to determine


whether it improves overall survival. Some data suggest
that anti-VEGF therapies may prolong survival by virtue of
potently reducing vascular permeability.43 This is a wellknown effect of antiangiogenic treatment that likely accounts for the reduction in contrast enhancement typically
seen within days of the first dose of bevacizumab or similar
agents.44
Although antiangiogenic drugs are generally welltolerated and lack the toxicities that are typical of cytotoxic
agents, substantial preclinical data obtained since the late
1990s suggest that blocking VEGF signaling promotes an
infiltrative tumor growth pattern based on co-option of
existing cerebral vasculature.45-48 Several uncontrolled, retrospective clinical studies reported that high-grade gliomas
treated with bevacizumab showed increased infiltrative tumor growth on T2/FLAIR sequences.49-52 Indeed, patients
for whom there is MRI evidence of prolonged disease control
on bevacizumab sometimes experience clinical progression
that seems consistent with this phenomenon. In a small
study that pathologically characterized the areas of nonenhancing, infiltrative tumor, there were thin-walled, relatively normal-appearing blood vessels and elevated levels of
insulin-like growth factor binding protein-2 and matrix
metalloprotease-2.53
Some recent data challenge the assumption that antiangiogenic therapy promotes an infiltrative growth pattern. In
one study, patients treated with bevacizumab-treated were
compared with matched pairs of patients treated with conventional therapies.54 The rates of distant or diffuse recurrence were approximately 20% in both groups with no
significant difference detected. Another study examined preand posttreatment recurrence patterns in patients with
recurrent GBM treated with bevacizumab or bevacizumab/
irinotecan on the BRAIN trial.55 Among patients treated

122

with bevacizumab alone, 16% experienced a change in recurrence pattern from local to diffuse. For reasons that are
unclear, a higher proportion (39%) of patients treated with
bevacizumab and irinotecan experienced this change. In a
retrospective report that examined recurrence patterns in
80 patients with GBM who were treated with bevacizumab,
there was no significant difference in recurrence pattern
after bevacizumab treatmentas compared with before bevacizumab treatment.56 Approximately 70% to 80% of recurrences were described as local, which is consistent with older
data.57
Whether antiangiogenic therapy actually promotes infiltrative tumor growth or merely unmasks it is an unanswered question. By controlling peritumoral edema and
durably reducing contrast enhancement, bevacizumab may
lead to the false impression of increased nonenhancing
tumor progression compared with the prebevacizumab era.
Further data are required to address this. Regardless, there
is no question that bevacizumab therapy renders the radiological diagnosis of progressive disease more challenging
than before. There does appear to be a subset of patients
with recurrent high-grade glioma whose tumors progress
primarily in a nonenhancing fashion who would be missed
when the conventional Macdonald criteria is applied. The
RANO criteria for progressive disease therefore include
. . . significant increase in T2/FLAIR nonenhancing lesion
on stable or increasing doses of corticosteroids not caused by
comorbid events (eg, radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or
other treatment effects).6 Although the ability to determine
the etiology of T2/FLAIR changes is challenging, these
criteria represent an important step toward optimally assessing progressive disease in the current era of antiangiogenic therapy.

CONCEPTS IN BRAIN TUMOR IMAGING

Authors Disclosures of Potential Conflicts of Interest

Author
Andrew D. Norden*
Whitney B. Pope
Susan M. Chang

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Genentech
Novartis;
Schering-Plough

*No relevant relationships to disclose.

REFERENCES
1. Lauterbur PC. Image formation by induced local interactions. Examples
employing nuclear magnetic resonance. 1973. Clin Orthop Relat Res. 1989;
3-6.
2. Doyle FH, Gore JC, Pennock JM, et al. Imaging of the brain by nuclear
magnetic resonance. Lancet. 1981;2:53-57.
3. Carr DH, Gadian DG. Contrast agents in magnetic resonance imaging.
Clin Radiol. 1985;36:561-568.
4. Bilaniuk LT, Zimmerman RA, Wehrli FW, et al. Cerebral magnetic
resonance: comparison of high and low field strength imaging. Radiology.
1984;153:409-414.
5. Kates R, Atkinson D, Brant-Zawadzki M. Fluid-attenuated inversion
recovery (FLAIR): clinical prospectus of current and future applications. Top
Magn Reson Imaging 1996;8:389-396.
6. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology
working group. J Clin Oncol. 2010;28:1963-1972.
7. Pope WB, Sayre J, Perlina A, et al. MR imaging correlates of survival in
patients with high-grade gliomas. AJNR Am J Neuroradiol. 2005;26:24662474.
8. Rees JH, Smirniotopoulos JG, Jones RV, et al. Glioblastoma multiforme:
radiologic-pathologic correlation. Radiographics. 1996;16:1413-1438; quiz
1462-1463.
9. Clarke JL, Chang S. Pseudoprogression and pseudoresponse: challenges
in brain tumor imaging. Curr Neurol Neurosci Rep. 2009;9:241-246.
10. Brandsma D, van den Bent MJ. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22:633-638.
11. Hirai T, Murakami R, Nakamura H, et al. Prognostic value of perfusion
MR imaging of high-grade astrocytomas: long-term follow-up study. AJNR
Am J Neuroradiol. 2008;29:1505-1510.
12. Law M, Young RJ, Babb JS, et al. Gliomas: predicting time to progression or survival with cerebral blood volume measurements at dynamic
susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology.
2008;247:490-498.
13. Mangla R, Singh G, Ziegelitz D, et al. Changes in relative cerebral blood
volume 1 month after radiation-temozolomide therapy can help predict
overall survival in patients with glioblastoma. Radiology. 2010;256:575-584.
14. Sorensen AG, Batchelor TT, Zhang WT, et al. A vascular normalization index as potential mechanistic biomarker to predict survival after a
single dose of cediranib in recurrent glioblastoma patients. Cancer Res.
2009;69:5296-5300.
15. Bidault F, Sahnoun, M., Rousseau, V., et al.: High-Grade Gliomas
Treated with Bevacizumab: Assessment of Tumor Response with Dynamic
Susceptibility Contrast Perfusion MRI (DSC-MRI) presented at the Radiological Society of North America Annual Meeting, Chicago, IL., 2011.
16. Sawlani RN, Raizer J, Horowitz SW, et al. Glioblastoma: A method for
predicting response to antiangiogenic chemotherapy by using MR perfusion
imaging-pilot study. Radiology. 2010;255:622-8.
17. Barajas RF Jr, Chang JS, Segal MR, et al. Differentiation of recurrent
glioblastoma multiforme from radiation necrosis after external beam radiation therapy with dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology. 2009;253:486-496.
18. Hu LS, Baxter LC, Smith KA, et al. Relative cerebral blood volume
values to differentiate high-grade glioma recurrence from posttreatment
radiation effect: direct correlation between image-guided tissue histopathology and localized dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging measurements. AJNR Am J Neuroradiol. 2009;30:552-558.
19. Sugahara T, Korogi Y, Tomiguchi S, et al. Posttherapeutic intraaxial
brain tumor: the value of perfusion-sensitive contrast-enhanced MR imaging
for differentiating tumor recurrence from nonneoplastic contrast-enhancing
tissue. AJNR Am J Neuroradiol. 2000;21:901-909.
20. Lev MH, Ozsunar Y, Henson JW, et al. Glial tumor grading and
outcome prediction using dynamic spin-echo MR susceptibility mapping
compared with conventional contrast-enhanced MR: confounding effect of

elevated rCBV of oligodendrogliomas [corrected]. AJNR Am J Neuroradiol.


2004;25:214-221.
21. Ellingson BM, Malkin MG, Rand SD, et al. Validation of functional
diffusion maps (fDMs) as a biomarker for human glioma cellularity. J Magn
Reson Imaging 2010;31:538-548.
22. Moffat BA, Chenevert TL, Meyer CR, et al. The functional diffusion
map: an imaging biomarker for the early prediction of cancer treatment
outcome. Neoplasia. 2006;8:259-267.
23. Hamstra DA, Chenevert TL, Moffat BA, et al. Evaluation of the
functional diffusion map as an early biomarker of time-to-progression and
overall survival in high-grade glioma. Proc Natl Acad Sci U S A. 2005;102:
16759-16764.
24. Hamstra DA, Galban CJ, Meyer CR, et al. Functional diffusion map as
an early imaging biomarker for high-grade glioma: correlation with conventional radiologic response and overall survival. J Clin Oncol. 2008;26:33873394.
25. Ellingson B, Malkin M, Rand S, et al. Functional diffusion maps
applied to FLAIR abnormal areas are valuable for the clinical monitoring of
recurrent brain tumors. Proc Intl Soc Mag Reson Med. 2009;102:17:285.
26. Ellingson BM, Rand SD, Malkin MG, et al. Utility of functional
diffusion maps to monitor a patient diagnosed with gliomatosis cerebri.
J Neurooncol. 2010;97:419-423.
27. Ellingson BM, Malkin MG, Rand SD, et al. Comparison of cytotoxic and
anti-angiogenic treatment responses using functional diffusion maps in
FLAIR abnormal regions. Proc Intl Soc Mag Reson Med. 2009;102:17:1010.
28. Ellingson BM, Malkin MG, Rand SD, et al. Volumetric analysis of
functional diffusion maps is a predictive imaging biomarker for cytotoxic and
anti-angiogenic treatments in malignant gliomas. J Neurooncol. 2011:102;95103.
29. Pope WB, Kim HJ, Huo J, et al. Recurrent glioblastoma multiforme:
ADC histogram analysis predicts response to bevacizumab treatment. Radiology. 2009;252:182-189.
30. Pope WB, et al. Title forthcoming. J Neurooncol. In press.
31. Macdonald DR, Cascino TL, Schold SC Jr, et al. Response criteria for
phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:
1277-1280.
32. Watling CJ, Lee DH, Macdonald DR, et al. Corticosteroid-induced
magnetic resonance imaging changes in patients with recurrent malignant
glioma. J Clin Oncol. 1994;12:1886-1889.
33. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med.
2005;352:987-996.
34. Brandes AA, Franceschi E, Tosoni A, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after
concomitant radiochemotherapy in newly diagnosed glioblastoma patients.
J Clin Oncol. 2008;26:2192-2197.
35. Taal W, Brandsma D, de Bruin HG, et al. Incidence of early pseudoprogression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer. 2008;113:405-410.
36. Chamberlain MC, Glantz MJ, Chalmers L, et al. Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma.
J Neurooncol. 2007;82:81-83.
37. de Wit MC, de Bruin HG, Eijkenboom W, et al. Immediate postradiotherapy changes in malignant glioma can mimic tumor progression.
Neurology. 2004;63:535-537.
38. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and
benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997-1003.
39. Ulmer S, Braga TA, Barker FG 2nd, et al. Clinical and radiographic
features of peritumoral infarction following resection of glioblastoma. Neurology. 2006;67:1668-1670.
40. Scott JN, Brasher PM, Sevick RJ, et al. How often are nonenhancing
supratentorial gliomas malignant? A population study. Neurology. 2002;59:
947-949.

123

NORDEN, POPE, AND CHANG


41. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in
combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;
27:4733-4740.
42. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent
bevacizumab followed by bevacizumab plus irinotecan at tumor progression
in recurrent glioblastoma. J Clin Oncol. 2009;27:740-745.
43. Kamoun WS, Ley CD, Farrar CT, et al. Edema control by cediranib, a
vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol.
2009;27:2542-2552.
44. Pope WB, Lai A, Nghiemphu P, et al. MRI in patients with high-grade
gliomas treated with bevacizumab and chemotherapy. Neurology. 2006;66:
1258-1260.
45. Ebos JM, Lee CR, Cruz-Munoz W, et al. Accelerated metastasis after
short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer
Cell. 2009;15:232-239.
46. Keunen O, Johansson M, Oudin A, et al. Anti-VEGF treatment reduces
blood supply and increases tumor cell invasion in glioblastoma. Proc Natl
Acad Sci U S A. 2011;108:3749-3754.
47. Lamszus K, Kunkel P, Westphal M. Invasion as limitation to antiangiogenic glioma therapy. Acta Neurochir Suppl. 2003;88:169-177.
48. Pa`ez-Ribes M, Allen E, Hudock J, et al. Antiangiogenic therapy elicits
malignant progression of tumors to increased local invasion and distant
metastasis. Cancer Cell. 2009;15:220-231.

124

49. Fischer I, Cunliffe CH, Bollo RJ, et al. High-grade glioma before and
after treatment with radiation and Avastin: initial observations. Neuro Oncol.
2008;10:700-708.
50. Iwamoto FM, Abrey LE, Beal K, et al. Patterns of relapse and prognosis
after bevacizumab failure in recurrent glioblastoma. Neurology. 2009;73:
1200-1206.
51. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent
malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology.
2008;70:779-787.
52. Narayana A, Kunnakkat SD, Medabalmi P, et al. Change in pattern of
relapse after antiangiogenic therapy in high-grade glioma. Int J Radiat Oncol
Biol Phys. 2012;82:77-82.
53. de Groot JF, Fuller G, Kumar AJ, et al. Tumor invasion after treatment
of glioblastoma with bevacizumab: radiographic and pathologic correlation in
humans and mice. Neuro Oncol. 2010;12:233-242.
54. Wick A, Dorner N, Schafer N, et al. Bevacizumab does not increase the
risk of remote relapse in malignant glioma. Ann Neurol. 2011;69:586-592.
55. Pope WB, Xia Q, Paton VE, et al. Patterns of progression in patients
with recurrent glioblastoma treated with bevacizumab. Neurology. 2011;76:
432-437.
56. Chamberlain MC. Radiographic patterns of relapse in glioblastoma.
J Neurooncol. 2011;101:319-323.
57. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology. 1980;30:907-911.

