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2016 ASCO EDUCATIONAL BOOK

This publication is supported by an


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Amgen
Merck & Co., Inc.

AMERICAN SOCIETY OF CLINICAL ONCOLOGY

2016 EDUCATIONAL BOOK

Support for this program is funded through


Collective Wisdom: The Future of Patient-Centered Care and Research

A PEER-REVIEWED, INDEXED PUBLICATION


52nd Annual Meeting | June 37, 2016 | Chicago, Illinois | Volume 36

Vol. 36
American Society of Clinical Oncology Educational Book
The 2016 ASCO Educational Book (Print ISSN: 1548-8748; Electronic ISSN: 1548-8756) is published by American Society of Clinical Oncology,
Inc. (ASCO).

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American Society of
Clinical Oncology
Educational Book
Editor in Chief: Don S. Dizon, MD

Associate Editor: Nathan Pennell, MD, PhD


Managing Editor: Lindsay Pickell, MFA
Production Manager: Donna Dottellis

2016 American Society of Clinical Oncology, Alexandria, VA


Contents
2016 ASCO Annual Meeting Disclosure xiii

20152016 Cancer Education Committee xiv

2016 Educational Book Expert Panel xvi

2016 Annual Meeting Supporters xx

Letter From the Editor 1

INVITED ARTICLES
Collaborative Practice in an Era of Multidisciplinary Care
Michael P. Kosty, Todd Pickard, and Pamela Viale 3
Value in Oncology: Balance Between Quality and Cost
Derek Raghavan and Mark W. Legnini 9
Womens Health Issues for BRCA Mutation Carriers
Mary E. Sabatini and Leif W. Ellisen 14
Collective Wisdom: Lobular Carcinoma of the Breast
George W. Sledge, Anees Chagpar, and Charles Perou 18

POINTS OF VIEW
Compassionate Use: A Modest Proposal
Arthur L. Caplan, Alison Bateman-House, and Joanne Waldstreicher e2
Less Is More: The Evolving Surgical Approach to Breast Cancer
Laura Esserman, Etienne Gallant, and Michael Alvarado e5
Strategies for Sustainable Cancer Care
David J. Kerr, Anant Jani, and Sir Muir Gray e11
The Role of Nephrectomy for Kidney Cancer in the Era of Targeted and Immune Therapies
Ulka N. Vaishampayan e16

BREAST CANCER
Breast Cancer Survivorship: Strategies for Optimal Care
Issues in Breast Cancer Survivorship: Optimal Care, Bone Health, and Lifestyle Modifications
Michelle E. Melisko, William J. Gradishar, and Beverly Moy e22

The 2016 ASCO Educational Book is published online at asco.org/edbook. Articles can also be accessed
from the Attendee Resource Center at am.asco.org/ARC. Articles that are only available online are
denoted with an e ahead of the page number.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK iii


Less Is More: A Multidisciplinary Conversation on Treatment Options
Tailoring Chemotherapy in Early-Stage Breast Cancer: Based on Tumor Biology or Tumor Burden?
Domen Ribnikar and Fatima Cardoso e31

Targeted Therapies in Hormone ReceptorPositive Breast Cancer


Improving Response to Hormone Therapy in Breast Cancer: New Targets, New Therapeutic Options
Hope S. Rugo, Neelima Vidula, and Cynthia Ma e40

Treatment of Premenopausal Women With Endocrine-Sensitive Breast Cancer


Challenges in Treating Premenopausal Women with Endocrine-Sensitive Breast Cancer
Hatem A. Azim Jr., Nancy E. Davidson, and Kathryn J. Ruddy 23

Triple-Negative Breast Cancer: Is Change on the Horizon?


The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics
Carey K. Anders, Vandana Abramson, Tira Tan, and Rebecca Dent 34

Updates and Controversies in HER2-Positive Breast Cancer


A Value-Based Approach to Treatment of HER2-Positive Breast Cancer: Examining the Evidence
Nancy Nixon and Sunil Verma e56
Emerging Therapeutic Options for HER2-Positive Breast Cancer
Miguel Martin and Sara Lopez-Tarruella
e64

CANCER PREVENTION, HEREDITARY GENETICS, AND EPIDEMIOLOGY


Controversies in Genetic Evaluation
How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing
Filipa Lynce and Claudine Isaacs e72

Evolving Recommendations on Prostate Cancer Screening


Evolving Recommendations on Prostate Cancer Screening
Otis W. Brawley, Ian M. Thompson Jr., and Henrik Gronberg e80

Refining Breast Cancer Risk Assessment: Additional Genes, Additional Screening


Refining Breast Cancer Risk Stratification: Additional Genes, Additional Information
Allison W. Kurian, Antonis C. Antoniou, and Susan M. Domchek 44

CARE DELIVERY AND PRACTICE MANAGEMENT


Access to Cancer Therapeutics in Low- and Middle-Income Countries
Access to Cancer Therapeutics in Low- and Middle-Income Countries
Sana Al-Sukhun, Charmaine Blanchard, Lawrence N. Shulman, and Paul Ruff 58

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Integrating Patient-Reported Outcomes Into Real-Life Medical Decisions
Patient-Reported Outcomes in Cancer Clinical Trials: Measuring Symptomatic Adverse Events With
the National Cancer Institutes Patient-Reported Outcomes Version of the Common Terminology
Criteria for Adverse Events (PRO-CTCAE)
Paul G. Kluetz, Diana T. Chingos, Ethan M. Basch, and Sandra A. Mitchell 67

Optimizing Team-Based Oncology Care: Building the Village


Electronic Patient-Reported Outcomes: The Time Is Ripe for Integration Into Patient Care and
Clinical Research
Lee Schwartzberg e89
Oncology Advanced Practitioners Bring Advanced Community Oncology Care
Wendy H. Vogel e97

Quality and Value: Measuring and Utilizing Both in Your Practice


Why the Quality Oncology Practice Initiative Matters: Its Not Just About Cost
Anne C. Chiang e102

The Oncology Care Model: The Man Behind the Curtain


The Oncology Care Model: A Critique
Christian A. Thomas and Jeffrey C. Ward e109

CENTRAL NERVOUS SYSTEM TUMORS


Multidisciplinary Management of Brain Metastases
Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment
Anna S. Berghoff, Vyshak A. Venur, Matthias Preusser, and Manmeet S. Ahluwalia e116
Targeted Therapy in Brain Metastases: Ready for Primetime?
Vyshak A. Venur and Manmeet S. Ahluwalia e123

The Future of Immunotherapy in Glioblastoma


Current State of Immune-Based Therapies for Glioblastoma
Michael Lim, Michael Weller, and E. Antonio Chiocca e132

Treatment of Low-Grade Gliomas in the Era of Genomic Medicine


Treatment of Adult Lower-Grade Glioma in the Era of Genomic Medicine
Susan M. Chang, Daniel P. Cahill, Kenneth D. Aldape, and Minesh P. Mehta 75

DEVELOPMENTAL THERAPEUTICS AND TRANSLATIONAL RESEARCH


Biomarkers, Blood-Based Testing, and the Heterogeneous Tumor
Tumor Evolutionary Principles: How Intratumor Heterogeneity Influences Cancer Treatment
and Outcome
Subramanian Venkatesan and Charles Swanton e141

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Biosimilars: Here and Now
Biosimilars: Here and Now
Steven J. Lemery, Francisco J. Esteva, and Martina Weise e151

Clinical Trial Eligibility Criteria: Tradition Versus Reality


Transforming Clinical Trial Eligibility Criteria to Reflect Practical Clinical Application
Edward S. Kim, Jennifer Atlas, Gwynn Ison, and Jennifer L. Ersek 83

Immunotherapy: Beyond Checkpoint Inhibitors


Arming the Immune System Through Vaccination to Prevent Cancer Recurrence
Diane F. Hale, Timothy J. Vreeland, and George E. Peoples e159
Overcoming Therapeutic Resistance by Targeting Cancer Inflammation
Gregory L. Beatty e168

Pharmacokinetics, Dynamics, and Genomics in the Era of Immunotherapy and Small Molecules
Pharmacogenomics, Pharmacokinetics, and Pharmacodynamics in the Era of Targeted Therapies
Emiliano Calvo, Christine Walko, E. Claire Dees, and Belen Valenzuela e175

GASTROINTESTINAL (COLORECTAL) CANCER


Potentially Resectable Metastatic Colorectal Cancer: A Multidisciplinary Discussion
Liver Metastases in Colorectal Cancer
Gunnar Folprecht e186

Questions on Treatment of Locally Advanced Rectal Cancer


Multimodal Rectal Cancer Treatment: In Some Cases, Less May Be More
Julio Garcia-Aguilar, Rob Glynne-Jones, and Deborah Schrag 92

GASTROINTESTINAL (NONCOLORECTAL) CANCER


Biliary Tract Cancer: The New and the Old
Biliary Tract Cancer: Epidemiology, Radiotherapy, and Molecular Profiling
John A. Bridgewater, Karyn A. Goodman, Aparna Kalyan, and Mary F. Mulcahy e194

Designing Clinical Trials to Achieve Breakthrough Results in Upper Gastrointestinal Malignancies


The Past, Present, and Future of Pancreatic Cancer Clinical Trials
Lynn M. Matrisian and Jordan D. Berlin e205

HER2, VEGFR, and Beyond: Genomic Profiling of Upper Gastrointestinal Tract Cancers and the Future of
Personalized Treatment
Gastric Adenocarcinoma: An Update on Genomics, Immune System Modulations, and Targeted Therapy
Jeeyun Lee, Adam J. Bass, and Jaffer A. Ajani 104

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Localized Pancreatic Cancer: Multidisciplinary Management With Incorporation of ASCO Guidelines
Localized Pancreatic Cancer: Multidisciplinary Management
Andrew L. Coveler, Joseph M. Herman, Diane M. Simeone, and E. Gabriela Chiorean e217

GENITOURINARY (NONPROSTATE) CANCER


Elderly Patients With Bladder Cancer: Perspectives From a Surgeon, Medical, and Radiation Oncologist
Treatment of Muscle-Invasive Bladder Cancer in Older Patients
Eila C. Skinner e228

Renal Cell Carcinoma: Systemic Treatment, Evolving TKIs, and Immuno-Oncology


The Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma
Thomas E. Hutson, Gregory R. Thoreson, Robert A. Figlin, and Brian I. Rini 113

GENITOURINARY (PROSTATE) CANCER


Contemporary Active Surveillance for Prostate Cancer: Do We Need Better Imaging and Molecular Testing?
Active Surveillance of Prostate Cancer: Use, Outcomes, Imaging, and Diagnostic Tools
Jeffrey J. Tosoian, Stacy Loeb, Jonathan I. Epstein, Baris Turkbey, Peter L. Choyke,
and Edward M. Schaeffer e235

Oligometastatic Disease in Prostate Cancer: Treating the Patient or the Scan?


Approach to Oligometastatic Prostate Cancer
Brandon Bernard, Boris Gershman, R. Jeffrey Karnes, Christopher J. Sweeney, and Neha Vapiwala 119

Precision Medicine in Advanced Prostate Cancer: Understanding Genomics, Androgen Receptor Splice
Variants, and Imaging Biomarkers
Emerging Molecular Biomarkers in Advanced Prostate Cancer: Translation to the Clinic
Himisha Beltran, Emmanuel S. Antonarakis, Michael J. Morris, and Gerhardt Attard 131

GYNECOLOGIC CANCER
Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer
Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer
Keiichi Fujiwara, Jessica N. McAlpine, Stephanie Lheureux, Noriomi Matsumura, and Amit M. Oza e247

Divide and Conquer: Epithelial Gynecologic Cancers Beyond BRCA


Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency
Rebecca S. Kristeleit, Rowan E. Miller, and Elise C. Kohn e259

Intraperitoneal Chemotherapy for Ovarian Cancer: Trials and Tribulations


Update on Intraperitoneal Chemotherapy for the Treatment of Epithelial Ovarian Cancer
Charlie Gourley, Joan L. Walker, and Helen J. Mackay 143

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Neoadjuvant Chemotherapy: Location, Location, Location
Primary Surgery or Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: The Debate
Continues
Alexandra Leary, Renee Cowan, Dennis Chi, Sean Kehoe, and Matthew Nankivell 153

Practical Challenges in Endometrial Cancer


Treatment of Older Women With Endometrial Cancer: Improving Outcomes With Personalized Care
Linda Duska, Armin Shahrokni, and Melanie Powell 164

Symptom Management for the Patient with Gynecologic Cancer


Enhancing Care of the Survivor of Gynecologic Cancer: Managing the Menopause and Radiation
Toxicity
Linda Van Le and Mary McCormack e270

HEAD AND NECK CANCER


Best of the Rest: Top Abstracts on Head and Neck Cancer From 20152016 Oncology Meetings
Whats New in Head and Neck Cancer: Key Findings in 20152016 From ECCO/ESMO, ASTRO,
and the Multidisciplinary Head and Neck Cancer Symposium
Sue S. Yom, Apar K. Ganti, and Andreas Dietz 176

Integrating Immune Checkpoint Inhibitors and Targeted Agents With Surgery and Radiotherapy for Patients
With Head and Neck Cancer
Immunotherapy and Checkpoint Inhibitors in Recurrent and Metastatic Head and Neck Cancer
Nooshin Hashemi Sadraei, Andrew G. Sikora, and David M. Brizel e277

Multimodality Management of Locoregionally Recurrent or Second Primary Head and Neck Cancer
Locoregional Recurrent or Second Primary Head and Neck Cancer: Management Strategies
and Challenges
Stuart J. Wong, Dwight E. Heron, Kerstin Stenson, Diane C. Ling, and John A. Vargo e284

HEALTH SERVICES RESEARCH AND QUALITY OF CARE


Defining and Measuring Quality
Challenges and Opportunities in Delivering High-Quality Cancer Care: A 2016 Update
Patricia A. Ganz, Michael J. Hassett, and David C. Miller e294

Removing Barriers to Clinical Trial Participation


The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies
Joseph M. Unger, Elise Cook, Eric Tai, and Archie Bleyer 185

Using Social Media, Wearables, and Electronic Medical Records to Improve Quality of Cancer Care
Using Technology to Improve Cancer Care: Social Media, Wearables, and Electronic Health Records
Michael J. Fisch, Arlene E. Chung, and Melissa K. Accordino 200

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HEMATOLOGIC MALIGNANCIESLEUKEMIA, MYELODYSPLASTIC SYNDROMES,
AND ALLOTRANSPLANT
Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?
Evolving Therapies in Acute Myeloid Leukemia: Progress at Last?
Daniel J. DeAngelo, Eytan M. Stein, and Farhad Ravandi e302

Molecularly and Phenotypically Defined Subtypes of Acute Lymphoblastic Leukemia: Implications


for Management
Advances in the Genetics and Therapy of Acute Lymphoblastic Leukemia
Sabina Chiaretti, Valentina Gianfelici, Susan M. OBrien, and Charles G. Mullighan e314

Progress in Myeloproliferative Neoplasms: Are We Ready?


Individualizing Care for Patients With Myeloproliferative Neoplasms: Integrating Genetics, Evolving
Therapies, and Patient-Specific Disease Burden
Ruben A. Mesa and Francesco Passamonti e324

Why Are Myelodysplastic Syndromes So Difficult to Cure?


Integrating Frailty, Comorbidity, and Quality of Life in the Management of Myelodysplastic
Syndromes
Gregory A. Abel and Rena Buckstein e337
Searching for a Light at the End of the Tunnel? Beyond Hypomethylating Agents in Myelodysplastic
Syndromes
Rami S. Komrokji e345

HEMATOLOGIC MALIGNANCIESLYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA


Current Management Concepts: Primary Central Nervous System Lymphoma, Natural Killer T-Cell Lymphoma
Nasal Type, Post-transplant Lymphoproliferative Disorder
Current Management Concepts: Primary Central Nervous System Lymphoma, Natural Killer T-Cell
Lymphoma Nasal Type, and Post-transplant Lymphoproliferative Disorder
Tracy T. Batchelor, Lim Soon Thye, and Thomas M. Habermann e354

PET-Directed Strategies in Lymphoma


Functional Imaging Using 18-Fluorodeoxyglucose PET in the Management of Primary Mediastinal
Large B-Cell Lymphoma: The Contributions of the International Extranodal Lymphoma Study Group
Franco Cavalli, Luca Ceriani, and Emanuele Zucca e368
Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT
Ryan C. Lynch and Ranjana H. Advani e376

Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When, How Long,
How Much, and in Which Combination?
Chemoimmunotherapy Versus Targeted Treatment in Chronic Lymphocytic Leukemia: When,
How Long, How Much, and in Which Combination?
Jennifer R. Brown, Michael J. Hallek, and John M. Pagel e387

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HEMATOLOGIC MALIGNANCIESPLASMA CELL DYSCRASIA
Consolidation and Maintenance: Moving Beyond Autotransplant
Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance,
Allogeneic Transplant, and Immune Therapy
Amrita Krishnan, Ravi Vij, Jesse Keller, Binod Dhakal, and Parameswaran Hari 210

Defining and Redefining Myeloma


Future Directions in the Evaluation and Treatment of Precursor Plasma Cell Disorders
Salomon Manier, Karma Z. Salem, David Liu, and Irene M. Ghobrial e400
The Role of Imaging in the Treatment of Patients With Multiple Myeloma in 2016
Evangelos Terpos, Meletios A. Dimopoulos, and Lia A. Moulopoulos e407
Updated Diagnostic Criteria and Staging System for Multiple Myeloma
S. Vincent Rajkumar e418

Multiple Myeloma: Are We Ready for Personalized Therapy?


Minimal Residual Disease by Next-Generation Sequencing: Pros and Cons
Herve Avet-Loiseau e425
New Targets and New Agents in High-Risk Multiple Myeloma
Ajay K. Nooka and Sagar Lonial e431
Next-Generation Sequencing Informing Therapeutic Decisions and Personalized Approaches
Raphael Szalat and Nikhil C. Munshi e442

LUNG CANCER
Immunotherapy: Beyond AntiPD-1 and AntiPD-L1 Therapies
Immunotherapy: Beyond AntiPD-1 and AntiPD-L1 Therapies
Scott J. Antonia, Johan F. Vansteenkiste, and Edmund Moon e450

Local Therapies in the Management of Oligometastatic and Metastatic NonSmall Cell Lung Cancer
Local Therapy for Limited Metastatic NonSmall Cell Lung Cancer: What Are the Options and Is
There a Benefit?
Puneeth Iyengar, Steven Lau, Jessica S. Donington, and Robert D. Suh e460

Lung Cancer Screening and Prevention


Lung Cancer Screening With Low-Dose CT: Implementation Amid Changing Public Policy at One
Health Care System
Abbie Begnaud, Thomas Hall, and Tadashi Allen e468
Lung Cancer Screening, Cancer Treatment, and Addressing the Continuum of Health Risks Caused
by Tobacco
Graham W. Warren, Jamie S. Ostroff, and John R. Goffin 223

Lung Cancer, Small Cell Lung Cancer: On the Move (Again?)


Seeking New Approaches to Patients With Small Cell Lung Cancer
Marie Catherine Pietanza, Stefan Zimmerman, Solange Peters, and Walter J. Curran Jr. e477

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Treatment of Lung Cancer in Medically Compromised Patients
Treatment of Lung Cancer in Medically Compromised Patients
Jeffrey Crawford, Paul Wheatley-Price, and Josephine Louella Feliciano e484

MELANOMA/SKIN CANCERS
Clinical Conundrums in Melanoma Therapy
Biomarkers for Immunotherapy: Current Developments and Challenges
Kristen R. Spencer, Jianfeng Wang, Ann W. Silk, Shridar Ganesan, Howard L. Kaufman,
and Janice M. Mehnert e493

Curing High-Risk Melanoma: Are We There Yet?


Surgical Management and Adjuvant Therapy for High-Risk and Metastatic Melanoma
Alexander C.J. van Akkooi, Michael B. Atkins, Sanjiv S. Agarwala, and Paul Lorigan e505

PATIENT AND SURVIVOR CARE


Cancer Survivorship: Is Every Patients Journey the Same?
The Cancer Survivorship Journey: Models of Care, Disparities, Barriers, and Future Directions
Michael T. Halpern, Mary S. McCabe, and Mary Ann Burg 231

Cancer Treatment as an Accelerated Aging Process


Cancer Treatment as an Accelerated Aging Process: Assessment, Biomarkers, and Interventions
Arti Hurria, Lee Jones, and Hyman B. Muss e516

New and Improved? Use of White Blood Cell Growth Factors in Oncology Practice
Real-World Conundrums and Biases in the Use of White Cell Growth Factors
Thomas J. Smith and Bruce E. Hillner e524
Issues on the Use of White Blood Cell Growth Factors in Oncology Practice
Gary H. Lyman e528

Optimizing Palliative and End-of-Life Care: Evidence-Based Practice Improvement


Discussing the Evidence for Upstream Palliative Care in Improving Outcomes in Advanced Cancer
Myles S. Nickolich, Areej El-Jawahri, Jennifer S. Temel, and Thomas W. LeBlanc e534

Rehabilitation of Patients and Survivors: Seizing the Opportunity


Developing High-Quality Cancer Rehabilitation Programs: A Timely Need
Catherine M. Alfano, Andrea L. Cheville, and Karen Mustian 241

PEDIATRIC ONCOLOGY
Controversies in Germline Genetic Testing and Disclosure in Pediatric Oncology
The Advantages and Challenges of Testing Children for Heritable Predisposition to Cancer
Chimene Kesserwan, Lainie Friedman Ross, Angela R. Bradbury, and Kim E. Nichols 251

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Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors
Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors
Giles W. Robinson, Hendrik Witt, and Adam Resnick e540

The State of the Art in Neuroblastoma: From Biology to Survivorship


Neuroblastoma: A Tough Nut to Crack
Frank Speleman, Julie R. Park, and Tara O. Henderson e548

PROFESSIONAL DEVELOPMENT
Curing Burnout in Oncology: Mindful Self-Compassion, Communication, and Practice
Addressing Burnout in Oncology: Why Cancer Care Clinicians Are At Risk, What Individuals Can Do,
and How Organizations Can Respond
Fay J. Hlubocky, Anthony L. Back, and Tait D. Shanafelt 271

SARCOMA
Is There a Future for Immunotherapy in Sarcoma?
Immunotherapy for Soft Tissue Sarcoma: Tomorrow Is Only a Day Away
Alex Lee, Paul Huang, Ronald P. DeMatteo, and Seth M. Pollack 281
Manipulating the Immune System With Checkpoint Inhibitors for Patients With Metastatic Sarcoma
Sandra P. DAngelo e558

Noncytotoxic Approaches to the Treatment of Metastatic Soft Tissue Sarcoma


Local Ablative Therapies to Metastatic Soft Tissue Sarcoma
Alessandro Gronchi, B. Ashleigh Guadagnolo, and Joseph Patrick Erinjeri e566

TUMOR BIOLOGY
Expanding the Clinically Actionable Cancer Genome
Interrogating the Cancer Genome to Deliver More Precise Cancer Care
Joaquin Mateo and Johann S. de Bono e577

Molecular Diagnostics in Cancer


Considerations for Implementation of Cancer Molecular Diagnostics Into Clinical Care
Daniel F. Hayes 292

Tumor Heterogeneity and Therapeutic Resistance


Tumor Heterogeneity and Therapeutic Resistance
Christine M. Lovly, April K.S. Salama, and Ravi Salgia e585

Whats Next in Cancer Immunotherapy?