PERSPECTIVES ON HEADLINE-MAKING NEWS IN


NEURO-ONCOLOGY
CHAIR
Timothy F. Cloughesy, MD
University of California, Los Angeles
Los Angeles, CA
SPEAKERS
E. Antonia Chiocca, MD, PhD
The Ohio State University Medical Center
Columbus, OH
Philip H. Gutin, MD
Memorial Sloan-Kettering Cancer Center
New York, NY

Noninvasive Application of Alternating


Electric Fields in Glioblastoma: A Fourth
Cancer Treatment Modality
By Philip H. Gutin, MD, and Eric T. Wong, MD

Overview: Tumor treating fields (TTF) therapy is a novel


antimitotic, electric field based treatment for cancer. This
nonchemical, nonablative treatment is unlike any of the established cancer treatment modalities, such as surgery, radiation, and chemotherapy. Recently, it has entered clinical use
after a decade of intensive translational research. TTF therapy
is delivered to patients by a portable, battery-operated, medical device using noninvasive transducer arrays placed on the
skin surface surrounding the treated tumor. TTF therapy is

HE DEFINITION of the electric field is attributed to


Michael Faraday in the 1820s and was later formulated
by James Clerk Maxwell in his electromagnetic theory in
1865.1 It is a field of electric forces that surround a source
charge. When a test charge is placed within an electric field,
a force acts on it. Negative charges attract positive charges,
while similar signed charges repel each other. As seen in
Fig. 1A, an electric field surrounding a source charge can be
described using diverging lines of force. The closer the test
charge is to the source charge, the closer the lines of force are
to each other, which represents higher field intensity.
To understand the effects of electric fields within cells, it is
important to introduce three definitions. First, electric fields
can be uniform or nonuniform. A uniform electric field is
represented by parallel lines of force (Fig. 1B). A nonuniform
electric field is represented by converging or diverging lines
of force (Fig. 1A and 1D). Second, an electric field can be a
constant field or a time-varying field, resulting in electrostatic or electrodynamic phenomena, respectively. In a constant field, the source charges remain the same over time. A
test charge will move in one direction within a constant
electric field toward the oppositely charged source (Fig. 1B).
In a time-varying or alternating electric field, the charge of
the sources alternates over time (Fig. 1C). Third, the test
charge can be an electric charge or an electric dipole (an
element with a positive charge on one end and a negative
charge on the opposite end). An electric charge will move
back and forth, while a dipole will rotate within an alternating uniform electric field and align with the direction of the
field. In a nonuniform converging electric field, both dipoles
and charges move in the direction of the higher field intensity through a process known as dielectrophoresis (Fig. 1D).
Mechanism of Action of TTF Therapy

Over 100 years after Maxwells original publication,


Yoram Palti, MD, PhD, hypothesized that properly tuned
alternating electric fields at physiological intensities (i.e.,
13 V/cm) would disrupt the mitotic process of dividing
cancer cells.2,3 Dr. Palti hypothesized and subsequently
demonstrated in vitro that at frequencies between 100 and
300 kHz, alternating electric fields disrupt the formation of
the mitotic spindle during metaphase and lead to dielectrophoretic movement of charged and/or polar molecules and
organelles during anaphase and telophase, disrupting normal cytokinesis and leading to apoptosis.2,3 According to this
model, the first mechanism of action is explained by the fact

126

now a U.S. Food and Drug Administration (FDA)approved


treatment for patients with recurrent glioblastoma (GBM) who
have exhausted surgical and radiation treatments. This article
will introduce the basic science behind TTF therapy, its
mechanism of action, the preclinical findings that led to its
clinical testing, and the clinical safety and efficacy data
available to date, as well as offer future research directions on
this novel treatment modality for cancer.

that the tubulin subunits are one of the most polar molecules in the cell. These tubulin subunits align in the direction of the applied electric field (Fig. 2A), interfering with
the normal polymerization of the mitotic spindle, which
results in formation of abnormal mitotic figures in vitro.3
The second mechanism of action is explained by examining
the change in shape of the electric field within a dividing cell
from anaphase to telophase. When the cell division axis is
aligned with the direction of the electric field, the field lines
that enter the cell at one end converge at the cytokinetic
furrow between the developing daughter cells and then
diverge on the opposite side (Fig. 2B). This nonuniform
electric field within the cell generates dielectrophoretic
forces that act on polar and charged elements in the cell,
pushing them toward the cytokinetic furrow leading to
violent blebbing of the plasma membrane.3 This finding was
also validated by researchers from Beth Israel Deaconess
Medical Center and may be mediated by improper placement of the contractile elements that form the cytokinetic
ring on anaphase entry.4
Preclinical Studies of the Antitumor Effects of
TTF Therapy

Between 2004 and 2010, a series of publications and


conference presentations addressed the issue of the applicability range of TTF therapy to different in vitro and in vivo
cancer models either alone or in combination with standard
chemotherapy.3,5-8 Tables 1 and 2 summarize the state-ofthe-art preclinical research with TTF therapy. TTF therapy
has been shown to effectively inhibit cancer cell growth in
various cell lines in vitro (Table 1). This effect was clearly
dose (field intensity) dependent in the range of 1 to 3 V/cm.5
The optimal frequency for the inhibitory effect of TTF
therapy differed between cell types and was inversely related to cell size (Table 1; e.g., glioma cell cultures at 200
kHz3,5). In addition, based on the directional nature of TTF

From the Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center Brain


Tumor Center, New York, NY; and Brain Tumor Center and Neuro-Oncology Unit, Beth
Israel Deaconess Medical Center, Boston, MA.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Philip H. Gutin, MD, Department of Neurosurgery, C-703,
Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email:
gutinp@mskcc.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

TTF THERAPY IN GLIOBLASTOMA

Fig. 1. Electric field theory. (A) Opposite charges attract. (B) A constant, uniform, electric field. (C) Charges
and dipoles in a time-varying, uniform electric field. (D) A
dipole in a time-varying, nonuniform electric field (dielectrophoresis).

therapy, its antimitotic effect in cultures was enhanced by


sequentially applying more than one field direction to the
treated cells.5 The combination of TTF therapy with different chemotherapeutic agents has been shown to have at
least additive if not synergistic effects.7,9 Specifically, the
combination of TTF therapy with temozolomide in glioma
cell lines was shown to be additive. Interestingly, in breast
cancer cells, TTF therapy showed overt synergism with
taxanes (e.g., paclitaxel), probably a result of the temporal

KEY POINTS

Tumor treating fields (TTF) therapy is an emerging,


low-toxicity treatment modality for solid tumors
based on the delivery of antimitotic alternating electric fields to the tumor, which interfere with cytokinesis and microtubule assembly that eventually lead
to cell death.
As a monotherapy, TTF therapy is at least as effective as currently available active chemotherapy and
biologic therapies for the treatment of recurrent glioblastoma (GBM).
The efficacy of this noninvasive treatment modality is
achieved with significantly less toxicity and a better
quality of life compared with chemotherapy.
Preliminary data suggest TTF therapy acts synergistically with temozolomide and other chemotherapy in
both preclinical and clinical trials.
Future research should focus on integrating TTF
therapy into the treatment of GBM in the adjuvant
and maintenance settings, as well as in the treatment
of other solid tumor malignancies.

proximity of taxanes effect in metaphase and TTF therapys


mitotic interference on cell entry into anaphase.5
TTF therapy has been tested in numerous in vivo cancer
models (Table 2).3,5,8,10 Noninvasive application of TTF
therapy to animals was performed using electrically insulated transducer arrays placed on the head or torso surrounding the region of the tumor. Inhibition of tumor growth
was seen in each of these models when the correct frequency
of TTF therapy was applied. Specifically, 200 kHz TTF
therapy applied in two sequential and perpendicular field
directions lead to significant (p 0.01) inhibition of a
syngeneic, orthotopic F-98 glioma in rats after 7 days of
treatment.5 An additional syngeneic, orthotopic model of
non-small cell lung cancer in mice showed that 150 kHz TTF
therapy significantly (p 0.01) inhibited tumor growth
within 7 days of treatment.8,11 Furthermore, the additive
effect of TTF therapy with chemotherapy seen in vitro was
recapitulated in different in vivo models.5,8 Finally, in a
metastatic tumor model using a squamous carcinoma tumor
implanted in the kidney capsule of rabbits, TTF therapy
applied to the abdomen blocked metastatic spread of tumor
from the kidney to the lungs.10,27
Translating TTF Therapy into Clinical Use

Since TTF therapy is a physical antimitotic modality with


no half-life, its application should be continuous. Kinetic
modeling was used to predict the minimal treatment duration needed with TTF therapy.12 Based on these data, a
minimal treatment course of 4 weeks was defined and
implemented in clinical studies. In vivo animal experiments
and pilot clinical data subsequently verified the 4-week
minimal treatment duration.12 Such continuous delivery
was made possible by the development of a portable, batteryoperated, medical device that patients can use at home
(NovoTTF-100A, Novocure, Haifa, Israel). Finally, extensive
toxicity studies of TTF therapy were performed in healthy

127

GUTIN AND WONG

Fig. 2. Effects of tumor treating fields therapy on


intracellular structures during mitosis. (A) During metaphase, tubulin dimers align with the external electric
field, interfering with the formation of the mitotic spindle. (B) During cytokinesis, the nonuniform electric field
formed within the dividing cell drives charged and polar
macro-molecules and organelles toward the cleavage
furrow.

mice, rats, and rabbits.5,9 Clinical, laboratory, and pathologic analyses showed that TTF therapy is well tolerated and
does not lead to systemic toxicity in animals. As expected by
the frequency range of TTF therapy (100 300 kHz), these
electric fields do not have any effect on excitable tissues
(neural, muscular, or cardiac), nor do they cause significant
heating.13-15

Clinical Testing of TTF Therapy as a Monotherapy

The NovoTTF device was first applied to patients in a


small feasibility trial in Switzerland in 2003.16 In 2004, TTF
therapy was tested in a pilot clinical trial in patients with
recurrent GBM (Table 3).5 This single-center, single-arm
trial included patients with favorable prognostic character-

Table 1. In Vitro Evidence Overview


Histology

High-grade glioma
Breast adenocarcinoma

Non-small cell lung cancer (adenocarcinoma)

Colorectal adenocarcinoma
Malignant melanoma
Prostate
Cervical cancer

Cell Line

F-98; C-6; RG-2


U-118; U-87
Normal:
MDA-MB-231
MCF7
Multiple drug resistant:
MDA-MB-231Dox
AA8/EmtR1
MCF7/Mx
H1299
LLC
CT-26
B16F1 Patricia
PC-3
HeLa

Optimal/Effective
TTF Frequency (kHz)

Additive/Synergistic
with Chemotherapy

200

Temozolomide (dacarbazine)

120

Cyclophosphamide

Can Res, 20043


Proc Natl Acad Sci U S A, 20075
Can Res, 20043

120

Doxorubicin
Paclitaxel

Neuro Oncol, 20114


BMC Cancer, 20107

150

100*
100
100*
200*

Abbreviations: TTF, tumor treating fields; NA, not available (was not reported by the authors).
* Effect seen at this frequency; additional frequencies were not tested.

128

Doxorubicin
Paclitaxel
Paclitaxel
Pemetrexed
NA
NA
NA
NA

Reference

ERS, 20108
AACR, 20076
Can Res, 20043
Can Res, 20043
Can Res, 20043
Can Res, 20043
Neuro Oncol, 20114

TTF THERAPY IN GLIOBLASTOMA


Table 2. In Vivo Evidence Overview
Tumor Type

Anatomic Location

Animal Model

Frequency (kHz)

GBM
Non-small cell lung cancer

Right hemisphere
Lung parenchyma

Rat
Mouse

200
150

Malignant melanoma

Intradermal

Mouse

100

Malignant melanoma
VX-2 (anaplastic)

Intravenous
Kidney capsule

Mouse
Rabbit

100
150200

Effect of TTF

References

Tumor growth inhibition with 2 and 3 field directions


1. Tumor growth inhibition with 2 field directions
2. Additive tumor inhibition with pemetrexed
Tumor growth inhibition with 1 and 2 field directions
Inhibition of metastatic seeding in the lungs
1. Tumor growth inhibition seen with 2 field directions
2. Increase in median survival
3. Inhibition of metastatic seeding in the lungs
4. Additive tumor inhibition with paclitaxel

Proc Natl Acad Sci U S A, 20075


ERS, 20108
Can Res, 20043
Proc Natl Acad Sci U S A, 20075
Clin Exp Metastasis, 200910
Clin Exp Metastasis, 200910
AACR, 200927
Neuro Oncol, 201012

Abbreviation: GBM, glioblastoma.

ASCO Annual Meeting and were updated at the 2011


Society for Neuro-Oncology (SNO) Annual Meeting.18,19
Baseline characteristics of patients were balanced between
the two treatment groups. In both groups, patients had poor
prognostic predictors compared with previous clinical trials
of recurrent GBM (90% of patients were at their second or
subsequent recurrence; 20% had failed bevacizumab before
entering the trial; and the average tumor diameter was
above 5 cm). In the conservative intent-to-treat (ITT) analysis, the study showed that patients with recurrent GBM
treated with NovoTTF alone had comparable OS to that of
patients who received chemotherapy and/or bevacizumab
(6.6 months vs. 6.0 months, respectively; p 0.26; hazard
ratio [HR] 0.86; Table 3). Although NovoTTF did not show
superiority over active chemotherapies, it was clear that it
was at least as effective as these treatments. Secondary
endpoints in the trial were supportive: blinded radiology
review showed that PFS at 6 months was 21.4% in the
NovoTTF group compared with 15.2% in the chemotherapy
group (p 0.24). There were more radiological responses
seen in the NovoTTF group compared with the chemotherapy group (12% vs. 6%, respectively; p 0.07), including

istics. Treatment with the device was well tolerated, and no


treatment-related serious adverse events were reported.
Most patients developed grade 1 to 2 contact dermatitis
beneath the transducer arrays on the scalp. Efficacy endpoints were very encouraging with a 20% objective response
rate, progression-free survival (PFS) at 6 months of 50%,
median time to progression (TTP) of 26 weeks, and median
overall survival (OS) of 62.2 weeks (14.4 months). Compared
to the historic results of salvage chemotherapy, these results
showed clear activity of TTF therapy when used as a
monotherapy in recurrent GBM.17
Based on the results of this pilot trial, a pivotal phase III,
multicenter, randomized (1:1) clinical study was initiated in
patients with recurrent GBM (Table 3). The randomized
study, which recruited 237 patients between 2006 and 2009,
compared the efficacy and safety of monotherapy with the
NovoTTF device to that of the best available active chemotherapy according to physicians choice. Thirty-six patients
received bevacizumab, 36 received nitrosureas, 12 received
temozolomide, and 33 received other agents. This was the
largest randomized study in recurrent GBM to be completed
to date. The results of the study were presented at the 2010

Table 3. Clinical Evidence Overview

Indication (Analysis Group)

Trial Phase
(# of Subjects)
Analysis

Phase I-II (n 10)


ITT Analysis
Recurrent GBM (at second and
Phase III (n 237)
ITT analysis
fourth relapse)
Recurrent GBM (treated patients only)
Phase III (n 210)
PP Analysis
Recurrent GBM (KPS 80, age 61)
Phase III (n 110)
Subgroup analysis
Recurrent GBM (after bevacizumab failure) Phase III (n 43)
Subgroup analysis
Recurrent GBM (TTF versus bevacizumab) Phase III (n 156)
Subgroup analysis
Newly diagnosed GBM
I-II (n 10)
ITT Analysis
(together with temozolomide)
Relapsed advanced NSCLC
I-II (n 42)
ITT Analysis
(together with pemetrexed)
Recurrent GBM (at first relapse)

Overall Survival
(Months)
TTF

Hazard
Ratio (p)

Chemo

Progression-Free
Survival (PFS)
at 6 Months or
Median PFS (Weeks)
TTF

Chemo

14.5 m 6.0 m*

Non-randomized 50%

15%*

6.6 m

6.0 m

21.4%

15.2%

7.8 m

6.0 m

26.2%

15.2%

8.8 m

6.6 m

25.6%

7.7%

4.4 m

3.1 m

HR 0.86
(p 0.26)
HR 0.67
(p 0.012)
HR NA
(p 0.01)
(p 0.02)

NA

NA

21%

21%

90%
155 w
28 w

50%*
26 w
12 w*

HR 0.65
(p 0.048)
39 m 14.7 m* (p 0.002)
6.6 m

5.0 m

13.8 m 8.2 m*

NA

P value

References

NA

Proc Natl Acad Sci U S A,


20075
p 0.24 J Clin Oncol, 201018
Neuro Oncol, 201119
p 0.03 J Clin Oncol, 201018
Neuro Oncol, 201119
NA
Neuro Oncol, 201019
NA

Neuro Oncol, 201020

p 0.05 Neuro Oncol, 201121


NA

BMC Med Phys, 20099


ESMO, 201025
ERS, 20108
Expert Opin Investig Drugs,
201011

Abbreviations: GBM, glioblastoma; ITT, intention to treat; NA, not available (was not reported by the authors); HR, hazard ratio; PP, per protocol; KPS, Karnofsky
performance status; TTF, tumor treating fields; NSCLC, non-small cell lung cancer.
* Single-arm trials with literature control.