Basic Overview of Current Immunotherapy Approaches in Cancer
Vamsidhar Velcheti and Kurt Schalper 298

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2016 ASCO Annual Meeting Disclosure
As the CME provider for the 2016 Annual Meeting, ASCO is committed to balance, objectivity, and scientific rigor in the management of
financial interactions with for-profit health care companies that could create real or perceived conflicts of interest. Participants in the
Meeting have disclosed their financial relationships in accordance with ASCOs Policy for Relationships with Companies; review the policy at
asco.org/rwc.

ASCO offers a comprehensive disclosure management system, using one disclosure for all ASCO activities. Members and participants in
activities use coi.asco.org to disclose all interactions with companies. Their disclosure is kept on file and can be confirmed or updated with
each new activity.

Please email coi@asco.org with specific questions or concerns.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xiii


20152016 Cancer Education Committee
The Cancer Education Committee assesses the need for, plans, develops, and initiates the education programs for the Annual Meeting.

Apar Kishor Ganti, MD, MBBSChair GASTROINTESTINAL (NONCOLORECTAL) CANCER


Michael A. Thompson, MD, PhDChair-Elect Vincent J. Picozzi, MDTrack Leader
John Vernon Cox, DO, FACP, FASCO, MBAImmediate Past Chair Tanios S. Bekaii-Saab, MD
Lillian L. Siu, MDBoard Liaison Jimmy J. Hwang, MD
Se Hoon Park, MD
BREAST CANCER Manish A. Shah, MD
Hope S. Rugo, MDTrack Leader William Small, MD
Judy Caroline Boughey, MD
Jennifer A. Brown, MD
Raquel Nunes, MD GENITOURINARY (NONPROSTATE) CANCER
Debra A. Patt, MD, MPH, MBA Stephen Boyd Riggs, MDTrack Leader
Rinaa S. Punglia, MD Thomas E. Hutson, DO, PharmD
Elizabeth C. Reed, MD Jose A. Karam, MD
Tallal Younis, MBBCh, FRCP Ulka N. Vaishampayan, MD

CANCER PREVENTION, HEREDITARY GENETICS, GENITOURINARY (PROSTATE)


AND EPIDEMIOLOGY CANCER
P. Kelly Marcom, MDTrack Leader Himisha Beltran, MDTrack Leader
Margreet Ausems, MD, PhD Chris Parker, BA, BM Bchir, MD, FRCR, FRCP
Monique A. De Bruin, MD Edward M. Schaeffer, MD, PhD
Jeri Kim, MD Nicholas J. Vogelzang, MD, FASCO
Howard L. McLeod, PharmD
Electra D. Paskett, PhD GERIATRIC ONCOLOGY
Surendra Srinivas Shastri, MD, MBBS
Andrew S. Artz, MD, MSTrack Leader
William P. Tew, MD
CARE DELIVERY AND PRACTICE MANAGEMENT William Tse, MD
Jeffery C. Ward, MDTrack Leader
Aditya Bardia, MBBS, MPH
GYNECOLOGIC CANCER
Kelly Bugos, RN, ANP, MS
Helen Mackay, MDTrack Leader
Moshe C. Chasky, MD
Elise C. Kohn, MD
John Emmett Hennessy, CMPE, MBA
Linda Duska, MD
Lee Steven Schwartzberg, MD, FACP
Linda Van Le, MD

CENTRAL NERVOUS SYSTEM TUMORS


Manmeet Singh Ahluwalia, MDTrack Leader HEAD AND NECK CANCER
Eric L. Chang, MD Joseph Kamel Salama, MDTrack Leader
Nicole A. Shonka, MD John Truelson, MD
Roger Stupp, MD John A. Ridge, MD, PhD
Irina Veytsman, MD
CLINICAL TRIALS
Sumithra J. Mandrekar, PhDTrack Leader HEALTH SERVICES RESEARCH AND QUALITY OF CARE
Janet Dancey, MD Bruce Lee Jacobs, MDTrack Leader
Ethan M. Basch, MD
DEVELOPMENTAL THERAPEUTICS AND TRANSLATIONAL Daniel Jacob Becker, MD
RESEARCH Dawn L. Hershman, MD
Howard A. Burris, MD, FASCOTrack Leader Nicole Maria Kuderer, MD
Julia A. Beaver, MD Jennifer W. Mack, MD
Francisco J. Esteva, MD, PhD
John Charles Morris, MD HEMATOLOGIC MALIGNANCIESLEUKEMIA,
MYELODYSPLASTIC SYNDROMES,
GASTROINTESTINAL (COLORECTAL) CANCER AND ALLOTRANSPLANT
Donald A. Richards, MD, PhDTrack Leader Jorge E. Cortes, MDTrack Leader
Chris R. Garrett, MD Steven M. Devine, MD
Chi Lin, MD, PhD Jonathan Michael Gerber, MD
Ashwin Reddy Sama, MD Hanna Khoury, MD
Henry Q. Xiong, MD David Leibowitz, MD

xiv 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


HEMATOLOGIC MALIGNANCIESLYMPHOMA PEDIATRIC ONCOLOGY
AND CHRONIC LYMPHOCYTIC LYMPHOMA Tara O. Henderson, MD, MPHTrack Leader
Grzegorz S. Nowakowski, MDTrack Leader Gregory T. Armstrong, MD, MSCE
Matthew Alexander Lunning, DO Stewart Goldman, MD
Jeffrey Matous, MD Joel A. Weinthal, MD
John M. Pagel, MD, PhD
Michael A. Thompson, MD, PhD PROFESSIONAL DEVELOPMENT
Anne S. Tsao, MDTrack Leader
HEMATOLOGIC MALIGNANCIESPLASMA Kristin Anderson, MD, MPH
Kelly J. Cooke, DO
CELL DYSCRASIA Jill Gilbert, MD
Sagar Lonial, MDTrack Leader Laura Goff, MD
Asher Alban Chanan-Khan, MD Roberto Leon-Ferre, MD
Parameswaran Hari, MD
Irene M. Ghobrial, MD SARCOMA
Ravi Vij, MD Gary K. Schwartz, MDTrack Leader
L. Johnetta Blakely, MD
LUNG CANCER Robin Lewis Jones, MD, BSc, MBBS, MRCP
Martin J. Edelman, MDTrack Leader Min S. Park, MD, MS
Arkadiusz Z. Dudek, MD, PhD
Shirish M. Gadgeel, MD TUMOR BIOLOGY
Puneeth Iyengar, MD, PhD Kimryn Rathmell, MD, PhDTrack Leader
Craig H. Reynolds, MD Ravi Salgia, MD, PhD
David R. Spigel, MD Eliezer Mendel Van Allen, MD
Vamsidhar Velcheti, MD
MELANOMA/SKIN CANCERS
Sanjiv S. Agarwala, MDTrack Leader LIAISONS
Jason John Luke, MD, FACP Sana Al-Sukhun, MD, MScInternational Affairs Committee
Janice M. Mehnert, MD Howard Bailey, MDCancer Prevention Committee
Ahmad A. Tarhini, MD, PhD Gregg Franklin, MD, PhDClinical Practice Committee
Alexander Christopher Jonathan Van Akkooi, MD, PhD Melissa Johnson, MDCancer Research Committee
Thomas Leblanc, MD, MAEthics Committee
PATIENT AND SURVIVOR CARE Leonard Saltz, MDValue Task Force
Nagendra Tirumali, MDTrack Leader Manish Shah, MDClinical Practice Guidelines Committee
Deborah Mayer, PhD, RN, AOCN, FAAN Charles Shapiro, MDCancer Survivorship Committee
Kathi Mooney, PhD, RN William Tew, MDGeriatrics Special Interest Group
Maria Alma Rodriguez, MD Gina Villani, MDClinical Practice Guidelines Committee
Louise Christie Walter, BS, MD Ann Von Gehr, MDClinical Practice Guidelines Committee

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xv


2016 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 of the ASCO Educational Book articles.

Ghassan K. Abou-Alfa, MD Emily K. Bergsland, MD Franco Cavalli, MD


Memorial Sloan Kettering Cancer Center, University of California, San Francisco University of Bellinzona
Weill Cornell Medical College
Axel Bex, MD, PhD Andrea Cercek, MD
Donald I. Abrams, MD The Netherlands Cancer Institute Memorial Sloan Kettering Cancer Center
San Francisco General Hospital
William Blum, MD Anthony Chan, MBBS, MD, FRCP, FHKCP,
Manmeet S. Ahluwalia, MD The Ohio State University FHKAM
Cleveland Clinic Sir YK Pao Centre for Cancer, Prince of Wales
Sharon Bober, PhD Hospital
Fabrice Andre, MD, PhD Dana-Farber Cancer Institute
Institut Gustave Roussy Alice Chen, MD
Diane Bodurka, MD, MPH National Cancer Institute at the National
Christina Annunziata, MD, PhD The University of Texas MD Anderson Institutes of Health
National Cancer Institute at the National Cancer Center
Allen M. Chen, MD
Insitutes of Health
Joann Bodurtha, MD, MPH University of California, Los Angeles
Stephen Maxted Ansell, MD Johns Hopkins University School of Medicine Stephen K.L. Chia, MD
Mayo Clinic BC Cancer Agency
George J. Bosl, MD
Frederick Appelbaum, MD Memorial Sloan Kettering Cancer Center Laura Quan Man Chow, MD
Fred Hutchinson Cancer Research Center University of Washington
Alba Brandes, MD
Saro Armenian, DO, MPH Bellaria Hospital Jessica Clement, MD
City of Hope University of Connecticut Health Center
Eduardo Bruera, MD
Gregory Armstrong, MD, MSCE The University of Texas MD Anderson Cancer Anthony Cmelak, MD
St. Jude Childrens Research Hospital Center Vanderbilt-Ingram Cancer Center

Christina Baik, MD, MPH Alan Haruo Bryce, MD Ezra Cohen, MD


Seattle Cancer Care Alliance Mayo Clinic University of California, San Diego

Lodovico Balducci, MD Jan C. Buckner, MD Robert Coleman, MD


Moffitt Cancer Center Mayo Clinic The University of Texas MD Anderson Cancer
Center
Carlos H. Barrios, MD Howard A. Burris, MD, FASCO
Pontifical Catholic University of Rio Grande Sarah Cannon Research Institute, Tennessee Frances Collichio, MD
do Sul School of Medicine Oncology The University of North Carolina at Chapel
Hill
Brigitta G. Baumert, MD, PhD, MBA Harold Burstein, MD, PhD, FASCO
Roisin Connolly, MBBCh
University of Bonn Medical Center Dana-Farber Cancer Institute
The Sidney Kimmel Comprehensive Cancer
Tanios S. Bekaii-Saab, MD Toby Christopher Campbell, MD Center at Johns Hopkins
The Ohio State University Comprehensive University of Wisconsin Carbone Cancer Rena M. Conti, PhD
Cancer Center Center The University of Chicago
Himisha Beltran, MD Beverly E. Canin Daniel Costa, MD, PhD
Weill Cornell Medical College Breast Cancer Options Beth Israel Deaconess Medical Center
Robert S. Benjamin, MD Lisa Carey, MD Carien L. Creutzberg, MD, PhD
The University of Texas MD Anderson The University of North Carolina at Leiden University Medical Center
Cancer Center Chapel Hill
Sia Daneshmand, MD
Michael F. Berger, PhD William L. Carroll, MD University of Southern California
Memorial Sloan Kettering Cancer Center NYU Langone Medical Center
Molly S. Daniels, MS, CGC
P. Leif Bergsagel, MD, FASCO Richard Carvajal, MD The University of Texas MD Anderson Cancer
Mayo Clinic Columbia University Medical Center Center

xvi 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


Jonas De Souza, MD James M. Foran, MD Neil N. Hayes, MD, MPH
The University of Chicago Mayo Clinic The University of North Carolina at Chapel
Hill
H. Joachim Deeg, MD James Ford, MD
Fred Hutchinson Cancer Research Center Stanford University Medical Center Bryan Hennessy, MD
The University of Texas MD Anderson Cancer
Egidio Del Fabbro, MD William Foulkes, MBBS, PhD Center
VCU Massey Cancer Center Jewish General Hospital
John Emmett Hennessy, MBA, CMPE
Pierre-Yves Dietrich, MD Jonathan Freidberg, MD, MMSc Sarah Cannon Research Institute
Hopitaux Universitaires de Geneve
` University of Rochester
Norah Henry, MD, PhD
Mary L. Disis, MD Richard R. Furman, MD University of Michigan
University of Washington Weill Cornell Medical College, New York-
Presbyterian Hospital Peter Hillmen, PhD
Tanya B. Dorff, MD
Leed University
USC Norris Comprehensive Cancer Center Leena Gandhi, MD, PhD
Dana-Farber Cancer Institute Jeffrey Hoch, PhD
Mitchell Dowsett, PhD
Cancer Care Ontario
The Royal Marsden NHS Foundation Trust David E. Gerber, MD
The University of Texas Southwestern Christine Holmberg, DPhil, MPH
Martin Dreyling, MD Medical Center Charite Universitatsmedizin Berlin
University Hospital Grosshadern
Peter Gibbs, MBBS, FRACP, MD Gabriel Hortobagyi, MD, FACP
Dan Duda, DMD, PhD The Royal Melbourne Hospital The University of Texas MD Anderson Cancer
Massachusetts General Hospital
Center
Sharon Hermes Giordano, MD, MPH
Reinhard Dummer, MD The University of Texas MD Anderson Cancer Clifford A. Hudis, MD, FACP
University Hospital Zurich Center Memorial Sloan Kettering Cancer Center
Linda R. Duska, MD Robert G. Gish, MD
University of Virginia Health System Kevin S. Hughes, MD, FACS
Stanford Medicine Harvard Medical School, Massachusetts
Grace K. Dy, MD Bernardo H.L. Goulart, MD, MS General Hospital
Roswell Park Cancer Institute Fred Hutchinson Cancer Research Center Kelly Hunt, MD
Craig Earle, MD, MSc Ramaswamy Govindan, MD The University of Texas MD Anderson Cancer
Institute for Clinical Evaluative Sciences Washington University School of Medicine in Center
St. Louis Maha Hussain, MD, FACP, FASCO
Martin J. Edelman, MD
University of Maryland School of Medicine Timothy Graubert, MD University of Michigan
Massachusetts General Hospital
Lawrence H. Einhorn, MD Thomas Hutson, DO, PharmD, FACP
Indiana University Melvin and Bren Simon Gordon Hafner, MD, FACS Texas Oncology, Baylor Charles A. Sammons
Cancer Center Inova Health System Cancer Center

Hatem El Halabi, MD Peter Hammerman, MD, PhD David H. Ilson, MD, PhD
Cancer Treatment Centers of America Dana-Farber Cancer Institute Memorial Sloan Kettering Cancer Center,
Weill Cornell Medical College
Marwan Fakih, MD Hans Hammers, MD, PhD
City of Hope Johns Hopkins University School of Medicine Syma Iqbal, MD
University of Southern California
Lesley Fallowfield, DPhil, BSc Nasser H. Hanna, MD
Sussex Health Outcomes Research and Indiana University Melvin and Bren Simon David Jablons, MD
Education in Cancer Cancer Center University of California, San Francisco
Michelle A. Fanale, MD Michelle Harvie, PhD Sekwon Jang, MD
The University of Texas MD Anderson Cancer Nightingale and Genesis Prevention Centre, Inova Comprehensive Cancer and Research
Center Wythenshawe Hospital Institute
Adele K. Fielding, MBBS, PhD Hege Haugnes, MD, PhD Michalina Janiszewska, PhD
University College London University Hospital of North Norway Dana-Farber Cancer Institute
Paul Graham Fisher, MD Axel Hauschild, MD Connie Jimenez,
PhD
Stanford University University of Kiel Vanderbilt University Medical Center
Gini F. Fleming, MD Gillian Haworth, MBBS Maxine S. Jochelson, MD
University of Chicago Medical Center Great Ormond Street Hospital for Children Memorial Sloan Kettering Cancer Center

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xvii


Joseph Jurcic, MD Rami Manochakian, MD Ray D. Page, DO, PhD
Columbia University Medical Center Case Western Reserve University, Louis The Center for Cancer and Blood Disorders
Stokes Cleveland VA Medical Center
Matthew Katz, MD, FACS Sumanta Pal, MD
The University of Texas MD Anderson Cancer Mara-Victoria Mateos, MD, PhD City of Hope
Center University Hospital of Salamanca-IBSAL
Alberto Pappo, MD
Steven Katz, MD, MPH Rana McKay, MD St. Jude Childrens Research Hospital
University of Michigan Medical School Dana-Farber Cancer Institute
Chris Parker, FRCR, BA, MBBCh, MD
Stanley B. Kaye, MBBS, MRCP, MD, FRCP, Usha Menon, MD The Royal Marsden NHS Foundation Trust
FRCPS, FRSE, FMedSci University College London
Donald Williams Parsons, MD, PhD
The Institute of Cancer Research, The Royal
Paul A. Meyers, MD Texas Childrens Cancer Center, Baylor
Marsden NHS Foundation Trust
Memorial Sloan Kettering Cancer Center College of Medicine
Andrew Kennedy, MD, FACRO Lynne Penberthy, MD, MPH
Linda R. Mileshkin, MBBS, MD, MBioeth
Sarah Cannon Research Institute National Cancer Institute at the National
Peter MacCallum Cancer Centre
Institutes of Health
Gretchen Kimmick, MD
Matthew Milowsky, MD
Duke University Medical Center Vincent J. Picozzi, MD
The University of North Carolina at Chapel
Hill Virginia Mason Medical Center
Hedy Kindler, MD
The University of Chicago Blase N. Polite, MD, MPP
Shanu Modi, MD
Memorial Sloan Kettering Cancer Center The University of Chicago
Heidi D. Klepin, MD, MS
Wake Forest University School of Medicine Sandro V. Porceddu, MD
Ana Molina, MD
Weill Cornell Medical College Princess Alexandra Hospital
Theresa Koppie, MD
Oregon Health & Science University Michael Andrew Postow, MD
Alison Moliterno, MD
Johns Hopkins University Memorial Sloan Kettering Cancer Center
Thomas Krivak, MD
Magee-Womens Hospital of UMPC Thomas Powles, MD
Silvio Monfardini, MD
Barts Health
Istituto Palazzolo Fondazione Don Gnocchi
Ian Krop, MD, PhD
Dana-Farber Cancer Institute Kumar Prabhash, MD, DM
Halle C.F. Moore, MD
Tata Memorial Centre
Cleveland Clinic
Geoff Ku, MD, MBA
Memorial Sloan Kettering Cancer Center Amanda Psyrri, MD, PhD
Kathleen N. Moore, MD
Attikon Hospital National Kapodistrian
The University of Oklahoma Health Sciences
Shaji Kumar, MD University of Athens
Center
Mayo Clinic
Cornelis J.A. Punt, MD, PhD
Philippe Moreau, MD University of Amsterdam
Stephen Yenzen Lai, MD, PhD
CHU de Nantes, Hotel DieuHME
The University of Texas MD Anderson Cancer
Mark J. Ratain, MD
Center Lindsay Morton, PhD The University of Chicago
National Cancer Institute at the National
James M.G. Larkin, MD, PhD Institutes of Health John Ridge, MD, PhD
The Royal Marsden NHS Foundation Trust
Fox Chase Cancer Center
Michael Neuss, MD
Jonathan Ledermann, MD, FRCP Vanderbilt-Ingram Cancer Center Danny Rischin, MBBS, MD, FRACP
University College London Cancer Institute Peter MacCallum Cancer Centre
Lee Nisley Newcomer, MD
Stuart M. Lichtman, MD United Health Group Miriam B. Rodin, MD, PhD
Memorial Sloan Kettering Cancer Center Saint Louis University School of Medicine
Grzegorz S. Nowakowski, MD
Nancy Lin, MD Mayo Clinic Julia Rowland, PhD
Dana-Farber Cancer Institute National Cancer Institute at the National
Olatoyosi Odenike, MD Institutes of Health
Tracy Lively, PhD The University of Chicago
National Cancer Institute at the National David P. Ryan, MD
Institutes of Health Francesco Onida, MD Massachusetts General Hospital
University of Milan
Ravi Madan, MD Gilles A. Salles, MD, PhD
National Cancer Institute at the National Eric Padron, MD Hospices Civils de Lyon, Universite Claude
Institutes of Health Moffitt Cancer Center Bernard