129

GUTIN AND WONG

three sustained complete responses in the NovoTTF group


compared with none in the chemotherapy group. These
results were accompanied by significantly (p 0.05) less
treatment-related adverse events with NovoTTF compared
with chemotherapy. Patients in the NovoTTF group reported a higher quality of life compared with patients
treated with chemotherapy. This analysis was based on the
European Organisation for Research and Treatment of Cancer QLQ-C30 and mirrored the lack of chemotherapy-related
toxicities in the NovoTTF group. Interestingly, patients in
the NovoTTF group reported better cognitive and emotional
functioning and much less pain than patients in the chemotherapy group, although these domains of the questionnaires are not related to known side effects of chemotherapy.
To date, several exploratory analyses of the study data
have been performed. The first analysis compared patients
who received the same amount of therapy in both groups.
This prospectively defined per-protocol analysis excluded
patients from both groups who received less than one predefined treatment course. The analysis demonstrated superior survival in the NovoTTF group compared with the
chemotherapy group (7.8 months vs. 6.0 months; p 0.012,
HR 0.67).18,19 The rationale behind this analysis is that
TTF is a physical modality with no half-life, so that the
moment the therapy is stopped, its antimitotic effect stops
as well. In contrast, chemotherapies have measurable
plasma and tissue half-life, which results in continued
efficacy and toxicity long after a dose has been given.
Therefore, to achieve pharmacokinetic balance in the
amount of treatment in both groups, this analysis used a
simplified criterion that one course of chemotherapy (e.g., 1
day of carmustine or 5 days of temozolomide) is equivalent to
four weeks of continuous TTF therapy.
Two more analyses of the study data were presented at
the 2010 and 2011 SNO Annual Meetings.20,21 The first
study analyzed known clinical prognostic factors of age and
Karnofsky performance status (KPS). This analysis demonstrated that in patients age 60 and younger with a KPS
greater than 70, treatment with NovoTTF resulted in superior OS compared with chemotherapy (8.8 months vs. 6.6
months; p 0.01). This survival advantage could be attributed to better compliance with TTF therapy in this group of
patients. In support of this finding, a statistically significant
correlation was seen in the NovoTTF group between treatment compliance (as measured by the device computerized
log file) and OS (p 0.0475).
The second analysis is a post hoc, exploratory analysis of
the treatment of 120 patients with NovoTTF compared with
36 patients with bevacizumab. Although without a prespecified analysis in the trial, patients in the study treated with
NovoTTF lived significantly longer than those treated with
bevacizumab (6.6 months vs. 5.0 months, respectively; p
0.048, HR 0.65).21 This analysis included all ITT patients
who received either bevacizumab or NovoTTF. Patient characteristics were almost identical and, in fact, favored the
bevacizumab group prognostically. Clearly, this analysis
cannot be taken as final evidence of superiority of NovoTTF
over bevacizumab; however, it should be treated as
hypothesis-generating data for future clinical studies. Finally, in the 43 patients who entered the study after bevacizumab therapy failure (approximately 20% of patients in
both groups), OS was significantly longer with TTF therapy

130

than with chemotherapy (4.4 months vs. 3.1 months, respectively; p 0.02). The data for the chemotherapy-treated
group is in line with previous publications, which showed
that following bevacizumab failure, the survival of patients
with recurrent GBM is limited.22
Based on the results of this pivotal phase III study, the
FDA approved the NovoTTF-100A device on April 8, 2011,
through the premarket approval (PMA) regulatory pathway.
The PMA pathway is reserved for class III (high-risk)
medical devices and requires preclinical, clinical, and manufacturing evidence, including review of both efficacy and
safety data by a panel of independent experts. The FDA
concluded that the study results showed NovoTTF to be
comparable in efficacy to active chemotherapy, without
many of the side effects associated with chemotherapies and
with a better quality of life.23
Clinical Trials Evaluating TTF Therapy in Combination
with Chemotherapy

Two studies of combined TTF therapy and chemotherapy


have been published to date. The first was a single-arm,
single-center trial performed in 2006 in patients with newly
diagnosed GBM.9 Patients received the Stupp protocol with
TTF therapy added to maintenance temozolomide.24 This
trial showed promising PFS and OS data (PFS 14 months;
OS 39 months; Table 3) and served as the basis for an
ongoing, multicenter, pivotal phase III, randomized clinical
study comparing TTF therapy and temozolomide with temozolomide alone in the maintenance stage of the Stupp
protocol.
The second study tested TTF therapy together with pemetrexed in 42 patients with pretreated, advanced non-small
cell lung cancer.8,11,25 Efficacy and safety with this combined treatment paradigm were promising. Time to local
disease progression in the lungs and liver (where TTF was
applied) was 28 weeks, and OS was 13.8 months. In contrast, TTP and OS for pemetrexed alone were previously
reported to be 12 weeks and 8.3 months, respectively.26
TTF therapy is still in its early days. However, it has an
established mechanism of action, and a growing body of
preclinical evidence has shown its wide applicability in solid
tumor malignancies either alone or in combination with
standard chemotherapies. Objective antitumor activity and
an unprecedented safety profile of this treatment modality
have been seen in patients with recurrent GBM. Although
TTF monotherapy has been shown to be at least as effective
as the best available chemotherapies today for recurrent
GBM, in-depth analysis of the phase III study data identified at least two subgroups where TTF therapy was superior
to chemotherapy and could be offered to patients as an
alternative to chemotherapy: younger patients with a better
functional status and patients in whom bevacizumab treatment has failed in the past.
Conclusion

The approval of TTF therapy for recurrent GBM ushers in


a fourth modality of cancer treatment. More importantly,
TTF treatment has a superior safety profile, and its minor
side effects do not appear to overlap with those of cytotoxic
chemotherapies, targeted agents, or antiangiogenesis drugs.
Therefore, the rational combination of TTF therapy with
specific pharmacologic agents may enhance tumor cell death

TTF THERAPY IN GLIOBLASTOMA

because of potential additive or synergistic effects. First, as


demonstrated in preclinical and clinical models, chemotherapy administered together with TTF therapy may result in
additive or synergistic tumor control without increasing
systemic toxicities. Second, TTF treatment could be combined with targeted agents that block survival signaling
within the tumor cell. This block may be sufficiently strong
to enhance the cytotoxic effect of TTF therapy or vice versa.

Third, the combination of TTF and antiangiogenesis agents


may be another promising path that combines different
antitumor treatments to improve tumor control. Lastly, the
proper scheduling of TTF therapy with other agents is
unknown. Additional research may shed light on the optimal
scheduling that may achieve a synergistic effect on tumor
growth leading to long-term tumor control and enhanced
patient survival.

Authors Disclosures of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Philip H. Gutin

Novocure

Eric T. Wong

Novocure

Expert
Testimony

Other
Remuneration
Novocure

REFERENCES
1. Maxwell JC. A Dynamical Theory of the Electromagnetic Field. Royal
Society Transactions. CLV:1865.
2. Palti Y, Schneiderman R, Gurvich Z, et al. Cell proliferation arrest and
tumor cell destruction by low intensity, frequency tuned electric fields. 2004
AACR Meeting Abstracts. (abstr 1000).
3. Kirson ED, Gurvich Z, Schneiderman R, et al. Disruption of cancer cell
replication by alternating electric fields. Cancer Res. 2004;64:3288-3295.
4. Lee SX, Wong ET, Swanson KD. Mitosis Interference of Cancer Cells
During Anaphase By Electric Field from NovoTTF-100A. Neuro Oncol.
2011;13:iii10-iii25 (suppl 3; abstr CB-17).
5. Kirson ED, Dbaly V, Tovarys F, et al. Alternating electric fields arrest
cell proliferation in animal tumor models and human brain tumors. Proc Natl
Acad Sci U S A. 2007;104:10152-10157.
6. Schneiderman R, Shmueli E, Kirson E, et al. Synergism between
chemotherapy and alternating electric fields in the inhibition of cancer cell
proliferation in-vitro. 2007 AACR Meeting Abstracts. (abstr 2276).
7. Schneiderman RS, Shmueli E, Kirson ED, et al. TTFields alone and in
combination with chemotherapeutic agents effectively reduce the viability of
MDR cell sub-lines that over-express ABC transporters. BMC Cancer. 2010;
10:229.
8. Weinberg U, Fresard I, Kueng M, et al. An Open Label Pilot Study of
Tumor Treating Fields (TTFields) in Combination with Pemetrexed for
Advanced Non-small Cell Lung Cancer (NSCLC). 2010 ERS Annual Congress.
(abstr 363).
9. Kirson ED, Schneiderman RS, Dbaly V, et al. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric
fields (TTFields). BMC Med Phys. 2009;9:1.
10. Kirson ED, Giladi M, Gurvich Z, et al. Alternating electric fields
(TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp
Metastasis. 2009;26:633-640.
11. Pless M, Weinberg U. Tumor treating fields: Concept, evidence and
future. Expert Opin Investig Drugs. 2010;20:1099-1106.
12. Kirson ED, Wasserman Y, Izhaki A, et al. Modeling tumor growth
kinetics and its implications for TTFields treatment planning. Neuro Oncol.
2010;12:iv36-iv57 (suppl 4; abstr NO-54).
13. Palti Y. Stimulation of muscles and nerves by means of externally
applied electrodes. Bull Res Counc Isr Sect E Exp Med. 1962;10:54-56.
14. Shizgal P, Mathews G. Electrical stimulation of the rat diencephalon:
Differential effects of interrupted stimulation on on- and off-responding.
Brain Res. 1977;129:319-333.

15. Yearwood TL, Hershey B, Bradley K, et al. Pulse width programming in


spinal cord stimulation: A clinical study. Pain Physician. 2010;13:321-335.
16. Salzberg M, Kirson E, Palti Y, et al. A pilot study with very lowintensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. 2008;31:362-365.
17. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors
in recurrent glioma patients enrolled onto phase II clinical trials. J Clin
Oncol. 1999;17:2572-2578.
18. Stupp R, Kanner A, Engelhard H, et al. A prospective, randomized,
open-label, phase III clinical trial of NovoTTF-100A versus best standard of
care chemotherapy in patients with recurrent glioblastoma. J Clin Oncol.
2010;28:18s (suppl; abstr LBA2007).
19. Wong ET, Ram Z, Gutin PH, et al. Updated survival data of the phase
III clinical trial of NovoTTF-100A versus best standard chemotherapy for
recurrent glioblastoma. Neuro Oncol. 2011;13:iii85-iii91 (suppl 3; abstr OT09).
20. Ram Z, Gutin PH, Stupp R. Subgroup and quality of life analyses of the
phase III clinical trial of NovoTTF-100A versus best standard chemotherapy
for recurrent glioblastoma. Neuro Oncol. 2010;12:iv36-iv57 (suppl 4; abstr
NO-55).
21. Ram Z, Gutin PH, Wong ET. Comparing the effect of NovoTTF to
Bevacizumab in Recurrent GBM: A Post-Hoc Sub-Analysis of the Phase III
Trial Data. Neuro Oncol. 2011;13:iii41-iii68 (suppl 3; abstr NO-50).
22. Iwamoto FM, Abrey LE, Beal K, et al. Patterns of relapse and prognosis
after bevacizumab failure in recurrent glioblastoma. Neurology. 2009;73:
1200-1206.
23. FDA: NovoTTF-100A Information for Use, 2011. http://www.access
data.fda.gov/cdrh_docs/pdf10/P100034c.pdf. Accessed February 23, 2012.
24. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus
concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med.
2005;352:987-996.
25. Pless M, Betticher DC, Buess M, et al. A phase II study of tumor
treating fields (TTFields) in combination with pemetrexed for advanced non
small cell lung cancer (NSCLC). Ann Oncol. 2010:viii122-viii161.
26. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial
of pemetrexed versus docetaxel in patients with non-small-cell lung cancer
previously treated with chemotherapy. J Clin Oncol. 2004;22:1589-1597.
27. Kirson E, Gurvich Z, Izhaki A, et al. Alternating electric fields
(TTFields) inhibit metastatic spread of solid tumors to the lungs in-vivo. 2009
AACR Meeting Abstracts. (abstr 151).

131

ADAPTIVE CLINICAL TRIAL DESIGNS:


WHAT ARE THEY AND SHOULD THEY BE USED?
CHAIR
Mary Weber Redman, PhD
Fred Hutchinson Cancer Research Center
Seattle, WA
SPEAKERS
J. Jack Lee, PhD, DDS
University of Texas M. D. Anderson Cancer Center
Houston, TX
Marc Buyse, ScD
International Drug Development Institute
Louvain-la-Neuve, Belgium

Limitations of Adaptive Clinical Trials


By Marc Buyse, ScD

Overview: Adaptive designs are aimed at introducing flexibility in clinical research by allowing important characteristics
of a trial to be adapted during the course of the trial based
on data coming from the trial itself. Adaptive designs can be
used in all phases of clinical research, from phase I to phase
III. They tend to be especially useful in early development,

ITH THE large number of promising new molecules


that are currently available for clinical testing, clinical trials must detect a drugs benefit (or harm) as quickly
as possible. In parallel to the explosion in the number of
drugs awaiting clinical testing, the costs of clinical trials
have sky-rocketed, which adds to the pressure of optimizing
trials, to the extent possible, in terms of sample sizes,
timelines, and risk of failure. A new class of designs has
emerged to address these challenges, collectively known as
adaptive designs. In this chapter, we review different types
of adaptive designs and briefly mention some situations in
which such designs can be useful. Much of this chapter,
however, is devoted to a discussion of the limitations and
drawbacks of adaptive designs, which might partly explain
why these designs have not been commonly used and might
in the future have less of an effect on clinical research than
claimed by their advocates.
Types of Adaptive Designs

One of the difficulties surrounding adaptive designs is


that the term is used to encompass different situations. For
clarity, we divide group adaptive designs into three broad
categories.
The first category is treatment effectindependent adaptive designs. In these designs, some of the design features
can be adapted on observation of predefined patient characteristics (such as baseline prognostic factors) or outcomes
(such as response rate or hazard rate overall or in the control
group) but in ignorance of the treatment effect.
The second category is treatment effect dependent adaptive designs. In these designs, one or more of the design
features (such as the sample size, the patient inclusion
criteria, the treatment groups being compared, the treatment allocation ratio, or even the primary endpoint) can be
adapted, depending on the observed treatment effect.
The third category is other types of adaptive designs,
which include the continual reassessment method (CRM) for
phase I trials and seamless phase II/III designs.
Treatment EffectIndependent Adaptive Designs

In these designs, adaptations do not depend on the treatment effect. As such, these adaptations raise few issues and
have little effect on the statistical inference; in particular,
they do not inflate the type I error. In fact, such adaptations are so mild that trials using them are not referred to
as adaptive. We provide two examples but do not discuss
these designs in detail.
Covariate-Adaptive Randomization

One instance of treatment effectindependent adaptation


is covariate-adaptive randomization, for which the probabil-

when the paucity of prior data makes their flexibility a key


benefit. The need for adaptive designs lessened as new
treatments progress to later phases of development, when
emphasis shifts to confirmation of hypotheses using fully
prespecified, well-controlled designs.

ity of allocating the next patient to one of the trials treatment groups is computed dynamically to ensure good
balance among the treatment groups with respect to important prognostic factors (center or country, clinicopathologic
features, and, increasingly, biomarkers measured at baseline). A common implementation of this approach is minimization, for which a predefined algorithm is used to minimize
the imbalance between the distributions of important prognostic factors at baseline among treatment groups. When
minimization is used, the treatment group the next patient
is allocated to can depend on the baseline characteristics of
previously accrued patients but not on their outcome.1
Sample Size Increases