xviii 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


Hanna Kelly Sanoff, MD, MPH Zsofia K. Stadler, MD Catherine H. Van Poznak, MD
University of North Carolina at Chapel Hill Memorial Sloan Kettering Cancer Center University of Michigan Comprehensive
School of Medicine Cancer Center
Stephan Stilgenbauer, MD
Gary K. Schwartz, MD University Hospital Ulm Brian Van Tine, MD, PhD
Columbia University Medical Center Washington University School of Medicine in
Richard Sullivan, PhD St. Louis
David W. Scott, MBCHB, PhD
Kings Health Partners Integrated Cancer
BC Cancer Agency Anna Varghese, MD
Centre
Memorial Sloan Kettering Cancer Center
Tanguy Y. Seiwert, MD
The University of Chicago Joel Tepper, MD Dian Wang, MD, PhD
The University of North Carolina at Chapel Rush University Medical Center
Charles L. Shapiro, MD Hill
Ichan School of Medicine at Mount Sinai Lari B. Wenzel, PhD
William P. Tew, MD University of California, Irvine
Liran Shlush, MD, PhD Memorial Sloan Kettering Cancer Center,
Princess Margaret Cancer Centre Weill Cornell Medical College William Wierda, MD, PhD
The University of Texas MD Anderson Cancer
Marc Shuman, MD Center
Mike Thompson, MD, PhD
USCF Helen Diller Comprehensive Cancer
Aurora Clinic
Center Peter Yu, MD
Palo Alto Medical Foundation
Sonali Smith, MD Andreas Ullrich, MD, MPH
The University of Chicago World Health Organization Andrew Zelenetz, MD, PhD
Memorial Sloan Kettering Cancer Center
John David Sprandio, MD Saad Zafar Usmani, MD
Consultants in Medical Oncology and Levine Cancer Institute/Carolinas Healthcare Clive Zent, MD
Hematology System University of Rochester

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xix


2016 Annual Meeting Supporters*
MISSION ENDOWMENT FOUNDING DONORS
Genentech BioOncology
GlaxoSmithKline Oncology
Novartis Oncology
Sanofi Oncology

MISSION ENDOWMENT SUSTAINING DONORS


AbbVie, Inc.
Amgen
Astellas
AstraZeneca
Celgene Corporation
Eisai Inc.
Gilead Sciences, Inc.
HELSINN
Incyte Corporation
Lilly
Onyx Pharmaceuticals
Sanofi Oncology
Takeda Oncology

ENDOWED FUND DONORS


Anonymous
Sally Gordon YIA Endowment Fund
Conquer Cancer Foundation of ASCO Young Investigator Award, in memory of Sally Gordon
American Society of Clinical Oncology
Jane C. Wright, MD, YIA Endowment Fund
Jane C. Wright, MD, Young Investigator Award
Friends, Family, and Colleagues of Dr. Ronald Beller and Mrs. Judith Beller
Bradley Stuart Beller Endowment Fund
Bradley Stuart Beller Merit Award
Breast Cancer Research Foundation
Evelyn H. Lauder YIA Endowment Fund
Conquer Cancer Foundation of ASCO Young Investigator Award, in memory of Evelyn H. Lauder
Celgene Corporation
John R. Durant, MD, YIA Endowment Fund
Conquer Cancer Foundation of ASCO Young Investigator Award, in memory of John R. Durant, MD
GlaxoSmithKline Oncology
Gianni Bonadonna Award and Lecture Endowment Fund
Gianni Bonadonna Breast Cancer Award and Fellowship
HELSINN
Anna Braglia YIA Endowment Fund
Anna Braglia Young Investigator Award in Cancer Supportive Care, supported by HELSINN
Friends, Family, and Colleagues of Dr. James B. Nachman
James B. Nachman Pediatric Oncology Fund
James B. Nachman ASCO Junior Faculty Award in Pediatric Oncology
Aaron and Barbro Sasson
Bertil Eriksson YIA Endowment Fund
Ake
Bertil Eriksson Endowed Young Investigator Award
Ake

* This list reflects commitments as of April 18, 2016.

xx 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


CANCERLINQ MAJOR SUPPORTERS Bayer HealthCare Pharmaceuticals Inc. Merck & Co., Inc.
Amgen Genitourinary Cancer Tracks Bundle Annual Meeting Proceedings and
Astellas Educational Book Bundle
Boehringer Ingelheim Pharmaceuticals, Inc.
AstraZeneca Best of ASCO Meetings
Best of ASCO Meetings
Bayer HealthCare Pharmaceuticals Inc. Breast Cancer Track
Lung Cancer Track
Boehringer Ingelheim Pharmaceuticals, Inc. Development Therapeutics and Translational
Cancer Treatment Centers of America Bristol-Myers Squibb Research/Clinical Trials Tracks Bundle
Chan Soon-Shiong Family Foundation Pre-Annual Meeting Seminar: Hematology Gastrointestinal (Colorectal) Cancer Track
Genentech BioOncology for the Oncologist Gastrointestinal (Noncolorectal) Cancer Track
HELSINN Genitourinary Cancer Tracks Bundle
Celgene Corporation
Janssen Oncology Head and Neck Cancer Track
Breast Cancer Track
Lilly Hematologic Malignancies Tracks Bundle
Gastrointestinal (Noncolorectal) Cancer
Raj Mantena, RPh Lung Cancer Track
Track
Novartis Oncology Melanoma/Skin Cancers Track
Hematologic Malignancies Tracks Bundle
Pfizer Oncology Pre-Annual Meeting Seminar: How to
Lung Cancer Track
Thomas G. Roberts Jr., MD, and Susan M. Integrate Tumor Immunotherapy Into Your
DaSilva Conquer Cancer Foundation & Conquer Clinical Practice
Susan G. Komen Cancer Foundation Mission Endowment Merrimack Pharmaceuticals
Cancer Survivorship Symposium Gastrointestinal (Noncolorectal) Cancer
EDUCATIONAL SUPPORT
Ferring Pharmaceuticals Track
Ambry Genetics Genitourinary Cancer Tracks Bundle Novartis Oncology
Cancer Prevention, Hereditary Genetics, Best of ASCO Meetings
and Epidemiology Track Genentech BioOncology
Breast Cancer Track
Pre-Annual Meeting Seminar: Genetics Breast Cancer Track
Gastrointestinal (Noncolorectal) Cancer
and Genomics for the Practicing Lung Cancer Track
Track
Clinician Gilead Sciences, Inc. Hematologic Malignancies Tracks Bundle
Best of ASCO Meetings Melanoma/Skin Cancers Track
Amgen
Development Therapeutics and Translational Pre-Annual Meeting Seminar: Hematology
Annual Meeting Proceedings and
Research/Clinical Trials Tracks Bundle for the Oncologist
Educational Book Bundle
Hematologic Malignancies Tracks Bundle Pre-Annual Meeting Seminar: How to
Best of ASCO Meetings
Integrate Tumor Immunotherapy Into Your
Gastrointestinal (Colorectal) Cancer HELSINN
Clinical Practice
Track Patient and Survivor Care/Health Services
Pre-Annual Meeting Seminar: New Drugs in
Hematologic Malignancies Tracks Research and Quality of Care Tracks Bundle
Oncology
Bundle
Incyte Corporation Patient Access Network Foundation
Melanoma/Skin Cancers Track
Pre-Annual Meeting Seminar: How to Annual Meeting Patient Advocate
Pre-Annual Meeting Seminar: How to
Integrate Tumor Immunotherapy Into Your Scholarship Program (2)
Integrate Tumor Immunotherapy Into
Clinical Practice
Your Clinical Practice Pharmacyclics LLC
Pre-Annual Meeting Seminar: New Drugs Janssen Oncology Hematologic Malignancies Tracks Bundle
in Oncology Patient and Survivor Care/Health Services
Pre-Annual Meeting Seminar: The TAIHO Oncology, Inc.
Research and Quality of Care Tracks Bundle
Economics of Cancer Care Gastrointestinal (Colorectal) Cancer Track
Kidney Cancer Association Pre-Annual Meeting Seminar: New Drugs in
Astellas Genitourinary Cancers Track Oncology
Best of ASCO Meetings
Lilly TESARO
Genitourinary Cancer Tracks Bundle
Best of ASCO Meetings Best of ASCO Meetings
Astellas and Genentech BioOncology Breast Cancer Track Gynecologic Cancer Track
Lung Cancer Track Development Therapeutics and Translational
Research/Clinical Trials Tracks Bundle GENERAL SUPPORT
AstraZeneca Gastrointestinal (Colorectal) Cancer Track
Best of ASCO Meetings Head and Neck Cancer Track AbbVie, Inc.
Lung Cancer Track Lung Cancer Track Annual Meeting iPlanner Mobile Application
Pre-Annual Meeting Seminar: How to Pre-Annual Meeting Seminar: New Drugs in and Website Bundle
Integrate Tumor Immunotherapy Into Your Oncology ASCO Live
Clinical Practice Sarcoma Track Young Investigator Award