Another type of treatment effectindependent adaptation


consists of a sample size increase if the incidence of the event
of interest is much lower than expected in the control group
(to preserve the power of the trial) or if the event rate is
much lower than expected overall (to preserve the timelines
of event-driven analyses when the outcome of interest is a
time-to-event, such as disease-free survival or overall survival). Again, these sample size increases are implemented
in ignorance of the treatment effect; hence, they generally
have no effect on type I error and, if implemented appropriately, raise no special statistical concerns.2
Treatment EffectDependent Adaptive Designs

These designs are truly adaptive insofar as adaptations


depend on the observed treatment effect, which requires
caution to be exercised and a proper statistical approach to
be used. If, for instance, the sample size of a trial was
increased (or decreased) simply because the observed treatment effect was smaller (or larger) than anticipated, the
final results of the trial could be biased.3 For instance, a
randomly large treatment effect could lead to a reduction
in sample size even though the true effect were as expected.
Note that a group sequential design is not subject to this
problem because its sample size is fixed and can only be
decreased if the trial is stopped for efficacy or futility at an
interim analysis.4

From the International Drug Development Institute, Houston, TX; Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek,
Belgium.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Marc Buyse, ScD, IDDI Inc, 363 N. Sam Houston Pkwy. E.,
Suite 1100, Houston, TX 77060; email: marc.buyse@iddi.com.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

133

MARC BUYSE
Sample Size Recalculation

The most obvious adaptation to consider for an ongoing


comparative (phase III) trial is a sample size recalculation if
the treatment effect turns out to be vastly different from
that assumed to design the trial. It might make sense, for
example, to consider an increase in sample size if the
assumed treatment effect was grossly overestimated (e.g., as
a result of highly promising phase II results), but there are
serious theoretical and practical objections to doing so (Table 1).
Theoretically, the treatment effect assumed in the protocol was the smallest effect considered to be clinically worthwhile; hence, there is no reason to lower this effect merely to
reach statistical significance. In practice, however, the sample size is often based on a larger treatment effect than the
minimum considered worthwhile, especially when the findings of phase II trials suggest that a larger treatment effect
can potentially be achieved. Commonly, other considerations
come into play, including budgetary constraints that tend to
drive sample sizes down. It is tempting, especially for small
companies with limited financial resources, to shoot for large
treatment effects, hope for the best, and increase the sample
size only if needed. Great caution must, however, be exercised when a sample size increase is triggered by the
observation of a smaller than expected treatment benefit,
insofar as such an adaptation can lead to changes in the
types of patients accrued into the trial so that the trial after
the adaptation is no longer the same as before the adaptation. It has also been proven that for any adaptive design one
might consider, there exists a group sequential design that
uniformly outperforms it (i.e., has better power for any given

KEY POINTS

134

Adaptive designs can be useful in specific situations


(e.g., in phase I trials aimed at determining a maximum tolerated dose or in dose-finding trials when a
wide range of doses needs to be investigated).
Despite the hype surrounding adaptive designs, they
have been used infrequently so far; the flexibility
afforded by adaptive designs might not be compensated for by the potential loss in credibility associated
with their use.
Although adaptive designs can be useful to rescue
trials that are based on incorrect assumptions, they
should not generally replace well-designed trials that
use conventional approaches (e.g., group sequential
designs that are more statistically efficient).
Generally speaking, treatment effectindependent
adaptations raise few difficulties, whereas treatment
effect dependent adaptations are to be implemented
with caution and use of appropriate statistical methods.
Covariate-adaptive randomization is useful to minimize imbalances in prognostic factors among treatment groups; in contrast, outcome-adaptive
randomization is unhelpful statistically, difficult logistically, and unnecessary ethically.

Table 1. Pros and Cons of Adaptive Sample Size Increases


Pros

Potential to rescue a trial that would


miss statistical significance
Flexibility if design considerations
were inadequate

Cons

Statistically inefficient
Emphasis on statistical significance
rather than clinical relevance
Changes in patient population or other
temporal trends
Can often be substituted by nonadaptive
sample size increases that do not affect
the type I error

treatment effect).5 In other words, adaptive designs are


inefficient compared with group sequential designs. This
mathematical result has profound consequences because it
implies that even the most astute adaptive design can, in
theory, be replaced by a group sequential counterpart that
has better statistical power and none of the dangers created
by adaptations made to an ongoing trial. In fairness to
adaptive designs, the superior efficiency of group sequential
designs assumes that the appropriate spending function can
be prespecified and that interim analyses come at no cost,
which is not the case in practice.6
Figure 1 compares a group sequential design with an
adaptive design in the same situation. This figure illustrates
the putative advantage of the adaptive design that starts
with a small sample size based on a large treatment effect
and increases the sample size if the observed effect is
smaller than anticipated, whereas the group sequential
design starts with a large sample size based on a small
treatment effect and stops early if the observed effect is
larger than anticipated. Stated differently, adaptive designs
take an optimistic view and adapt if required, whereas
group sequential designs take a pessimistic view and stop
early if indicated. In the example of Fig. 1, the group
sequential design is based on a difference in proportions of
0.05 and requires 1,400 patients but can stop after 350, 700,
or 1,050 patients if the difference is equal to approximately
0.15, 0.075, or 0.05, respectively. In contrast, the adaptive
design is based on a difference in proportions of 0.10 and
requires only 400 patients, but the sample size can be
increased if the conditional power at 200 patients or 400
patients is too low.
The conditional power is the power that the trial is
expected to have at its final analysis, given the data from the
already accrued patients and assuming that the protocolspecified difference will apply to all patients still to be
accrued. Note that at the beginning of the trial, the conditional power is simply equal to the power because no data
are available yet. As stated above, it is essential, when
recalculating the sample size in an adaptive manner, to use
appropriate statistical methods. Several methods for this
exist; Tsiatis and Mehta provide a review and examples of
these methods.5
Outcome-Adaptive Randomization

In outcome-adaptive randomization, the probability of


allocating the next patient to one of the trials treatment
groups is computed dynamically to favor the treatment
group with the best outcome so far.7 For instance, if response (tumor shrinkage) was the outcome of interest,
patients would be allocated preferentially to the treatment
group with the highest response rate. This approach has

LIMITATIONS OF ADAPTIVE CLINICAL TRIALS

Fig. 1.

Comparison between a group sequential design and an adaptive design.

been called a play-the-winner strategy.8 A crucial distinction needs to be made between covariate-adaptive randomization and outcome-adaptive randomization. Indeed,
although the former raises no particular issue, the latter is
fraught with problems.
First, the outcome that is used to adapt the randomization has to be observed early and reliably, and it must be
reasonably predictive of important clinical endpoints for the
adaptation to succeed at placing more patients in the better
treatment group.
Second, adaptive randomization can result in major imbalances among treatment arms, which in turn negatively
affects the statistical power of the trial.
Third, the statistical inference is complicated because the
treatment assignments and the responses are correlated; as
a consequence, rerandomization tests must be used instead
of traditional likelihood-based tests.
Fourth, adaptive randomization can cause accrual bias (if
patients wait for the probability of receiving the better
treatment to increase) and/or selection bias (if patients are
aware of the emerging difference among the treatment
groups).
Last but not least, it is incorrect to claim that adaptive,
randomization is ethically superior to fixed randomization
because equipoise mandates that allocation to any of the
treatment groups be considered equally desirable. It might
make sense to allocate more patients to the experimental
group than to the control group, but the justification for
doing so is that more information is needed about a new
treatment than about a well-established standard treatment. When such is the case, a fixed unequal allocation ratio
(such as a 2:1 ratio in favor of the experimental group) will
do just as well as adaptive randomization, without being
subject to the problems listed above.9
Other Types of Adaptive Designs

There are many other types of adaptive designs, some of


which do not fall into the two clear-cut categories discussed.
We briefly mention two types of designs that have attractive
properties but have also been rarely used in practice.

CRM in Phase I Trials

Classic phase I cancer trials are aimed at determining the


maximum tolerated dose (MTD) of a new drug or combination of drugs.10 They are usually performed according to a
fixed design called the 3 3 design. The design proceeds in
cohorts of three patients, with the first cohort being treated
at the minimum dose of interest and the next cohorts being
treated at increasing dose levels according to a predetermined dose escalation scheme. The dose escalation proceeds
until at least one dose-limiting toxic effect is observed in a
cohort of three patients, in which case a second cohort of
three patients is treated at the same dose level. The dose
escalation stops as soon as at least two patients experience
a dose-limiting toxic effect, either in the first cohort of three
patients treated at that dose level or in the two cohorts of
three patients treated at that dose level. Although this
design is used in almost every phase I cancer trial today, it
has several limitations.11 First, too many patients may be
treated at low doses, with virtually no chance of efficacy.
Second, dose escalation may be too slow because of an
excessive number of escalation steps, resulting in trials that
take longer than needed to get to the MTD. Third, too few
patients may be treated near the MTD, resulting in substantial residual uncertainty about the dose recommended for
further trials, which raises ethical concerns. Indeed, if the
recommended dose is chosen too low, it can fail to have
efficacy in phase II trials, whereas if it is chosen too high, it
can put patients at unacceptable risk in phase II trials. Last
but not least, the 3 3 design makes no allowance for
patient variability. An adaptive design known as the CRM
was originally proposed by OQuigley et al12 in the early
1990s. This design involves a statistical approach based on
an assumed dose-response relationship, which is described
through a mathematical function that links the probability
of a dose-limiting toxic effect and the dose level. The CRM
design is adaptive insofar as the dose to use for the next
patient is determined from the toxic effects experienced by
all the patients already treated so far. Many modifications to
the CRM have been proposed, and simulation studies have

135

MARC BUYSE
Table 2. Comparisons of Three Approaches for Late Clinical Development
Approach

Benefits

Phase II trial followed by phase III trial

Seamless phase II/III trial

Phase III trial with interim analyses

Costs and Risks

Standard approach
No regulatory risk
Phase III trial provides independent confirmation of
phase II results
Can adapt the phase III based on the phase II results
Statistical method well established
Upfront commitment for phase II only
Much experience with group sequential designs
No regulatory risk
Optimal statistical approach if several interim looks
are planned

shown that it generally outperforms the 3 3 design.13,14


Ironically, however, the CRM is not as popular as it should
be given its attractive properties, probably because it requires calculations to be performed for the next dose to be
determined, whereas the 3 3 design does not.
Seamless Phase II/III Designs

It is possible to embed a phase II trial into a phase III trial


so that the transition between the two phases is operationally seamlessas opposed to performing a randomized
phase II trial followed by a separate phase III trial. The
simplest version of this approach consists of using a classic
phase II design to screen for activity based on response and
to calculate the sample size required of the phase III trial
based on the final outcome of interest, such as time to
progression or survival. Because the purpose of the phase II
trial is only to stop for futility on the basis of lack of activity,
there is no inflation in type I error. One-stage or two-stage
phase II designs can be used, as well as a selection design if
several experimental arms are simultaneously screened. In
all cases, the phase II and phase III portions of the trial are
designed independently of each other. Table 2 contrasts a
seamless transition from phase II to phase III with two other
approaches. Some authors have proposed to use a Bayesian
approach to expand the phase II trial to a phase III trial.15
A different approach that is particularly useful in selecting one or more doses of a new investigational agent is to use

Longest development time


Largest total sample size

Negotiation with regulatory agencies essential


Less experience with adaptive designs
Requires large upfront commitment
Difficult to design or start phase III based on scanty
early data

an inferentially seamless design in which several doses are


tested in the phase II portion of the trial and to select only
the most promising one to continue in the phase III portion.16 Various designs have been proposed that control the
overall significance level of the trial, whether or not there
are adaptations of some design aspects at the end of the
phase II trial. Jennison and Turnbull offer a review and
useful guidance.17,18
Conclusion

There is little doubt that clinical research is in need of


reengineering to provide efficient readouts of efficacy and
safety on the large number of treatments currently developed by pharmaceutical, biotechnology, and medical device
companies. Running large-scale trials that have a high
probability of failure is clearly undesirable. Many innovative
methods have been proposed, including adaptive designs,
Bayesian designs, and biomarker-based designs. Some recent trial designs combine all of these ideas and constitute,
as such, exciting models for further developments.19,20 The
future will tell which of these innovations are useful and
when they constitute a definite improvement over classic
approaches. In the meantime, oncologists involved in clinical
research must be aware of the limitations of each approach
and adjust their expectations accordingly. Clinical trial
sponsors might wish to consult regulatory guidances already
available on adaptive designs.21,22

Authors Disclosures of Potential Conflicts of Interest

Author
Marc Buyse

Employment or
Leadership
Positions
IDDI

Consultant or
Advisory Role

Stock
Ownership
IDDI

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

REFERENCES
1. Rosenberger WF, Lachin JM. Randomization in Clinical Trials: Theory
and Practice. New York, NY: Wiley; 2002.
2. Gould AL. Planning and revising the sample size for a trial. Stat Med.
1995;14:1039-1051.
3. Mehta CR. Sample size reestimation for confirmatory clinical trials. In:
Harrington D (ed). Designs for Clinical Trials: Perspectives on Current Issues.
New York, NY: Springer; 2011.
4. Kim KM. Sequential designs for clinical trials. In: Harrington D (ed).
Designs for Clinical Trials: Perspectives on Current Issues. New York, NY:
Springer; 2011.
5. Tsiatis AA, Mehta C. On the inefficiency of the adaptive design for
monitoring clinical trials. Biometrika. 2003;90:367-e78.
6. Brannath W, Bauer P, Posch M. On the efficiency of adaptive designs for
flexible interim decisions in clinical trials. J Stat Planning Infer. 2006;136:
1956-1961.

136

7. Hu F, Rosenberger WF. The Theory of Response-Adaptive Randomization in Clinical Trials. New York, NY: Wiley; 2006.
8. Wei LJ, Durham S. The randomized play-the-winner rule in medical
trials. J Am Stat Assoc. 1978;73:840-843.
9. Korn EL, Freidlin B. Outcome-adaptive randomization: is it useful?
J Clin Oncol. 2003;90:367-378.
10. Eisenhauer E, Twelves C, Buyse M. Phase I Clinical Trials in Cancer.
Oxford, England: Oxford University Press; 2006.
11. Cheung YK. Designs for phase I trials. In: Harrington D (ed). Designs
for Clinical Trials: Perspectives on Current Issues. New York, NY: Springer;
2011.
12. OQuigley J, Pepe M, Fisher L. Continual reassessment method: a
practical design for phase 1 clinical trials in cancer. Biometrics. 1990;46:33-48.
13. Chevret S. The continual reassessment method in cancer phase I
clinical trials: a simulation study. Stat Med. 1993;12:1093-1108.

LIMITATIONS OF ADAPTIVE CLINICAL TRIALS


14. Goodman SN, Zahurak ML, Piantadosi S. Some practical improvements in the continual reassessment method for phase I studies. Stat Med.
1995;14:1149-1161.
15. Inoue LY, Thall PF, Berry DA. Seamlessly expanding a randomized
phase II trial to phase III. Biometrics. 2002;58:823-831.
16. Bretz F, Koenig F, Brannath W, et al. Adaptive designs for confirmatory clinical trials. Stat Med. 2009;28:1181-1217.
17. Jennison C, Turnbull BW. Confirmatory seamless Phase II/III clinical
trials with hypotheses selection at interim: opportunities and limitations.
Biom J. 2006;48:650-655.
18. Jennison C, Turnbull BW. Adaptive seamless designs: selection and
prospective testing of hypotheses. J Biopharm Statist. 2007;17:1135-1161.
19. Zhou X, Liu S, Kim ES, Herbst RS, Lee JJ. Bayesian adaptive design
for targeted therapy development in lung cancera step toward personalized
medicine. Clin Trials. 2008;5:181-193.

20. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman
LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 2009;86:97-100.
21. European Medicines Agency (EMA), Committee for Medicinal Products
for Human Use (CHMP). Reflection Paper on Methodological Issues in
Confirmatory Clinical Trials Planned With an Adaptive Design. http://home.
att.ne.jp/red/akihiro/emea/245902enadopted.pdf. Accessed February 10,
2012.
22. U.S. Department of Health and Human Services, Food and Drug
Administration (FDA). Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics. http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf. Accessed February 10, 2012.

137

ENDPOINTS FOR CANCER TRIALS IN 2012:


STATISTICAL, REGULATORY, AND CLINICAL
PERSPECTIVES (eQ&A)
CHAIR
Daniel J. Sargent, PhD
Mayo Clinic
Rochester, MN
SPEAKERS
Ann T. Farrell, MD
U. S. Food and Drug Administration
Silver Spring, MD
Deborah Watkins Bruner, PhD, RN
Abramson Cancer Center, University of Pennsylvania
Philadelphia, PA

Capturing the Patient Perspective:


Patient-Reported Outcomes as Clinical
Trial Endpoints
Deborah Watkins Bruner, RN, PhD, Benjamin Movsas, MD, and Ethan Basch, MD

Overview: Just as clinical trial design and rigor have evolved


with improvements in methods and processes, so too have
methods for capturing patient data in clinical trials. Substantial evidence suggests that standard physician reporting of
symptoms for which we lack objective diagnostics (e.g., pain)
is often discordant with patient self-report. Current reporting
using the National Cancer Institute Common Terminology
Criteria for Adverse Events (CTC[AE]) for symptom capture
relies on a filtering system, from patient to physician to
medical record to medical record abstraction to data entry,
with each step requiring interpretation and the possibility of
error. In contrast, patient-reported outcomes (PROs) eliminate
the filter and rely on direct report. Furthermore, the lack of
validation and training in use of the CTC(AE) creates an
inadequate data capture system. Inadequacies might be observed as underreporting or overreporting symptom preva-

HE TITLE of this chapter, Capturing the Patient


Perspective: Patient-Reported Outcomes as Clinical
Trial Endpoints, implies that the patient perspective is
separate from other clinical trial endpoints. All endpoints
involve patient data. Why then the emphasis on the patient
perspective? Currently, all cancer clinical trials use the
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTC[AE]), a descriptive system
that is used for adverse event reporting. The CTC(AE) uses
a grading (severity) scale for each adverse event term.1
Grading is performed by either the physician or research
assistants, who abstract information from the patients
medical records. Either method of grading requires interpreting or filtering the patient experience. In contrast, A
patient-reported outcome (PRO) is a measurement of any
aspect of a patients health status that comes directly from
the patient (i.e., without interpretation of the patients
responses by a physician or anyone else).2
The Pros and Cons for Use or Nonuse of PROs in
Clinical Trials

What do we gain over standard CTC(AE) reporting by


including the patient perspective in clinical trials? Table 1
lists the complementary benefits of the CTC(AE) and PROs.
However, given limited resources, what is the downside of
experienced physicians and research associates grading a
patients symptoms? The downside is they might not be
correctly grading symptoms and/or they might be missing
key information; either can occur for a host of reasons.

lence and severity compared with patient self-report.


Inaccuracies in symptom reporting can lead to missing important prognostic information, lack of understanding of patient
adherence with therapies, and lack of information for patient
decision making. They can also lead to opportunities lost in
terms of labeling claims and comparative effectiveness analyses. New developments in patient-reported outcome (PRO)
reporting, including the PRO-CTC(AE) and models for incorporation of PROs in clinical trials, might facilitate routine
PRO reporting complementary to CTC(AE) in clinical trials. In
addition, the cadre of validated PRO instruments already in
existence allows for more in-depth, hypothesis-driven evaluations. For standard toxicity reporting, the time has come for
mandatory routine PRO symptom reporting complementary to
the CTC(AE).

is evident in the rare instances when the CTC(AE) has been


tested for interrater reliability, which is modest at best.
Kabaet al4 evaluated the reliability of CTC version 2.0 with
five experienced research associates independently reviewing 17 different medical records and grading toxicities.
Agreement among raters was lowest for symptoms that are
difficult to directly observe and highest for symptoms that
have an associated laboratory test, for example, agreement
for nausea was 0.47 (0.23 0.71, 95% CI) and agreement for
febrile neutropenia was 0.88 (0.731, 95% CI).4 Atkinson
and colleagues5 assessed interrater reliability of multiple
CTC(AE) symptoms. In a study at an NCI-designated comprehensive cancer center, patients receiving active chemotherapy routinely had toxicity assessments performed by
two clinicians. The ratings were performed independently,
without access to the other physicians reports, on a medical
record form that included the name of each symptom, a
checkbox to note the grade of the toxicity, and a key with
definitions of each CTC(AE) grade for each symptom. Agreement among raters was low for most symptoms (e.g. diarrhea [0.58], constipation [0.5], nausea [0.52], and vomiting
[0.46]). In addition to poor interrater reliability, no assessments of validity of the CTC(AE) have been published,
meaning it is unknown whether grade 1 is clinically different from grade 2, etc. By contrast, the use of PROs in clinical
trials is held to stringent and rigorous development and
psychometric validation as described in detail in the U.S.
Food and Drug Administration (FDA) guidance for use of
PROs.2

Lack of Reliability and Validity of the Current


Grading System

The CTC(AE) was not designed as a physician checklist or


patient interview, and there are a variety of ways in which
the grading is performed and by whom it is performed,
which are described elsewhere.3 This variation in grading
leads to questions about training to use the grading system,
and the answer is there is no training. This lack of training

From the Nell Hodgson Woodruff School of Nursing, Winship Cancer Institute, Emory
University, Atlanta, GA; Radiation Oncology Department, Henry Ford Health System,
Detroit, MI; Memorial Sloan-Kettering Cancer Center, New York, NY.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Deborah Watkins Bruner, RN, PhD, Nell Hodgson Woodruff
School of Nursing, Winship Cancer Institute, Emory University, 1520 Clifton Rd., Room
232, Atlanta, GA 30322-4201; email: dwbrune@emory.edu.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

139

BRUNER, MOVSAS, AND BASCH


Table 1. Complementary Use of Common Terminology Criteria for Adverse Events (CTC[AE]) and Patient-Reported Outcomes (PROs)
in Clinical Trials

Primary use
Most useful for
Best captures
Valid
Reliable
Data capture method
Time of data capture
a

CTC(AE)

PROs

Toxic effects reporting


Objective assessment (e.g., diagnostic test, imaging,
overt sign, such as bleeding)
Severity, need for physician intervention
Not tested
No
Through layers of interpretation
As it occurs/as physician picks it up

Health status reporting


Subjective assessment (e.g., cannot be seen, felt, heard, observed,
or clinically tested by physician)
Severity, function, effect on quality of life and treatment adherence
Yesa
Yesa
Directly from the patient
At designated time points

Legacy instruments psychometrically tested to varying degrees; for current U.S. Food and Drug Administration use, must conform to stringent guidelines

Underreporting Prevalence of Symptoms

Data have demonstrated that PROs often identify more


symptoms than standard CTC(AE) reporting. In a phase III
trial of a cream compared with a placebo to prevent breast
cancer radiation therapyrelated dermatitis, PROs delineated a wider spectrum of toxicity than CTC(AE) and provided more information on rash, redness, pruritus, and
annoyance measures compared with CTC(AE) findings of
rash and pruritus.6
Underreporting and Overreporting Levels of Severity

A burgeoning body of evidence indicates that physicians


often underreport or overreport the level of severity of
symptoms compared with patient self-report. WatkinsBruner and colleagues,7 in the NCI-sponsored Radiation
Therapy Oncology Group (RTOG), reported discordance between physician and patient reporting in RTOGs first published PRO report (RTOG 90-20), A Phase II Trial of
Radiotherapy Plus a Radiosensitizer for Locally Advanced
Prostate Cancer. In a comparison of patient self-report of
symptoms on a validated measure with physician ratings

KEY POINTS

140

The current cancer clinical trial reporting system


using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTC[AE]) is
inadequate, by itself, to capture subjective symptoms.
Patient-reported outcome (PRO) measures, rigorously developed and validated, provide important and
accurate information required for robust clinical trials reporting.
The risk of not including PROs in routine reporting of
clinical trials is substantial inaccuracies in reporting
of prevalence and severity of symptoms related to
treatments, missing important prognostic information, lack of understanding of patient adherence with
therapies, and lack of information for patient decision
making.
Opportunities lost in not including PROs in routine
clinical reporting include lack of information for labeling claims and comparative effectiveness.
Validated and reliable PROs exist that are easily
available for both routine reporting of symptoms and
more complex evaluations of hypotheses-driven endpoints.

of the same symptoms on a toxicity scale, disagreement


between patient and physician reports of severity of dysuria,
diarrhea, and erectile dysfunction ranged from 13% to 45%.
The RTOG determined that the findings warranted routine
use of PROs in clinical trials. A larger initiative to assess
how well PROs correspond to reports of the same symptoms
as rated by the CTC(AE) across NCI cancer clinical trial
cooperative groups included a pooled analysis of 12 lung
cancer clinical trials conducted by three cooperative groups.8
Data were assessed in 1,013 patients who had both adverse
events and PROs recorded. Agreement between incidence of
any grade adverse event and a substantial decrease in PROs
ranged from 27% to 61% for grade 2 and higher and 36% to
61% for grade 3 and higher toxicities. Agreement between
the incidence of a specific grade adverse event and a substantial decrease in a corresponding PRO ranged from 0% to
38% for grade 2 and higher and 0% to 14% for grade 3 and
higher toxicities.8
Missing Prognostic Information

Data from clinical trials have shown validated PROs to be


prognostic for survival in almost every cancer disease site,
especially in more advanced stage disease. For example, in
an RTOG clinical trial of a radioprotectant for radiationinduced esophagitis in the treatment of nonsmall cell lung
cancer, baseline patient-reported scores on the European
Organisation for Research and Treatment of Cancer
Quality-of-Life Questionnaire replaced known prognostic
factors (performance status, stage, sex, age, race, marital
status, histologic features, and tumor location) as the sole
predictor of long-term overall survival. A 10-point higher
baseline quality-of-life score corresponded to a decrease in
the hazard of death by approximately 10% (p 0.004).9 A
Gynecologic Oncology Group analysis of a phase III trial
of cisplatin with or without topotecan in advanced cervical
cancer found the patient-reported Functional Assessment of
Cancer TherapyGeneral (FACT-G) plus the FACT-Cervix
subscale had a similar association with survival as the
RTOG study even though different PRO measures were used
and different disease sites were involved. A 10-point higher
baseline score on FACT-Cervix corresponded to a decrease
in hazard of death by approximately 10% (p 0.002).10 A
pharmaceutical companysponsored, phase III trial demonstrated efficacy of sunitinib, which prolonged progressionfree survival for patients with metastatic renal cell cancer.
Three baseline PRO measures were individually predictive
of progression-free survival. Higher scores at baseline on
FACT-G, the FACTKidney Symptom Index disease-related
symptoms subscale, and EuroQol Groups visual analog
scale were significantly associated with longer progression-

PATIENT-REPORTED OUTCOMES AS TRIAL ENDPOINTS

free survival (hazard ratios, 0.93, 0.89, and 0.91; p 0.001,


p 0.001, and p 0.008, respectively). These data indicate
that the risk of tumor progression or death was approximately 7%, 11%, and 9% lower, respectively, for every higher
change score of 5 points on FACT-G, 2 points on the
FACTKidney Symptom Index disease-related symptoms
subscale, and 10 points on EuroQol Groups visual analog
scale.11
Gotay et al12 confirmed this trend of the prognostic significance of PROs, Gotay et al in a systematic literature review
of cancer clinical trials in which they found that 36 (92%) of
39 studies had at least one PRO that was prognostic of
survival (p 0.05) in multivariate analysis. Of the 39
clinical trials that met inclusion criteria, most were lung (12
trials) and breast (eight trials) cancer trials, with a total of
13,874 patients. The European Organisation for Research
and Treatment of Cancer Quality-of-Life Questionnaire was
the most common PRO used, found in 56% of the trials.
Effect sizes varied, with 24 of 36 (66%) having a small effect
size, eight (23%) having a moderate effect size, and 4 (11%)
having a large effect size. Adjusting for performance status,
treatment arm, stage, weight loss, and serum markers,
PROs still provided distinct prognostic information for survival beyond standard clinical measures.
Lack of Understanding of Patient Adherence

Aromatase inhibitors provide an excellent example of how


not including PROs or not including them at the right time
points can mislead our understanding of patient adherence.
A large pivotal clinical trial of 5,187 patients demonstrated
the efficacy of an aromatase inhibitor to decrease local or
metastatic recurrence or new contralateral breast cancer.
The toxicities associated with aromatase inhibitors found
using CTC version 2.0 were reported as primarily grade 1 or
2, and those that were higher in the aromatase inhibitor
group compared with the placebo group were hot flashes,
arthritis, arthralgia, and myalgia. At a median of 2.4 years
of follow-up, no significance was found between discontinued
use of the aromatase inhibitor compared with placebo (4.5%
vs. 3.6%, p 0.11).13 In the quality-of-life analysis of the
same trial, Whelan and colleagues14 found small but meaningful worsening in mean change scores from baseline in the
PRO domains of vasomotor effects, bodily pain, vitality,
physical functioning, and sexual function, with the last two
domains having no corresponding detection using CTC reporting. However, the findings of studies in which adherence
was evaluated over shorter durations suggest better adherence than studies with longer follow-up. One-year aromatase inhibitor adherence rates range from 77% to 88%,
whereas 4- to 5-year prescription-based adherence rates
were 27% to 49% in other studies.15 PROs can help provide
the answer to decreasing adherence over time. PRO data
from two pivotal phase IV aromatase inhibitor trials found
high prevalence rates for joint pain (59.6%), hot flushes
(52%), lost interest in sexual intercourse (51.4%), and lack
of energy (40.3%). PROs resulted in higher prevalence rates
compared with physician ratings for most symptoms.16 A
recent study found that 36% of women who were prescribed
aromatase inhibitors for 5 years reported ending treatment
because of symptom bother.16

Lack of Information for Patient and


Clinical Decision Making

Patients often seek information that would help them


make decisions regarding treatments and symptom management. Without systematic PRO assessments in clinical trials, patients might seek out less rigorously gathered data.
For example, www.patientslikeme.com/ is a popular Webbased tool that seeks to provide users with information to
help make treatment decisions and manage symptoms. An
analysis of approximately 2,000 unique PRO reports on
modafinil use across five disease conditions indicated how
patients are easily able to gather information on the use of
the drug for management of symptoms. However, less than
1% of members who reported taking modafinil reported
taking it for an approved purpose (narcolepsy and excessive
daytime sleepiness resulting from sleep apnea). Patients are
able to access information on the other self-reported uses of
the drug, for example, general fatigue (68%), excessive
daytime sleepiness (16%), and difficulty concentrating (3%),
as well as perceived effectiveness of ameliorating each
symptom.18 In addition to the off-label use of the drug,
patients report adverse effects they attribute to the drug.
Routine reporting of PROs in clinical trials and a commitment to lay broadcasting beyond academic publication
would provide more accurate information for decision making.
Lack of Information for Labeling Claims