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xxi


Adenoid Cystic Carcinoma Research Bristol-Myers Squibb EMD Serono Inc.
Foundation Annual Meeting Onsite Connectivity Young Investigator Award
Career Development Award in Adenoid Resources Bundle
Fibrolamellar Cancer Foundation
Cystic Carcinoma Research Patient Advocate Scholarship Program Bundle
Young Investigator Award in Fibrolamellar
American Cancer Society Celgene Corporation Research
ASCO/American Cancer Society Award and Merit Awards
Patient Advocate Scholarship Program Bundle Florida Society of Clinical Oncology
Lecture
Young Investigator Award Florida-Based
Amgen The Cholangiocarcinoma Foundation Recipient
Career Development Award Young Investigator Award in
Diversity in Oncology Bundle Gateway for Cancer Research
Cholangiocarcinoma Research (1)
International Innovation Grant Young Investigator Award
Long-Term International Fellowship Coalition of Cancer Cooperative Groups
Genentech BioOncology
Merit Awards Clinical Trials Participation Award
Career Development Award (4)
Oncology Trainee Travel Award Patient Advocate Scholarship Program
CRDF Global, National Cancer Institute, and
Patient Advocate Scholarship Program Bundle Bundle
National Science Foundation
Young Investigator Award (2) Young Investigator Award (7)
International Development and Education
ASCO and Conquer Cancer Foundation Award in Palliative Care Gilead Sciences, Inc.
Boards of Directors Annual Meeting Onsite Connectivity
Young Investigator Award, in memory of Conquer Cancer Foundation
Resources Bundle
Jane C. Wright, MD Cancer.Net
Merit Awards
Career Development Award
Young Investigator Award (2)
ASCO State Affiliate Council and ASCO Guidelines USB
Clinical Practice Committee Journal of Global Oncology Fellows Program Guardant Health, Inc.
Young Investigator Award Long-Term International Fellowship (2) Annual Meeting iPlanner Mobile Application
Medical Student Rotation for and Website Bundle
Astellas
Underrepresented Populations
ASCO Meeting Library Bundle HELSINN
Merit Awards (2)
Career Development Award Annual Meeting iPlanner Mobile Application
Patient Advocate Scholarship Program
AstraZeneca and Website Bundle
Patient Materials
Merit Awards Foundation General Mission Support
Survivorship Forum
Young Investigator Award (2) Young Investigator Award Infinity Pharmaceuticals Inc.
Avon Foundation for Women Annual Meeting iPlanner Mobile Application
Conquer Cancer Foundation Mission and Website Bundle
International Development and Education
Endowment
Award in Breast Cancer Janssen Oncology
ASCO Community Research Forum Award
ASCO Policy Fellowship Diversity in Oncology Bundle
Bayer HealthCare Pharmaceuticals Inc.
ASCO University Maintenance of Merit Awards
International Development and Education
Certification Application Young Investigator Award (2)
Award
Cancer.Net
Janssen Scientific Affairs, LLC
Boehringer Ingelheim Pharmaceuticals, Inc. International Development and Education
Career Development Award in Deep Vein
Annual Meeting Onsite Connectivity Award in Palliative Care
Thrombosis
Resources Bundle Journal of Clinical Oncology Figures Program
Young Investigator Award in Deep Vein
Annual Meeting Special Attendees Lounge Journal of Global Oncology
Thrombosis
Bundle Journal of Oncology Practice, Special Series
Patient Advocate Scholarship Program Bundle Long-Term International Fellowship (2) Journal of Clinical Oncology
Young Investigator Award (2) NCI-ASCO Teams in Cancer Care Delivery Young Investigator Award
Breast Cancer Research Foundation Project
Kidney Cancer Association
Advanced Clinical Research Award in Breast patientACCESS
Annual Meeting Merit Awards in Kidney
Cancer Quality Measurement System
Cancer
Career Development Award in Breast Cancer (2) Resident Travel Award for
Young Investigator Award in Kidney
Comparative Effectiveness Research Underrepresented Populations
Cancer
Professorship in Breast Cancer Eisai Inc.
Young Investigator Award in Breast Cancer, Annual Meeting Onsite Connectivity The John and Elizabeth Leonard Family
in honor of Susan Hirschhorn and in Resources Bundle Foundation
memory of her mother Young Investigator Award (2) Young Investigator Award

xxii 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


Lilly Strike 3 Foundation
Annual Meeting Special Attendees Lounge Young Investigator Award in Pediatric
Bundle Oncology (2)
Career Development Award
Takeda Oncology
Medical Student Rotation for
ASCO Meeting Library Bundle
Underrepresented Populations
Career Development Award
Merit Awards
International Development and Education
Patient Advocate Scholarship Program
Award
Bundle
Merit Awards
Young Investigator Award (2)
Oncology Trainee Travel Award
Lung Cancer Alliance Young Investigator Award (3)
Young Investigator Award in Lung Cancer
Teva Oncology
J. Edward Mahoney Foundation Patient Advocate Scholarship Program
Young Investigator Award Bundle

McHenry and Lisa Tichenor Fund of Triple Negative Breast Cancer Foundation
Communities Foundation of Texas Career Development Award
Young Investigator Award in Sarcoma Young Investigator Award
Research, in memory of Willie Tichenor
The WWWW Foundation Inc. (QuadW) and
Medivation The Sarcoma Fund of the QuadW
Annual Meeting Special Attendees Lounge Foundation of Communities Foundation of
Bundle Texas
Young Investigator Award in Sarcoma
Merck & Co., Inc.
Research, in memory of Willie Tichenor
Annual Meeting Program Publications
Bundle
ASCO Meeting Library Bundle
Young Investigator Award (4)

NF Nimeh, MD
International Development and Education
Award in Palliative Care
Novartis Oncology
Merit Awards
Young Investigator Award

Susan K. Parsons, MD, and Walter


Armstrong
Young Investigator Award

Pfizer Oncology
Young Investigator Award

Roche
Career Development Award
Long-Term International Fellowship

Reid R. Sacco Adolescent and Young Adult


Alliance
Young Investigator Award

Sanofi Foundation for North America


Foundation General Mission Support

Sanofi Oncology
Drug Development Research Professorship

Spectrum Pharmaceuticals
Merit Awards

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK xxiii


Letter From the Editor
O n behalf of my Associate Editor, Dr. Nate Pennell, I welcome you to the 2016 American Society of Clinical Oncology (ASCO)
Annual Meeting. It is also my distinct honor to present the 36th volume of the NLM-indexed ASCO Educational Book. This
years theme, Collective Wisdom: The Future of Patient-Centered Care and Research, sits at the heart of what we aim to do as
oncologists: improve the lives of patients with cancer. Harnessing our combined knowledge, not just the expertise of one, is how
we must deliver the highest quality of personalized care to meet the diverse needs of our patients.

Dr. Julie Vose, 20152016 ASCO President, challenged us to bring our readers a volume that reflected the multidisciplinary
aspects of cancer care, representing not only the roles of the many different types of health care providers and their specialties,
but also topics such as quality, cost, and survivorship. We answered by requesting articles authored with this interdisciplinary
view in mind, and I am pleased to say that we have more co-authored articles than ever before represented in this years
volume. To be sure, the level of effort required for this impressive collaboration of minds was no small feat, and I humbly thank
the more than 100 authors who generously took the time to write and, in some cases, revise the articles in this volume.

In the same vein, the Invited Articles in this volume illustrate how, as our knowledge of cancer evolves, we must include
various areas of expertise to transform how we deliver care to our patients, such as enlisting genetic counselors and enhancing
the role of advanced practitioners. Beyond that, applying our collective wisdom into practice also means expanding com-
munication; we must incorporate results of molecular biology into treatment plans and converse honestly with patients about
treatment costs and care expectations, among other strategies. I graciously thank the authors of these articles for their
contributions to this volume.

This year, our readers will also find a new type of article that we are calling Points of View. Articles published under this
banner describe emerging and/or controversial topics in oncology care. I believe these articles are a most valuable addition to
the volume and highlight important care considerations for our patients as well as for the field of oncology.

Lastly, I want to recognize and thank our truly remarkable expert panel who dedicated their time and effort to careful,
thorough, and thoughtful reviews. Your commitment to education and ASCOs mission cannot be highlighted enough and is
tremendously underscored by this years theme.

It is my honor to invite you to read through the exceptional contributions that comprise the 2016 volume, only a selection of
which are found in the print edition. The print edition includes a curated selection of articles that most embody the power our
collective wisdom. For access to all of the 2016 ASCO Educational Book articles, as well as access to past volumes, please visit
www.asco.org/edbook.

Nate and I welcome your feedback and suggestions on how we can improve the content, so please contact us at edbook@
asco.org with your comments.

Sincerely,

Don S. Dizon, MD
Editor in Chief

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 1


INVITED ARTICLES
This years invited articles represent the 2016 ASCO Annual Meeting theme, Collective Wisdom: The Future
of Patient-Centered Care and Research. These important contributions to the 36th volume of the ASCO
Educational Book focus on the significance of a collaborative approach to how we provide care for our
patients. The authors represent a diverse, multidisciplinary set of expertise and backgrounds.

AUTHORS
Michael P. Kosty, MD, FACO, FASCO
Scripps Clinic
La Jolla, CA

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO


Levine Cancer Institute, Carolinas HealthCare System
Charlotte, NC

Mary E. Sabatini, MD, PhD


Massachusetts General Hospital
Boston, MA

George W. Sledge, MD, FASCO


Stanford University School of Medicine
Stanford, CA
INVITED ARTICLES COLLECTIVE WISDOM

Collaborative Practice in an Era of Multidisciplinary Care


Michael P. Kosty, MD, FACP, FASCO, Todd Pickard, MMSc, PA-C, and Pamela Viale, RN, MS, CNS, ANP

T he clinical practice of oncology has become increasingly


complex. An explosion of medical knowledge, increased
demands on provider time, and involved patients have
Clear communication and transparent, defined roles and
responsibilities help ensure that care needs are addressed
and timely decisions are made. Lasting change can only come
necessitated changes in the way many oncologists practice. from explicitly helping to transform individual clinicians and
What was an acceptable practice model in the past may separate groups into a team that works together.
now be relatively inefficient. The American Society of Clinical Teams are defined as two or more people who interact
Oncologys (ASCOs) annual National Oncology Census dem- dynamically, interdependently, and adaptively to accom-
onstrates that with each successive year there is a shift plish a shared goal.7 The field of primary care has actively
away from small independent group practice to larger in- engaged in reinventing care to form a patient-centered
dependent groups or hospital-based affiliations.1-3 It is medical home.8-10 Experiments are underway to apply the
unclear whether there will be further consolidation and/or same concepts to specialty care delivery.11-16 At the same
shift, or whether the rate of change will accelerate or time, public and private payers and ASCO are proposing
continue at its current pace. Ultimately, understanding the payment models that would move away from payment
practice environment surrounding providers who care for based on specific procedures and physician contributions
patients with cancer is important to ensure that increasingly toward an approach that provides bundled payments for
complex therapies are delivered in an efficient, value-based comprehensive care and allows greater flexibility in how
setting and that all patients have access to high-quality care is organized and delivered.17 A team-based approach
cancer care. can potentially leverage these changes, provide an oppor-
The 2015 ASCO State of Cancer Care in America report tunity to reexamine clinician roles and responsibilities, and
emphasized practice trends: workforce composition, health may enable the most efficient delivery of high-quality health
systems innovation, regulatory compliance, and the financial care services. Ongoing education, training, mentorship,
realities of cancer care today.4 Among the most pressing networking, and communication are necessary to cultivate
issues the report highlighted was a growing population of and maintain a collaborative team-based practice model.
patients with cancer, increased complexity of care provided, Integration of resources from each practice setting, com-
and an oncology workforce projected to fall short of the munity organizations, e-health technologies, and advocacy
expected demand (Fig. 1). In a recent survey of 22,000 groups is essential. Human factors, health system factors,
oncologists, 11,700 medical oncologists were estimated to situational factors, and socioeconomic factors are constantly
provide direct care, managing the majority of patients with changing within the continuum of care, and they must be
cancer over extended periods of time.5 Factors contributing considered in designing tailored patient and caregiver
to this predicted shortfall of providers and increasing support (Fig. 2).6 The National Cancer Institute (NCI) and
complexity of cancer care delivery are shown in Sidebar 1.6 ASCO have collaborated to bring clinicians, patient advo-
Efficient multimodality therapy requires coordinated care cates, and researchers together to explore application of the
delivery among many diverse groups of clinical providers as evidence of team effectiveness to clinical practice. This
patients move along the continuum of cancer carefrom project fits into the larger context of the transformation of
risk assessment, prevention, diagnosis, treatment, and sur- health care delivery and payment models. The NCI-ASCO
veillance to survivorship and care of advanced cancer. Teams in Cancer Care Delivery project was presented at
Within any given clinic, increasingly complex therapies the NCI-ASCO Teams in Cancer Care Delivery Workshop
require clinicians with advanced, specialized training. in February 2016. Their findings will be published in the