Few cancer drugs have received FDA approval for a


symptomatic benefit. A recent exception is the November
2011 approval of ruxolitinib for the treatment of myelofibrosis. FDA approval for symptomatic benefit before 2011 goes
back to 1998. However, between 1998 and 2011 almost 70
anticancer drugs have been approved. Incyte Corp. obtained
this rare symptom benefit labeling claim through close
interaction with the FDA. The primary endpoint was reduction in spleen volume, and the secondary PRO endpoint was
the total symptom score using a specifically developed
measure following the FDA PRO guidelines. The company
worked with the FDA for 2 years to finalize instrument
approval. The PRO measured six symptoms: night sweats,
itching, abdominal discomfort, pain under the ribs on the
left side, early satiety, and bone or muscle pain. Along with
rigorous instrument development, the clinical trial hypothesized a large effect of 50% or greater reduction in total
symptom score from baseline to week 24. Forty-six percent
of patients in the ruxolitinib arm met the PRO threshold
compared with 5.3% in the placebo group (p 0.0001).
Richard Pazdur, the director of FDAs Office of Hematology
Oncology Products, was quoted as saying, [The PRO] was a
secondary endpoint, but in our mind this is why we gave the
application full approval. One could quibble about the importance of reduction in spleen size, but with reduction in all
the symptoms, full approval was warranted.19
Lack of Information for Comparative Effectiveness

Without PRO data in clinical trials, we would have to rely


solely on toxicity data for comparative effectiveness of treatment modalities, but we have a preponderance of literature
showing that physician-reported toxicities do not tell the full
story. For example, in RTOG 0126, a phase III clinical trial,
patients were randomly assigned to high-dose (79.2-Gy) or

141

BRUNER, MOVSAS, AND BASCH


Table 2. Barriers and Solutions to Standard Use of PROs in Clinical Trials
Barrier

Solution

Lack of off-the-shelf validated instruments


Inadvertent unmasking

Need to make PROs publically available


Require a large effect size
Substantiate symptomatic benefits via objective measures (such as radiographic
or serum biomarker responses)
e-products for data capture, real-time reminders, real-time monitoring, telephone
interviews when patient is too ill to complete PRO
PROs better identify baseline symptoms related to disease or prior treatment than
current standard physician toxic effect reporting, making it clearer during a
trial which symptoms are attributable to study drug compared with preexisting
causes
Standard PRO reporting should be viewed no differently than standard CTC(AE)
reporting and routinely incorporated as such

Missing data
There may be concerns that systematic assessment will document more low
grade toxicities

Additional resources for routine inclusion of PROs in clinical trials for symptom
assessment may be needed since the NCI generally only funds PROs that
answer a specific hypothesis

Abbreviations: CTC(AE), Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute; PRO, patient-reported outcome.

standard-dose (70.2-Gy) radiation therapy for localized prostate cancer. A preliminary analysis of the high-dose arm,
comparing 3-dimensional conformal radiotherapy (3DCRT)
and intensity-modulated radiotherapy (IMRT), where each
institution declared its choice of 3DCRT or IMRT before trial
participation, was conducted. A total of 763 patients were
in the high-dose arm and included in the toxicity analysis,20
and 499 patients (65%) were included in the PRO analysis.21
Although the CTC version 2.0 toxicity report indicated a
benefit in favor IMRT for grade 2 or higher gastrointestinal
toxicities (22% 3DCRT vs. 15% IMRT, p 0.039) and in
favor of IMRT for combined gastrointestinal and genitourinary grade 2 or higher toxicities (15.1% 3DCRT vs. 9.7%
IMRT, p 0.042), PROs did not corroborate a benefit
patients could note. Corresponding PRO gastrointestinal
and genitourinary variables indicated no substantial differences between 3DCRT and IMRT. An important difference
that PROs demonstrated in favor of IMRT not found on

physician reporting was erectile dysfunction; of note, the


IMRT benefit was primarily in men younger than 70 years
(p 0.04). Given the higher cost of IMRT over 3DCRT for
the treatment of prostate cancer, the PRO data add an
important dimension to the comparative effectiveness equation.
Although the benefits of inclusion of PROs in clinical trials
and the risks of noninclusion have been delineated, there
are some barriers to routine inclusion of PROs in clinical
trials. However, solutions to these barriers exist (Table 2).
Numerous validated PRO instruments with the breadth and
depth to answer hypothesis-specific clinical trial questions
are available, but a more parsimonious method would help
routine inclusion in clinical trials.
A major step forward has been the development of the
PRO version of the CTC-AE (PRO-CTC[AE]).22 The PROCTC(AE) has been designed to capture a comprehensive
range of symptoms and functioning that enhances monitor-

Fig. 1. Radiation Therapy Oncology


Group (RTOG) outcomes model for guiding inclusion of patient-reported outcomes in clinical trials.
Abbreviations: RT, radiation therapy;
PSA, prostate specific antigen; QALYs,
quality-adjusted life years; PROs, patient reported outcomes.

142

PATIENT-REPORTED OUTCOMES AS TRIAL ENDPOINTS

ing of adverse events in cancer clinical trials. Approximately


78 CTC(AE) items have been converted to PROs, including,
for example, items purely or with a large subjective component, such as pain, fatigue, nausea or vomiting, elimination,
sexual function, swallowing, and dyspnea. This NCI investment lays the groundwork for standard inclusion of PROs in
clinical trials as a companion to the CTC(AE).
In addition to having publicly accessible validated measures for PRO assessments, a framework for incorporation
of PROs into clinical trials would help guide consistent
assessments. To that end, the RTOG developed an outcomes
model for guidance of clinical trials concept development.
This model was first developed as a triad of outcomes,
including clinical (e.g., standard survival and toxicity reporting), humanistic (patient-reported symptoms, quality
of life, functional status, and preferences), and economic
(quality-adjusted life-years and comparisons of effectiveness).23 The outcomes model has evolved with the increasing
focus on the complexity and interrelationships of additional
variables, including biomarkers and physical parameters
(particular to radiation treatment planning) that can influence and be influenced by patient-reported outcomes. Figure
1 depicts an example of the most recent iteration of this
model used to guide inclusion of endpoints on an active trial
(RTOG 0543), A Phase III Trial of Short Term Androgen
Deprivation With Pelvic Lymph Node or Prostate Bed Only

Radiotherapy in Prostate Cancer Patients With a Rising


PSA After Radical Prostatectomy.
Further advances in the area of PROs have recently
emerged from the September 2011 NCI-sponsored clinical
trials planning meeting, Identification of Core Symptoms
and Health-Related Quality of Life Domains for Use in
Cancer Research. An extensive process of literature and
source data review identified a lengthy list of symptoms
ranked by prevalence. A panel of experts narrowed the list to
a core set of symptoms that can serve as a guide to common
reporting across all cancer clinical trials. If adopted, this
core set of PROs could facilitate comparison and combination of data across cancer clinical trials around the world.
The publications from this meeting are in development.
Conclusion

This chapter provides a review of what we stand to lose


without the routine incorporation of PROs in clinical trials.
It is important to also consider what we stand to gain,
including more comprehensive reporting of prevalence of
symptoms, improved accuracy in reporting of levels of severity, increased prognostic specificity, greater understanding
of patient adherence, better information for patient and
clinical decision making, additional targets for labeling
claims, and information for comparative effectiveness. Most
importantly, we give voice to the one who counts most, the
patient.

Authors Disclosures of Potential Conflicts of Interest

Author
Deborah Watkins Bruner

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Endo
Pharmaceuticals

Bristol-Myers
Squibb

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Benjamin Movsas*
Ethan Basch*
*No relevant relationships to disclose.

REFERENCES
1. National Cancer Institute. Common Terminology Criteria for Adverse
Events (CTCAE) and Common Toxicity Criteria (CTC). 2009. http://evs.nci.
nih.gov/ftp1/CTCAE/About.htm. Accessed March 20, 2012.
2. U.S. Food and Drug Administration. Guidance for Industry: PatientReported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 2009. http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/UCM193282.pdf. Accessed March
20, 2012.
3. Bruner DW. Should patient-reported outcomes be mandatory for toxicity
reporting in cancer clinical trials? J Clin Oncol. 2007;25:5345-5347.
4. Kaba H, Fukuda H, Yamamoto S, Ohashi Y. Reliability at the National
Cancer Institute-Common Toxicity Criteria version 2.0 [in Japanese]. Gan To
Kagaku Ryoho. 2004;31:1187-1192.
5. Atkinson TM, Li Y, Coffey CW, et al. Reliability of adverse symptom
event reporting by clinicians. Qual Life Res. Epub 2011 Oct 8.
6. Neben-Wittich MA, Atherton PJ, Schwartz DJ, et al. Comparison of
provider-assessed and patient-reported outcome measures of acute skin
toxicity during a Phase III trial of mometasone cream versus placebo during
breast radiotherapy: the North Central Cancer Treatment Group (N06C4).
Int J Radiat Oncol Biol Phys. 2011;81:397-402.
7. Watkins-Bruner D, Scott C, Lawton C, et al. RTOGs first quality of life
study-RTOG 90-20: a phase II trial of external beam radiation with etanidazole for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys.
1995;33:901-906.
8. Bruner DW, Gotay C, Moinpour C, et al. Value-added of patient-reported
outcomes (pro) in cooperative group oncology clinical trials: a pooled analysis.
In: Proceedings of the 15th Annual Meeting of the International Society for

Quality of Life Research; October 22-25. 2008; Montevideo, Uruguay. Abstract 28.
9. Movsas B, Moughan J, Sarna L, et al. Quality of life supersedes the
classic prognosticators for long-term survival in locally advanced non-smallcell lung cancer: an analysis of RTOG 9801. J Clin Oncol. 2009;27:5816-5822.
10. Monk BJ, Huang HQ, Cella D, Long HJ III. Quality of life outcomes
from a randomized phase III trial of cisplatin with or without topotecan in
advanced carcinoma of the cervix: a Gynecologic Oncology Group Study.
J Clin Oncol 2005;23:4617-4625.
11. Cella D, Cappelleri JC, Bushmakin A, et al. Quality of life predicts
progression-free survival in patients with metastatic renal cell carcinoma
treated with sunitinib versus interferon alfa. J Oncol Pract. 2009;5:66-70.
12. Gotay CC, Kawamoto CT, Bottomley A, Efficace F. The prognostic
significance of patient-reported outcomes in cancer clinical trials. J Clin
Oncol. 2008;26:1355-1363.
13. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in
postmenopausal women after five years of tamoxifen therapy for early-stage
breast cancer. N Engl J Med. 2003;349:1793-1802.
14. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in
MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of
tamoxifen in postmenopausal women. J Clin Oncol. 2005;23:6931-6940.
15. Gotay C, Dunn J. Adherence to long-term adjuvant hormonal therapy
for breast cancer. Exp Rev Pharmacoecon Outcomes Res. 2011;11:709-715.
16. Oberguggenberger A, Hubalek M, Sztankay M, et al. Is the toxicity of
adjuvant aromatase inhibitor therapy underestimated? Complementary information from patient-reported outcomes (PROs). Breast Cancer Res Treat.
2011;128:553-561.
17. Wagner L, Zhao F, Chapman J, et al. Patient-reported predictors of

143

BRUNER, MOVSAS, AND BASCH


treatment discontinuation: quality of life among postmenopausal women with
primary breast cancer randomized to exemestane or anastrozole. Cancer Res.
2011;71(suppl):S6.
18. Frost J, Okun S, Vaughan T, et al. Patient-reported outcomes as a
source of evidence in off-label prescribing: analysis of data from Patients
LikeMe. J Med Internet Res. 2011;13:e6.
19. McCallister E, Usdin S. A professional trial. BioCentury. 2011;19:A1A4.
20. Michalski JM, Yan Y, Watkins-Bruner D, et al. Preliminary analysis of
3D-CRT vs. IMRT on the high dose arm of the RTOG 0126 prostate cancer
trial: toxicity report. Int J Radiat Oncol Biol Phys. 2011;81(suppl):S1-S2.

144

21. Watkins-Bruner D, Hunt D, Michalski J, et al. Preliminary analysis


of 3DCRT vs IMRT on the high dose arm of the RTOG 0126 prostate cancer trial: patient reported outcomes. Int J Radiat Oncol Biol Phys. 2011;
81(suppl):S44.
22. National Cancer Institute. Patient-Reported Outcomes (PRO) version
of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
2010. http://outcomes.cancer.gov/tools/pro-ctcae.html. Accessed March 20,
2012.
23. Bruner DW. Outcomes research in cancer symptom management trials:
the Radiation Therapy Oncology Group (RTOG) conceptual model. J Natl
Cancer Inst Monogr. 2007;37:12-15.

NEW LOOKS AND CHALLENGES FOR


COOPERATIVE GROUPS
CHAIR
Stephen S. Grubbs, MD
Helen F. Graham Cancer Center at Christiana Care
Newark, DE
SPEAKERS
Robert Leo Comis, MD
Coalition of Cancer Cooperative Groups
Philadelphia, PA
Gregory H. Reaman, MD
Childrens National Medical Center
Washington, DC

The New National Cancer Institute National


Clinical Trials Network
By Stephen S. Grubbs, MD

Overview: The National Cancer Institute (NCI) Cooperative


Group Program has been reviewed by three published studies
in the last 7 years evaluating the efficiency and effectiveness
of this national oncology clinical trials system. The recommendations for improvement from these reports have
prompted NCI to transform the Cooperative Group Program

HE NCI Cooperative Group Program has been an


essential contributor to the discovery of new cancer
therapies over the last 50 years. The program comprises
networks of cancer centers and community oncology practices that develop and conduct large-scale multicenter
clinical trials and promote discovery of correlative cancer
science. The cooperative groups have established the therapies now routinely used to diagnose, prevent, and treat
cancers.
In 2007, the NCI director requested the Institute of
Medicine (IOM) conduct a consensus study of clinical trials
and the NCI Cooperative Group Program and provide recommendations to improve the system. This evaluation was
preceded by an NCI review of the system by the Clinical
Trials Working Group (CTWG) in June 2005. The IOM
convened a 17-member committee representing a broad
range of the oncology research community. The activity
was supported by funding from the NCI and other cancer
research organizations, including ASCO. A report was
issued in April 2010 titled, A National Cancer Clinical
Trials System for the 21st Century. Key features of the
report are listed in Table 1.
The NCI has responded to the IOM, CTWG, and the
March 2010 NCI Operational Efficiency Work Group
(OEWG) reports with a proposed transformation and reorganization of the cooperative groups into a new NCI Clinical
Trials Network (NCTN). Network goals are listed in Table 2.
To achieve these goals, the NCI has embarked on cooperative group consolidation and reconfiguration of the network
evaluation process and funding.
The NCI has recommended the 10 cooperative groups
consolidate to four adult-oriented groups and one pediatric
group. The existing nine adult-oriented groups have elected
to merge or affiliate into the four entities listed in Table 3.
The NCI is in the process of developing a new funding
opportunity announcement (FOA) to be published in July
2012 that will establish the new evaluation and funding of
the network. The NCI has articulated the goals of the new
system evaluation (Table 4). NCI oversight and prioritization of the network will utilize the existing Disease Steering
Committees and a newly proposed Cross-Disease/Trials
Oversight Panel. More efficient clinical trials development
and activation have already been implemented by strict
timelines established in the OEWG report.
The new FOA is expected in July 2012, and competing
applications for the new FOA are to be submitted by November 2012, with NCI review in February 2013. Network
awards are expected in late 2013 with funding to begin in
2014.

146

into a new NCI National Clinical Trials Network (NCTN) to


improve the efficiency of large clinical trials and increase the
speed of cancer translational research. The new NCTN offers
community-based clinical investigators new opportunities to
advance cancer research in their community setting but also
presents challenges in promoting community-based research.