From the Scripps Green Cancer Center, Scripps Clinic, La Jolla, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Physiological Nursing, University of
California, San Francisco, San Francisco, CA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Michael P. Kosty, MD, FACP, FASCO, Scripps Green Cancer Center, Scripps Clinic, 10666 North Torrey Pines Rd., MS217, La Jolla, CA 92037; email: mkosty@
scripps.edu.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 3


KOSTY, PICKARD, AND VIALE

FIGURE 1. Baseline Projected Supply of and Demand Shulman18 suggested several goals for integrating advanced
for Oncologist Visits, 2005 to 20205 practice providers (APPs) into collaborative practice
in oncology: (1) improved patient care, (2) increased
clinical productivity, (3) improved access for patients,
(4) urgent care patient treatment, (5) long-term care of
patients with cancer, and (6) coverage for the academic
physician. 6 The oncology APP is a licensed health care
professional who has completed advanced training in
nursing or pharmacy or has completed training as a physician
assistant.
The use of APPs to help meet the workforce demands and
improve the quality and coordination of care has been one of
the proposed solutions since the ASCO board of directors
approved the initial workforce strategic plan in 2008. The
utilization of APPs in oncology practices can increase
practice efficiency, productivity, and professional satisfac-
tion of collaborating oncologists.19 The APPs role is diverse
and includes both inpatient and outpatient settings. Recent
Journal of Oncology Practice. In the context of increasingly publications have highlighted the practice of physician as-
complex care requirements, increasing demand, and de- sistants who provide intensive palliative care on inpatient
creasing physician and economic resources, how do we create a units through an interdisciplinary team model.20 Similarly,
collaborative team-based practice model that allows for the nurse practitioners have published their experiences as an
provision of high-quality, value-based oncology care? inpatient malignant hematology nurse practitioner service
working within a collaborative and multidisciplinary model.21
The utilization of APPs on an allogeneic stem cell transplant unit
INTEGRATING ADVANCED PRACTICE PROVIDERS resulted in decreased length of stay and reduced hospital
INTO ONCOLOGY PRACTICE charges with similar patient outcomes.22 Towle and col-
The cost of care is a primary concern in oncology today. leagues23 suggested similar roles for the APP in a collaborative
Collaborative practice models that provide mecha- practice model. These included (1) assisting patients during
nisms for revenue generation and reduce unnecessary treatment visits; (2) pain and symptom management; (3)
costs to patients through application of clinical practice follow-up care for patients in remission (survivorship care); (4)
guidelines will promote patient and provider satisfaction. patient education and counseling; (5) end-of-life care; and (6)

SIDEBAR 1. Factors Affecting the Demand and Complexity of Cancer Care6


1. Implementation of the Affordable Care Act has resulted in an increasing number of individuals gaining access to health care.
2. An aging population has Medicare as their primary insurance.
3. The number of cancer survivors is growing related to improvements in cancer detection, risk-adapted treatment strategies,
supportive care, and palliative care.
4. Increasing costs of care are resulting in a shift in practice models and the integration of formalized programs for preauthorization
and reimbursement.
5. The oncology workforce is aging (50% over the age of 50), with a shift toward group practices in urban settings (. 90%).
6. Cancer care initiatives are being set as standards of care or required for certification necessary to achieve designation or improve
revenue.
7. Meaningful Use benchmarks are being developed for the use of electronic health records and patient-reported outcomes and their
impact on physician productivity.
8. The American College of Surgeons Commission on Cancer published Cancer Program Standards 2012: Ensuring Patient-Centered
Care, which established new requirements around patient-centered needs and is expanding the focus on improving the quality of
care and patient outcomes. More recently, the Commission on Cancer has set a standard for distress screening for every patient
with cancer and their caregivers across the continuum of care.
9. Survivorship care: The Institute of Medicine, ASCO, and the Commission on Cancer have set guidelines for survivorship care. Cancer
survivors are projected to exceed 19 million by 2024.
10. Palliative care: The Institute of Medicine released its report, Improving Palliative Care for Cancer, in 2000. ASCO published
a provisional clinical opinion in 2012, recommending that palliative care be integrated into the care of every patient with cancer at
the time of diagnosis. The National Consensus Project put forth its Clinical Practice Guidelines for Palliative Care, a set of nationally
recognized guidelines that include quality measures and the eight domains of palliative care. The National Comprehensive Cancer
Network published the first clinical practice guidelines for palliative care in 2013.

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COLLABORATIVE PRACTICE IN AN ERA OF MULTIDISCIPLINARY CARE

FIGURE 2. Collaborative Practice Relationships can help meet future demand is unclear because the current
and projected workforce of APPs in oncology has been
challenging to determine. Based on census data from 2013,
the American Academy of Physician Assistants (AAPA) re-
ported that there were an estimated 2,140 practicing
physician assistants in adult medical, surgical, and radiation
oncology subspecialties.2 This represented a 25% increase
compared with 2010 census data.3 However, important
characteristics such as age, geographic distribution, education,
years of experience, and years to expected retirement are un-
known. Similar challenges are faced when trying to describe
the nurse practitioner workforce in oncology. The American
Association of Nurse Practitioners (AANP) publically reports
survey data for licensed nurse practitioners. In 2013, of the
more than 205,000 licensed nurse practitioners, approxi-
mately 2,050 worked in oncology and had been in practice for
an average of 7.7 years and had a median age of 48.25
Varied collaborative practice models are currently in use
based on the needs of the practice, patient volume, skills, and
training of the physician and the APP. Each has implications for
billing and productivity. The key to efficient integration of an
APP in oncology into a collaborative practice model is a careful
Collaborative practice in oncology is a dynamic process focused on assessment of skills and knowledge about oncology practice.
interdisciplinary support of patients and their caregivers with a broad range of
health care providers. The AP in oncology plays a critical role in the collaborative At a high level, potential roles of an APP include enabling
treatment of patients and their caregivers. Ongoing education, training, physicians to focus on more complex and higher acuity
mentorship, networking, and communication are necessary to cultivate and
maintain a collaborative practice model. Integration of resources from each patient needs; extending the range of high-level services for
practice setting, community organizations, e-health technologies, and advocacy patients without using additional physician time; and pro-
groups is essential. Human factors, health system factors, situational factors, and
socioeconomic factors are ever-changing within the continuum of care and must viding follow-up, symptom management, and survivorship
be considered in designing tailored patient and caregiver support.6 care to patients. To accomplish this, three models of care
Abbreviations: AP, advanced practice provider.
Reprinted with permission from the Advanced Practitioner Society for utilize APPs in the team-based care setting: (1) the auton-
Hematology and Oncology. omous or independent visit model, in which APPs pre-
dominantly see patients independently in a clinic but under a
ordering chemotherapy. The underlying theme in these collaborative practice agreement with their physicians; (2)
publications is that a collaborative practice model, with on- the shared visit model, in which patients are seen by both
cologists and APPs in oncology working together to the extent the APP and the physician during the same clinical en-
of their training and licensure, can improve patient and pro- counter; and (3) the mixed visit model, in which both the
vider satisfaction and safety and increase productivity and independent and shared visit models are used to manage the
revenue.24,25 However, the degree to which the use of APPs clinical volume but neither is the predominant encounter

FIGURE 3. Collaborative Practice Models Represented by the APSHO Practice Survey (192 patients)6,27

Abbreviation: APSHO, Advanced Practitioner Society for Hematology and Oncology.

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KOSTY, PICKARD, AND VIALE

used.26 The independent visit practice model goal is not to APPs as the most common reason not to use them in their
supplant or replace physician involvement but to allow practice.23 Exploring potential reasons for this lack of in-
physicians to delegate these tasks and medically direct terest is important to determine how to best motivate at-
without a required physical presence at the time of service. titudinal change. Because the ASCO report was primarily
The shared visit model goal is to allow for combining physician-owned private practices (73%) with only 8% sur-
the individual efforts of the APPs and physicians into a veyed in academic practice, it is possible this lack of interest
comanaged service that allows physicians to increase patient was based on the fear of decreased physician compensation.
volumes and the medical services they provide. This model It has been shown that the private practice model has
allows physicians to be continuously involved and to dele- significantly more oncologists compensated on an incentive-
gate aspects of the services provided to the APP. The col- based model compared with academic models (39.3% vs.
laborative practice models represented by the Advanced 3.1%). 28 Therefore, it may be important to focus on the
Practitioner Society for Hematology and Oncology (APSHO) increased practice productivity when using APPs to
practice survey are shown in Figure 3. encourage utilization in private practice. Furthermore,
To examine the differences between the different models, because a pure incentive-based model is associated with the
Buswell et al26 reported the effect of these practice models highest rate of burnout, increased professional satisfaction
on productivity, fees, and provider and patient satisfaction when working with APPs can be another educational point to
in an academic cancer center. They found that productivity change perceptions.
for the independent, mixed, and shared visit models, as Other challenges to incorporating APPs into clinical
measured by the number of new and established patients, practice are largely historical or based more on personal bias
was similar for all models (6.8, 6.7, and 7.0 patients seen than fact.29 For example, data do not substantiate the belief
per 4-hour session, respectively). Both physician and APPs that utilizing APPs will negatively affect the physician-
were very satisfied with the independent visit model and provider relationship or that patients will not accept APPs
reported patient-centered and productivity-based reasons as part of the care team. Studies have demonstrated high
influencing the decision to use their chosen model. The levels of patient and provider satisfaction with the collab-
shared visit model physicians were still very satisfied with orative practice model with increased utilization nation-
the model whereas APPs were only moderately satisfied. ally.23 It is likely that the portion of the workforce nearing
Reasons for utilizing the shared visit model were more retirement is also the same group that has less experience
physician-centered, focusing on physician preferences and and understanding of the physician assistant and nurse
perceptions. Importantly, there were extremely high levels practitioner professions and, therefore, more perceived
of patient satisfaction for both models (100% satisfaction bias. This attitude is changing as new oncologists entering
with care received from either model). the workforce come with experience working with APPs
In a much larger study in the private practice setting, the during their fellowship. In a survey of fellowship program
results of the ASCO study of collaborative practice arrange- directors in 2011, 90% of medical directors reported that
ments similarly noted high levels of patient and provider their fellows work with physician assistants and nurse
satisfaction with the different APP models.23 The most com- practitioners.30 What is unclear is how well prepared these
mon model in the survey was the independent visit model. The oncologists are to lead a medical team that incorporates
independent visit model was 19% more productive (based on APPs. It will be important moving forward for oncologists to
relative value units, RVUs) when the APP worked with the understand the different models for APP utilization, as well
entire group of physicians as compared with an independent as the regulatory and reimbursement requirements to lead
visit model when the APP worked exclusively with a limited the medical team effectively. Ideally, this educational need
number of physicians. However, it may not be correct to will be incorporated into fellowship training programs be-
conclude that the most productive RVU model is the ideal fore new oncologists enter the workforce and then will be
model in which to use APPs. Further insight into measures of further refined at the practice level based on state laws and
quality and continuity of care of the two models would be institutional policies.
important to distinguish. In addition, using RVUs as the sole
productivity measure is a limited assessment of the value an
APP might add to a practice. This study did not take into ac- Productivity and Reimbursement
count the nonrevenue-generating activity performed for each It is generally accepted that practices that incorporate APPs
model, which could be important in defining the preferred are more productive and efficient in providing quality care to
practice model. Value is not only about revenue generation; patients than practices that do not. However, as practices
quality of care and clinical productivity also are important and work to integrate APPs into clinical practice, they have been
might enhance physician quality of life.6,27 challenged with accurately assessing the productivity and
value of individual APPs. Practices that use a system strictly
BARRIERS TO INTEGRATION based on RVUs will likely underestimate the productivity and
Provider and Patient value of APPs because of the inability to accurately measure
ASCOs study of the collaborative practice arrangements of RVUs. For example, global surgical visits and the shared visit
APPs identified physicians lack of interest in working with model will render the time and effort of the APP invisible.31