KEY POINTS

The Institute of Medicine, the Clinical Trials Working Group, and the Operational Efficiency Working
Group have published evaluations recommending improvements of the National Cancer Institute (NCI)
Cooperative Group Program.
The NCI is transforming the Cooperative Group Program into a National Clinical Trials Network by
group consolidation and a new evaluation and funding model.
Nine adult disease oriented cooperative groups have
responded by consolidating into four groups, joining
the existing single pediatric-oriented cooperative
group.
Community clinical trial sites and investigators will
potentially gain access to a greater variety of trials,
will benefit from operational standardization between groups, and may achieve increase per case
reimbursement.
Community sites, however, will be challenged by
diminished volunteer investigator time and pressure
to produce high accrual volume and remain at risk for
per case funding below actual cost.

Community Needs from the NCI NCTN

Community clinical investigators are essential participants in a successful national oncology clinical trials system.
They have access to large numbers of newly diagnosed
patients and contribute significant accruals to phase III and
cancer control and prevention trials. The Community Clinical Oncology Program and cancer center community affiliate sites contribute over 50% of the patients annually to
the cooperative group total accrual. The new NCTN offers
opportunities and challenges for the community clinical
investigators.
A successful community clinical trials site requires five

From the Helen F. Graham Cancer Center, Delaware Christiana Care CCOP Newark,
DE.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Stephen S. Grubbs, MD, Helen F. Graham Cancer Center,
Delaware Christiana Care CCOP, 4701 Ogletown-Stanton Rd., Newark, DE, 19713-2055;
email: ssgrubbs@cbg.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

NCI NATIONAL CLINICAL TRIALS NETWORK


Table 1. IOM Committee Recommendations
Goal I. Improve the speed and efficiency of the design, launch, and conduct of
clinical trials.
Review and consolidate some front-office operations of the cooperative groups
on the basis of peer review.
Consolidate back-office operations and improve processes.
Streamline and harmonize government oversight.
Improve collaboration among stakeholders.
Goal II. Incorporate innovative science and trial design into cancer clinical trials.
Support and use biorepositories.
Develop and evaluate novel trial designs.
Develop standards for new technologies.
Goal III. Improve the means of prioritization, selection, support, and completion of
cancer clinical trials.
Reevaluate the National Cancer Institutes role in the clinical trials system.
Increase the accrual volume, diversity, and speed of clinical trials.
Increase funding for the cooperative group program.
Goal IV. Incentivize the participation of patients and physicians in clinical trials.
Support clinical investigators.
Cover the cost of patient care in clinical trials.

Table 2. National Cancer Institute Clinical Trials Network


Transformation Goals
Prioritize molecular characterization resources and develop molecularly driven
trial design.
Improve prioritization of phase III portfolio across disease entities.
Remove disincentives to study less common diseases.
Create a shared IT structure.
Harmonize procedures.
Integrate imaging technology.
Integrate national tissue banking resources.
Grant open access to the network for clinical and transitional investigations.

Table 4. National Clinical Trials Network Group Review


and Funding
Modified U10 program
Increased per case reimbursement for high accruing sites
National Cancer Institute (NCI) external peer review of groups in the same
review cycle
New review criteria to include evaluation of collaboration within the network and
other NCI-funded programs (e.g., Specialized Programs of Research Excellence),
operational efficiency, and overall scientific quality.

Table 5. Community Clinical Trial Site Desirables


I. Clinical Trial Access
Phase II and III treatment trials
Cancer control and prevention trials
Comparative effectiveness trials
Innovative scientific questions
Common diseases and expanded performance status eligibility
II. Group Participation
Group identity
Interaction with academic colleagues
Leadership opportunities in both scientific and operation activities
Publication authorships
Professional recognition
III. Operational and Regulatory Standardization
Common protocol templates and data submission
Consolidated audit system
Regulatory burden easement
IV. Patient Recruitment Enhancement
Electronic health record cues
Clinical trial marketing to the public
Underserved community accrual
V. Adequate Funding
Reimbursement for actual cost

Table 3. Adult Cooperative Group Consolidation


Table 6. Community Clinical Trial Site Challenges
American College of Surgeons Oncology Group, Cancer and Leukemia Group B,
North Central Cancer Treatment Group (Alliance for Clinical Trials in Oncology)
Gynecologic Oncology Group, National Surgical Adjuvant Breast and Bowel
Project, Radiation Therapy Oncology Group (Neuroinformatics Research Group
[NRG] Oncology)
American College of Radiologys Imaging Network, Eastern Cooperative
Oncology Group
Southwest Oncology Group

main areas of support from NCTN and NCI: (1) clinical trial
access, (2) group participation, (3) operation and regulatory
standardization, (4) patient recruitment enhancement, and
(5) adequate funding and support (Table 5). However, the
new proposed network poses both old and new challenges,
including NCTN membership issues, site trial portfolio
management, volunteer investigator time, and funding in a
time of stagnant and diminishing government resources
(Table 6).
The new NCI NCTN offers the promise of a more efficient
clinical trials system that will translate the rapidly expand-

I. Network Membership
High volume sites versus broad membership inclusion
Single versus multiple group membership
Trial accrual credit assignment
II. Site Trial Portfolio Management
Access to all four groups trials
Orphan or less common disease trial resource allocation
II. Volunteer Investigator Time
Engagement
Promotion
Value
III. Reimbursement
Tiered per case reimbursement
Anticipated static or decreasing National Cancer Institute budget

ing scientific knowledge of cancer to practice and provide


our patients and their families with innovative cancer management strategies in a more timely fashion. Surely our
community clinical investigators will embrace NCTN and
contribute to its success.

Authors Disclosure of Potential Conflicts of Interest

Author

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

Stephen S. Grubbs*
*No relevant relationships to disclose.

147

STEPHEN S. GRUBBS

REFERENCES
1. Nass J, Moses H, Mendelsohn J (eds). A National Cancer Clinical Trials
System for the 21st Century: Reinvigorating the NCI Cooperative Group
Program. Washington, DC: National Academies Press, 2010.
2. Abrams J. Transforming the NCI Trials System. 14th Meeting of the

148

Clinical Trials and Translational Research Advisory Committee. July 13, 2011.
3. Mack A, Nass S. Implementing a National Cancer Clinical Trials System
for the 21st Century: Workshop Summary. Washington, DC: National Academies Press, 2011.

Successful Integration of Cooperative


Groups: The Origin of the Childrens
Oncology Group
By Gregory H. Reaman, MD

Overview: In March 2000, the four legacy pediatric cooperative groups officially merged to become the Childrens Oncology Group (COG). This was accomplished by the ratification of
a new constitution by the respective executive committees
and voting membership of the four legacy groups. The actual
merger was preceded by a 12 to 18 month period of planning,
negotiation, and transition, overseen by a Transition Committee of select executive leadership under the direction of the
four current chairs of the existing pediatric groups. Despite
the constant threat of budget reductions and questions related to the judicious use of National Cancer Institute (NCI)
funds to support four pediatric groups when children constitute only 3% of the US cancer problem, the decision to unify
was initiated and driven internally. The merger was envisioned
as an opportunity to create efficiency by reducing duplicative
systems and processes, which was becoming increasingly
apparent as more planned clinical trials required intergroup
collaboration. It was also recognized that such intergroup
efforts would become more of a reality as clinical trial para-

ECENT DECISIONS to restructure the NCIs clinical


trial enterprise in accordance with recommendations
from the Institute of Medicine and external advisory groups
have intended to reduce the number of cooperative groups
through a process of integration. This integration of legacy
groups and reorganization of the nations cancer clinical
trials program has resulted in considerable angst for both
well-established clinical investigators and those beginning
their careers. All are now transitioning to a new reality of
team science and collaboration in clinical cancer research.
The well-intentioned motivation to move a somewhat fragmented, competitive, duplicative system with parallel and
under-resourced infrastructures to a system where scientific
discovery can be rapidly translated to design, implementation, and conduct of high-impact studies and dissemination
of results to improve care standards cannot be questioned.
Nonetheless, reasonable concerns remain: the proposed
model of centralized infrastructure supportincluding critical information systems, uncertainty about future budget
allocations and funding instruments, and the lack of concrete metrics by which to judge the performance and success
of this reorganization continue during a period of intense
transition. The anxiety of the integrated group leadership
and their membership is understandable and familiar.
Although the current changes are decidedly more far
reaching in scope, this is not the first integration or merger
within NCIs Cooperative Group Program. In 2000, the
Childrens Cancer Group, Pediatric Oncology Group (POG),
National Wilms Tumor Study Group, and Intergroup Rhabdomyosarcoma Study Group merged to become COG. More
than two decades before this, the pediatric divisions of the
Cancer and Leukemia Group B and the Southwest Oncology
Group came together to form POG.1,2 With the consolidation of the pediatric cooperative groups, well-recognized
names and acronyms disappeared, but sense of mission and
a strong foundation arising from legacy group accomplishments provided a framework for success. Naysayers may

digms were built on risk-adjusted approaches. Clinically,


biologically, and molecularly defined homogeneous subgroups
of patients were of insufficient sample size within each group
to design and conduct studies within a reasonable time frame.
In essence, this merger was motivated by an overwhelming
sense of necessity to preserve our mission of defining and
delivering compassionate and state-of-the-art care through
scientific discovery. The merger process itself was challenging, time consuming, not supported by any supplemental
funding, and at times painful. What has emerged as a result
is the largest pediatric cancer research organization in the
world. Accomplishments in epidemiology, biology, translational science, and improved clinical outcomes for some
pediatric cancers would have never been achieved without the
merger. The very fact that outcome improvements were not
realized in every type of pediatric cancer is testimony to the
commitment of the COG membership to continue to look and
move forward.

comment that pediatric oncology is now different. In fact,


pediatric oncology is different; the overall 5-year event-free
survival rates for children with cancer exceed 80%. The
clinical management of childhood cancer is integrally linked
to clinical and translational research. Improvement in survival outcomes and cure rates are, in large part, a direct
result of the fact that the overwhelming majority of children
with cancer are enrolled on clinical trials.3
The decision to unify the pediatric groups was conceived
and driven internally by a perceived affront to their missions
and a very real threat to their scientific agenda.2 This
resulted from the increasing focus on risk-adjusted therapy
approaches for childhood cancer and the increasing number
of subgroups defined by clinical and biologic prognostic
factors. Designing phase III clinical trials in homogenous
patient groups within each pediatric cancer diagnosis that
could be completed within reasonable timelines was severely
hampered by sample size constraints initially mandating
intergroup collaborations. Now such trials increasingly require consideration of international group collaborations.
Also, any future plans to explore the feasibility of personalized therapy approaches with molecularly targeted
agents in pediatric cancers would mandate a coordinated
and consolidated effort. Infrastructure duplication and lack
of process and procedure harmonization even within the
pediatric groupswere exaggerated by continual budget
shortfalls. Despite the expectation that consolidation of the
pediatric groups would result in improved efficiencies and

From the Center for Drug Evaluation and Research, US Food and Drug Administration,
Silver Spring, MD, and the Division of Oncology, Childrens National Medical Center,
Washington, DC 20010.
Authors disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Gregory H. Reaman, MD, Childrens National Medical
Center, Washington, DC 20010; email: greaman@childrensnational.org.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

149

GREGORY H. REAMAN

economies of scale, no predetermined metrics were developed and no resources were made available to collect and
analyze data to evaluate success. In fact, annual budget
reductions after the merger precluded any comprehensive,
detailed self-assessment.
There were considerable immediate challenges in the
transition process of unifying culturally and organizationally distinct, procedurally and operationally disparate, competing clinical trial networks. COG leadership focused
initially on individual, discipline-specific, and institutional
membership requirements; financial planning and new models for funds distribution (given the planned discontinuation
of institutional U-10 awards); consolidation of administrative functions; and coordination of data management and
statistical operations. The last of these was particularly
problematic since three separate sites served as statistics
and data management centers using different and noncompatible, internally generated, electronic, Web-based remote
data entry and registration systems. The importance of
providing adequate and centralized IT support and an
enterprise-wide Clinical Data Management System cannot
be overemphasized.
It was a priority to maintain active legacy study conduct
(80 phase III, 22 phase II, and 7 phase I) open studies using
different data management platforms while planning for the
importation of all legacy as well as new data to a single
common platform. Of equal and given resource constraints competing priority was the development and implementation of new biologically based and hypothesisdriven clinical trials.
Despite the lack of prespecified metrics, many successes
were realized as a direct result of the consolidation. Three
years after the merger, annual enrollment on therapeutic
studies increased by more than 25% and enrollment on

KEY POINTS

The merger of the legacy pediatric cooperative groups


was self-motivated and self-directed.
No preestablished metrics of success were developed
other than to maintain focus and achieve mission
success.
Supplemental resources during a challenging transition period were not made available.
The lack of supplemental resources precluded the
Childrens Oncology Groups ability to perform a
detailed assessment of evaluating efficiency, and progressive budget reductions made evaluation of any
cost-effectiveness impossible.
Significant accomplishments in pediatric cancer were
made possible only as a direct result of its planned
consolidation and successful integration.

nontherapeutic (epidemiology and biology) studies more


than doubled compared with combined enrollment statistics
of the legacy groups.4 COG became the largest childhood
cancer research organization in the world and expanded its
international collaborations. New clinical and biologically
based classification systems were developed for both acute
lymphoblastic and myeloid leukemia and neuroblastoma.5,6,7 Cytogenetic and molecular genetic predictors of
outcome were defined for these same diseases as well as for
Wilms tumor and medulloblastoma. The prognostic significance of minimal residual disease in a number of tumor
systems (acute leukemia, lymphoma, neuroblastoma) was
established and incorporated into the expansion of riskadjusted treatment approaches to these diseases.6,7 Expanding active programs in biomarker development for patient
enrichment and risk classification was made possible by
the retrospective analysis of independent data sets from
legacy groups as test and validation cohorts. Early in its
history, COG opened a frontline, randomized clinical trial
for osteosarcoma, designed and conducted in collaboration
with multiple European cooperative groups, which led to the
development of the Cancer Therapy Evaluation Program
guidelines for performance of international clinical trials.
By consolidating legacy bio-specimen banks, COGs Biopathology Center has become the national and international
resource for clinically well-annotated specimens of virtually
every type of pediatric cancer. Important genomic investigations in collaboration with the NCIs Cancer Genome
Atlas and the TARGET initiative have been made possible
through this resource. These investigations have identified
novel genetic lesions in acute leukemia and neuroblastoma,
which are being evaluated as predictive biomarkers and
for their potential therapeutic exploitation.7-11 Since the
consolidation, statistically significant improvements in
5-year event-free survival rates have been achieved in all
prognostic subgroups of acute lymphoblastic leukemia,
acute myeloid leukemia, high-risk neuroblastoma, and medulloblastoma.7,8,12,13 COG has developed Long-Term
Follow-Up Guidelines for childhood cancer survivors, which
are regularly updated in accordance with increasing evidence and utilized worldwide.7 Relevant portions of these
exposure-dependent risk assessments and recommended
surveillance parameters have been extrapolated for adult
cancer survivors.
Despite the initial challenges and anxiety experienced
during the early days of the consolidation, and despite the
criticism in response to the reduction in healthy competition, COG has emerged as more successful and impactful
than the sum of its legacy groups. With thoughtful transition, focus on mission, assurance of adequate centralized
resources and utilization of well-constructed, predetermined
metrics, the current cooperative group reorganization
should be viewed as a real opportunity to further advance
clinical and translational research.

Authors Disclosure of Potential Conflicts of Interest

Author
Gregory H. Reaman*
*No relevant relationships to disclose.

150

Employment or
Leadership
Positions

Consultant or
Advisory Role

Stock
Ownership

Honoraria

Research
Funding

Expert
Testimony

Other
Remuneration

COG: GIVING NEW MEANING TO COOPERATIVE

REFERENCES
1. Reaman GH. Pediatric oncology; current views and outcomes. Pediatr
Clin Nort Am. 2002;49:1305-1318.
2. Reaman GH. Clinical advances in pediatric hematology and oncology:
Cooperative group research. Clin Adv Hematol Oncol. 2005;3:133-135.
3. Anderson BD, Smith MA, Reaman GH, et al. Views of American
oncologists about the purposes of clinical trials. J Natl Cancer Inst. 2003;95:
630-631.
4. Steele JR, Wellemeyer AS, Hansen MJ, et al. Childhood cancer research
network; A North American pediatric cancer registry. Cancer Epidemiol
Biomarkers Prev. 2006;15:1241-1242.
5. Schultz KR, Pullen DJ, Sather HN, et al. Risk and response based
classification of childhood B precursor acute lymphoblastic leukemia: A
combined analysis of prognostic markers from the Pediatric Oncology Group
(POG) and the Childrens Cancer Group (CCG). Blood. 2007;109:926-935.
6. Borowitz MJ, Devidas M, Hunger S, et al. Clinical significance of
minimal residual disease in childhood acute lymphoblastic leukemia and its
relationship to other prognostic factors: A Childrens Oncology Group study.
Blood. 2008;111:5477-5485.
7. OLeary M, Krailo M, Anderson JR, et al. Progress in childhood cancer:

50 years of research collaboration: A report from the Childrens Oncology


Group. Semin Oncol. 2008;35:484-493.
8. Hunger SP, Devidas M, Camitta B, et al. Improved survival for children
with acute lymphoblastic leukemia (ALL) from 1990 2005: A report from the
Childrens Oncology Group. J Clin Oncol. In press.
9. Hunger SP, Raetz EA, Loh ML, et al. Improving outcomes for high-risk
ALL: Translating new discoveries into clinical care. Pediatr Blood Cancer.
2011;56:984-993.
10. Mullighan CC, Su X, Zhang J, et al. Deletion of IZKF1 and prognosis in
acute lymphoblastic leukemia. N Engl J Med. 2009;360:470-480.
11. Mullighan CC, Zhang J, Harvey RC, et al. JAK mutations in high risk
childhood acute lymphoblastic leukemia. Proc Natl Acad Sci U S A. 2009;106:
914-918.
12. OLeary MC, Reaman GH. Principles of pediatric oncology. Hong WK,
Bast RC, Hait W, et al (eds). Cancer Medicine 8th Edition. Shelton, CT: BC
Decker, 2010, pp. 1723-1741.
13. Smith MA, Seibel NL, Altekruse SF, et al. Outcomes for children and
adolescents with cancer: Challenges for the 21st century. J Clin Oncol.
2010;28:2625-2634.

151

OVERCOMING DISPARITIES IN CLINICAL TRIAL


ACCRUAL AMONG AFRICAN AMERICANS
CHAIR
Sandra M. Swain, MD
Washington Hospital Center
Washington, DC
SPEAKERS
Jean G. Ford, MD
Johns Hopkins School of Medicine
Baltimore, MD
Deliya R. Banda, PhD
Washington Hospital Center
Washington, DC
Worta McCaskill-Stevens, MD
National Cancer Institute
Bethesda, MD

A Critical Review of the Enrollment of Black


Patients in Cancer Clinical Trials
By Deliya R. Banda, PhD, Diane St. Germain, RN, MS, Worta McCaskill-Stevens, MD,
Jean G. Ford, MD, and Sandra M. Swain, MD

Overview: Although clinical trials represent a vital opportunity for improvements in cancer treatment, data show that a
small proportion of patients with newly diagnosed cancer
participate in clinical research. Black patients continue to
have a worse prognosis for most cancers compared with other
patients of other races/ethnicities. Racial/ethnic- and agerelated disparities in clinical trial accrual are also well documented. The recruitment and retention of minorities in these
trials present an even greater challenge despite regulatory
efforts and initiatives to increase representation. Treatment
data from homogenous populations prevent us from under-

CCRUAL TO clinical trials remains a longstanding


challenge, with 5% to 10% of patients with cancer from
the general population participating and even lower rates of
black patients participating.1 For the general population,
the reasons are numerous, including lack of trial availability, lack of physician engagement and awareness of available trials, ineligibility, lack of insurance coverage, time
commitment, and lack of knowledge and misperceptions
regarding the conduct of clinical trials.2-5 In addition to
these factors, a multitude of additional subgroup-specific
reasons have been reported, including a mistrust of the
research and medical system, awareness of historical clinical research abuse, a lack of access to state-of-the-art care, a
higher incidence of comorbidities (resulting in higher rates
of ineligibility), religious and cultural beliefs that influence
attitudes toward clinical trials, economic issues, and logistical concerns, such as child care and transportation.6-11
Cancer rates and incidence are disproportionately higher
for some cancers in black patients compared with white
patients.12 Inclusion of black patients in clinical trials is
therefore vital to gain an understanding of cancer biology
and response to treatment in this population and to provide
access to state-of-the-art care. Lack of access to state-of-theart care contributes to advanced disease at diagnosis, treatment morbidity, and decreased survival.13,14 It may also
increase the rate of comorbidities that deem many of this
population ineligible for clinical trials. Among 235 black
patients screened for protocol eligibility, only 8.5% were
eligible. Patients were deemed ineligible because of comorbidities (with respiratory failure, HIV positivity, and anemia
accounting for most), advanced disease stage, poor performance status, premature death, and short life expectancy.9
It is imperative that the rate of accrual of underserved
populations increase to maximize the generalizability of
results from clinical trials. Several efforts have been made
to increase accrual of underrepresented populations to
clinical trials. The National Institutes of Health Revitalization Act of 1993 mandates the inclusion of women and
minorities in federally sponsored cancer clinical trials. The
aim is to conduct subset analyses to determine whether
there are differences in effect based on race and sex. The
National Cancer Institute (NCI) established the MinorityBased Community Clinical Oncology Program in 1990,

standing therapeutic response and the true safety profile of


novel therapies. Patient-, physician-, and system-level factors
that affect trial participation have been extensively studied.
However, years of accrual data remain largely unchanged,
suggesting the challenge lies in effectively addressing these
factors. Furthermore, data showing that black patients tend to
have more advanced stage cancers at the time of diagnosis in
fact beg their overrepresentation on clinical trials. An inability
to successfully enroll diverse populations in clinical trials only
exacerbates racial/ethnic differences in cancer treatment and
survivorship.

which supports institutions with 40% minority population in


their catchment area to accrue racial minorities to treatment, cancer control, and prevention trials. This program
has had successful accrual rates of 60% (Table 1). The
National Medical Association (NMA) developed I.M.P.A.C.T.
(Increase Minority Participation and Awareness of Clinical
Trials), an initiative to increase awareness, knowledge, and
participation of black physicians and patients in biomedical
research and clinical trials. There has been an increase in
minority accrual to clinical trials sponsored by the NCI
(Fig. 1). This may be attributable to enhanced efforts or an
increase in minority populations.
The University of CaliforniaDavis Cancer Center has
recently embarked on a national effort to boost clinical trial
recruitment of minorities as part of a major grant from the
National Center on Minority Health and Health Disparities.15 This project, EMPaCT (Enabling Minority Participation in Clinical Trials), will engage five other centers and
assess existing efforts to accrue minorities into trials. The
goal is to develop consensus on evidence-based accrual
models that can be adopted by cancer centers across the
country.
There has been a heightened understanding of the issues
as evidenced by the plethora of published studies documenting the barriers to clinical trial enrollment in underserved
populations.3,4,13,16-18 However, methods to increase minority accrual elude clinicians largely because of the lack of
evidence-based strategies and practices in the literature.
One of the most extensive literature reviews identified only
14 articles that examined strategies to accrue underrepresented populations to cancer clinical trials. Notably, the
efficacy or effectiveness of the strategies was evaluated in
five of the 14 studies.19 The first was a randomized two-arm
study comparing the use of a media campaign involving
newspapers and fliers with a clinic registry strategy where

From the Washington Cancer Institute at Medstar Washington Hospital Center, Washington, DC; Medstar Health Research Institute, Hyattsville, MD; Division of Cancer
Prevention, National Cancer Institute, Bethesda, MD; Johns Hopkins Center to Reduce
Cancer Disparities, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
Authors disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Deliya R. Banda, PhD, 110 Irving St. NW, Suite CG-111,
Washington, DC 20010; email: Deliya.R.Banda@MedStar.net.
2012 by American Society of Clinical Oncology.
1092-9118/10/1-10

153

BANDA ET AL
Table 1. Minority-Based Community Clinical Oncology Program (MB-CCOP) Accrual, 2000 2009
Fiscal Year

No. of
Funded MB-CCOPs

No. of
Treatment Accruals

No. of Prevention
and Control Accruals

No. of
Overall Accruals

No. of
Minority Patients

Overall Minority
Participation, %

2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Total (20002009)

8
10
11
11
13
13
13
14
13
14
14

425
642
567
521
673
709
684
805
895
851
851

358
541
682
930
467
428
393
776
733
461
461

783
1183
1249
1451
1140
1137
1077
1581
1628
1312
1312

427
672
949
1249
718
569
612
962
1051
830
830

55
57
76
86
63
50
57
61
65
63
63

Courtesy of Worta McCaskill-Stevens, MD, MS, program director, MB-CCOP, National Institutes of Health.

women were invited to participate in person. The media


campaign proved more effective as evidenced by more
women consenting to participate and fewer no-shows in this
group compared with the clinic registry arm.20 In the second
study, a randomized study of older black men in a screening
trial, three progressively intensive recruitment methods
were compared. Intervention arms received different combinations of standard compared with enhanced mailings; baseline information gathered via telephone, via mail, or during
a church session; reminders by telephone or mail; and
consent forms mailed or administered during a church
session. The most intensive of the intervention arms yielded
the higher enrollment compared with the control and other
intervention arms.21 In the third study, enrollment in worksite cancer prevention programs was assessed comparing
passive (telephone contact using telephone numbers provided by the company) with active recruitment strategies (a
signup sheet). Enrollment and retention were lower among
employees recruited by passive methods than by active
methods. Passive methods, however, resulted in a representative employee sample.22 In the fourth study, the use of
minority outreach recruiters, a specialized recruitment
manual, and engagement of consultants for minority recruit-

KEY POINTS

154

Accrual to cancer clinical trials remains low and


largely unchanged despite initiatives and interventions to increase rates beyond the estimated 5% to
10%.
In the face of poorer prognosis, even lower rates of
accrual of minorities in cancer trials is compounded
by cultural-specific attitudes and sociodemographic
factors that must be addressed in addition to the
factors identified for other patients with cancer.
An intervention approach that directly addresses
attitudes through use of a culturally appropriate
video has been shown to affect the intention of black
patients with cancer to enroll in therapeutic clinical
trials.
Trial design factors, including eligibility criteria,
data collection, and quality, are among the systemwide factors that also must be addressed to improve
accrual.

ment failed to yield increases in recruitment of minority


participants in a prostate cancer prevention trial.23 In the
final study, from the Southeast Cancer Control Consortium,
no improvement was found in enrollment of patients with
cancer into clinical trials after their intervention. This
intervention involved use of nurse facilitators, quarterly
newspapers, and health educators.24
The problem is clearly complex, with multiple contributing factors. Developing strategies that target factors that
yield the greatest effect is thus a challenge. Among black
patients, this is further complicated by the need to ensure
such strategies are culturally sensitive. This review describes barriers to minority clinical trial accrual, a novel
approach to change black patients attitudes toward clinical
trial participation and strategies to enhance accrual.
Factors That Influence Black Patients Decisions to
Participate in Cancer Clinical Trials

A comprehensive review identified 150 distinct barriers to


accrual of underrepresented populations to cancer-related
clinical trials. The most frequently reported of these are
presented in Table 2.13 Often, barriers are categorized
according to their source (e.g., patient, physician, or institution or environment). A conceptual framework was developed that proposes that these barriers may influence accrual
through their effects on awareness of trials, the opportunity
to participate, and the decision to accept or refuse participation. The most frequently reported barrier related to
awareness of trials was lack of clinical trials education.
Education is crucial and can address other barriers, such as
mistrust of research and the medical system, perceived
harm, and fear. The most frequently reported barrier related
to opportunity to participate was physician attitudes and
patient eligibility. The most frequently reported barrier to
acceptance of enrollment was mistrust of research and the
medical system and costs of participation.13
Black Patients Attitudes Toward Clinical
Trial Participation

Many of the attitudes black patients have toward clinical


trial participation stem from historical abuses, such as the
U.S. Public Health Services Syphillis Study at Tuskegee,
and related concerns of ethical misconduct and mistrust.6,25-27
In focus group interviews with 33 black patients and a black
moderator, most participants viewed clinical research negatively and expressed concern they would be treated as a
guinea pig. They also believed black patients would not

BLACK PATIENTS AND CANCER CLINICAL TRIALS

Fig. 1. Minority enrollment in National Cancer Institute clinical


trials, 2000 2010. Courtesy of Worta McCaskill-Stevens, MD,
MS, program director, Minority Based Community Clinical Oncology Program, National Institutes of Health.
Abbreviations: CTEP, Cancer Therapy Evaluation Program; DCP,
Division of Cancer Prevention; RRP, Radiation Research Program.

benefit from clinical research because of racism and the


inability to pay for medical care.7
Participants were asked specifically about the U.S. Public
Health Services study and were found to have misinformation and misperceptions about the study. Many believed it
was a conspiracy and, as a result, expected that investigators would be dishonest and not provide full disclosure of the
risks related to research. They also believed in other conspiracies, such as the creation of HIV, military experiments with Agent Orange, and Central Intelligence Agency
distribution of crack cocaine in black communities.7
In another set of focus groups with black women, the
theme of trust also emerged.28 Women were suspicious of
how clinical research was funded and expressed concerns
regarding the termination of programs that specifically help
the black community.28 Focus group participants were presented with a hypothetical phase III randomized clinical
trial in which adjuvant oral and intravenous chemotherapy
were compared. Some participants did not understand the
concept of randomization and lost interest in participating
because of a lack of choice of treatment arm. Other participants, especially older women, were in favor of natural
treatments and stressed the importance of prayer or God as
healer. Most women were willing or at least open to considering a clinical trial using an oral chemotherapy agent.
Physician Attitudes Toward Enrolling Black Patients
in Clinical Trials

Physicians play an important role in clinical trial accrual.


Their perceptions and support of clinical research influence
the discussions they have with patients and consequently
the patients decision to participate in clinical trials. A
survey of 166 black physicians revealed several challenges of
Table 2. Frequently Reported Patient Barriers to Minority
Accrual to Clinical Trials 13
Mistrust of research and medical system
Perceived harm
Cost
Patient demographics
Transportation
Lack of education regarding clinical trials
Time commitment
Fear
Family issues

participating in clinical research,29 including additional


paperwork or telephone calls, masked drug assignment,
excess patient care costs, losing the patient from their
medical practice, and the potential effect of clinical research
on the managed care status of their medical practice. Although most physicians surveyed (97%) believed clinical
trials were important, only 63% referred patients and 64%
encouraged patients to participate in clinical trials. This
validated the focus group reports of mistrust of the medical
system, lack of awareness of clinical trials, communication