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COLLABORATIVE PRACTICE IN AN ERA OF MULTIDISCIPLINARY CARE

Even in the independent visit model, all incident-to visits and 30% to 50% higher than APPs, incident-to billing reimbursed
visits for many commercial payers are billed under the at 100%, and the savings on APP reduced recruitment and
physicians national provider identifier, despite all care being retention costs.
provided by the APP. In addition, numerous clinical care Currently, ASCO is exploring a project to assess the con-
activities that APPs provide are not billable encounters, but tribution of APPs in oncology practices. This project has
they bring quality and value to the practice. Importantly, if several goals: (1) count the number of APPs working in
the APP does not complete these nonrevenue-generating oncology practices; (2) identify the mix of direct patient care
activities, the physician would have to complete them. The services and other work that APPs conduct in oncology
challenges in assessing the productivity of APPs and the practices; (3) investigate the clinical, economic, and patient
limited benchmarking data available affect the ability to not effect of APPs in oncology practices; and (4) estimate how
only improve productivity of the APPs, but it also will hinder current and future APP workforces will affect the shortage
increased utilization. Practices will struggle to determine that exists between demands for services and the number of
when to hire new APPs and decide how their time should be physician oncology providers.
allocated to support the clinical enterprise. Also, practice
managers inherently will be unable to determine equitable
compensation, comparison, and accountability of APPs CONCLUSION
within a practice. Collaborative, multidisciplinary teambased care is es-
As to reimbursement, several common myths and sential if patients are to receive the highest quality value-
misconceptions can stymie the expansion of APPs in based oncology care. Achieving this goal will require ef-
oncology. Impressions such as APPs cant see new pa- fective integration of APPs into all aspects of patient care.
tients or APPs cant bill above a certain level are easily Although barriers remain, many are perceptual and rel-
debunked with a little education and, if needed, support atively easy to overcome. Understanding the APP work-
from national advocacy organizations. However, one of force, pipeline, and current utilizationas well as the
the more challenging misconceptions is the over- clinical, economic, and patient impact of APPs in oncology
estimation that the 85% reimbursement rate of the APPs practiceswill facilitate achieving the goal of optimal
compared with the physician rate will have on the cost- patient-centered cancer care. More information on the
effectiveness of APPs. Numerous studies on physician scope of practice of APPs, state regulations, payer policy,
assistants and nurse practitioners have demonstrated and information on integration into oncology practices
that APPs are cost-effective health care providers. This can be found on the AAPA, Association of Physician As-
can be explained by physician salaries being consistently sistants in Oncology, AANP, and APSHO websites.

References
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J Oncol Pract. 2013;9:9-19. 10. Jackson GL, Powers BJ, Chatterjee R, et al. Improving patient care: the
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17. Kosty MP, Bruinooge SS, Cox JV. Intentional approach to team-based 24. Brown CG. Commentary: new findings substantiate the successful use
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8 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


INVITED ARTICLES COLLECTIVE WISDOM

Value in Oncology: Balance Between Quality and Cost


Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, and Mark W. Legnini, DrPH

I t is a disturbing fact that the costs of health care are


spiraling upwards and that an exemplar of this troubling
trend is the domain of oncology treatment and research. By
were publicly funded (34.1% Medicare and 5.3% Medicaid);
resulting federal scrutiny of health care spending meant
Washington policy makers measures of success often
2020, it is projected that cancer care will cost more than became political and ideological footballs. Lobbying by the
$150 billion annually in the United States. Although this re- health care industry to protect economic interests has
presents only a relatively small fraction of total health care produced self-serving success stories, some from the
cost, cancer care is escalating more rapidly than most other pharmaceutical and device industries and others from
specialties. Many factors contribute to this unhappy situa- providers of care locked in competition for patients and
tion, including the aging of the population, persistence of revenues. The advocacy research behind these success
risk-taking by the community at large (smoking, excessive stories is frequently cited but often unvalidated and diverts
sun exposure, and lack of attention to industrial pollution, attention from a proper focus on the patient. Thus, oncol-
to name a few), increasingly expensive research, diagnostic ogists must address the challenges of responding to the
tests, surgical approaches, radiotherapy techniques, and communitys evolving requirements for greater value, with-
novel systemic therapies as well as some unrealistic expec- out loss of innovation, in a more proactive, creative, and
tations of patients, families, and the community at large (often structured fashion to preserve quality while attempting to
predicated on false claims from our profession and/or hype contain expense.
from the Fourth Estate). Of clear relevance is the consid- At its simplest, the value proposition in health care has
eration that another political declaration of war on cancer, been defined by Porter and Teisberg2,3 with the following
the third in 40 years, this time an amalgam of the State of the equation:
Union address and some opportunism from the biomedical
Value Outcomes=Cost
community, is unlikely to fix the problem. Although this type
of hyperbole might increase focus, and even funding, it will This equation makes sense and is routinely used in planning
create a renewed sense that death is optional and will en- the strategy of cancer care for our health care systems in the
courage patients and their physicians to continue futile at- Carolinas and Michigan, as it helps us to consider what is
tempts at active treatment of truly resistant disease, rather contributing to poor value in cancer care and allows reso-
than considering palliative care with its associated improve- lution of those elements that are accessible. Of key impor-
ment in quality of life and reduction in cost. tance is to critically consider the true benefits of the use of
A more sensible approach is to weave the concept of our diagnostic and treatment modalities, defining whether
value-based medical care into the equation, thus leveraging they contribute to prolongation of survival, increased quality
resource expenditure in a more productive and sensible way of life, or reduced morbidity of disease or its treatment, and
than has characterized much of modern medicine. However, also whether the most cost-efficient options are chosen.
one of the more substantial challenges in modern oncology In addition, Porter and Teisburg2,3 have emphasized the
practice is to provide true increase in value when so many important principles of transparency, provision of com-
new parameters of success are being introduced into the prehensive disease management and prevention services,
equation. Health care spending to treat cancer rose 55% in organization around medical conditions, and redefinition of
the decade from 2001 to 2011, and annual retail prescription the health plan/subscriber relationship (with an end to cost-
drug expenditures for cancer quintupled over the same shifting practices) as potential solutions to the current
period.1 Almost 40% of expenditures for cancer care in 2011 dysfunction in the provision of health care.

From the Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; University of Michigan Medical School, Institute for Healthcare Policy & Innovation, Ann Arbor, MI.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Dr., Charlotte, NC 28204;
email: derek.raghavan@carolinas.org.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 9


RAGHAVAN AND LEGNINI

The prospect of cancer treatment is daunting for most EXPERIMENTS IN THE DELIVERY OF
patients when one considers the nature of the treatment VALUE-BASED CANCER CARE
being offered and its potential consequences. In addition, Toward Symmetry of Care in the Carolinas
asymmetry of medical information, potential fiscal toxicity, Charlotte, the largest city in North Carolina, with a pop-
and dislocation of patients and their families for treatment ulation approaching 1 million (and a referral base of around
far from their homes mean patients lose control over their 2 million people) has not had local access to a comprehensive
lives, compounding their anxiety over a cancer diagnosis and cancer center. Specifically, there has been paucity of locally
the treatment that follows. The provision of symmetrical available bone marrow transplant facilities and of phase I
(i.e., evenly distributed) access to high-quality care, by and investigator-initiated clinical trials, although the latter
overcoming barriers of poverty, language, geographical have been intermittently available on a small scale. Qua-
isolation, and information while providing the key advances ternary cancer services have been provided by outstanding
in modern oncology, with a greater emphasis on palliative cancer centers at Emory, Duke, Wake Forest, and The
care optimization, should improve national cancer survival University of North Carolina at Chapel Hill, but have often
and morbidity figures without continuing to increase the required travel of more than 3 to 4 hours for geographically
strain on federal and state budgets.4,5 A focus on universally isolated patients and for those living in Charlotte who
distributed access contrasts with the continued reluc- have needed more specialized cancer services. Carolinas
tance of some medical institutions to accept indigent, un- HealthCare System, an amalgam of more than 40 hospitals
derinsured, Medicaid, or even Medicare patients, thus and medical centers spanning North Carolina and South
protecting their bottom lines from loss, an approach that is Carolina, employs more than 2,000 physicians and 50,000
unfair to the community.3 In addition to creating maldis- staff and sees more than 15,000 new cancer cases per year.
tribution of the costs of providing care, cherry-picking of the As the system has expanded to be one of the largest
wealthiest, most educated, and robust patients (who also nonprofit health systems in North America, it made sense
usually have the strongest health insurance coverage) may to establish a tertiary and quaternary referral cancer
lead to biased representation of outcomes. These centers center that would serve its network of smaller centers
publish data drawn from treatment of star patients, who throughout the Carolinas, but which would attempt to
have fewer of the adverse prognosticators and comorbid- provide a system of cancer care closer to the patients
ities of unselected patient populations, leading to inflated home, contrary to some of the more conventional models.
survival figures and artificially reduced morbidity and tox- In design, several criteria were deemed crucial and in-
icity data. Sadly, many politicians and community leaders corporated into the creation of this multisite institute, as
may fail to understand this nuance when they translate the summarized in the Sidebar.
resulting highly selected data into expectations for the Our strategy for the system throughout the Carolinas has
population at large, thus distorting the concept of true value. been to link with selected hospitals and their staffs,
Successful provision of symmetrical, high-quality out- establishing contractual relationships with the hospital
comes also requires easily accessible tertiary and quaternary leadership and personal and professional relationships with
level cancer care close to home, with access to clinical trials, their physicians, which includes the provision of centrally
extensive patient support and navigation, optimal palliative controlled Levine Cancer Institute clinical trial units. Where
and supportive care, and the benefits of the genomic rev- needed, additional faculty members have been recruited
olution as elements of routine cancer care.1,5 It also has to be from a range of other academic cancer centers. Academic
refined by the establishment of an evidence-based, system- and programmatic leadership has been drawn from National
wide set of standards for diagnosis and treatment, which are Cancer Institutedesignated comprehensive cancer centers,
routinely used by physicians. and trained clinical investigators have been placed at out-
In many major centers, following the innovative approach reach centers to ensure symmetry of access to trials. We
of Fox Chase Cancer Center in the Delaware Valley, outreach have thus created a hybrid academic-practice model, and
clinics have been established as a mechanism to provide this has led to dramatic increments in cancer trial accrual and
easier intake to attract new patients and provide access to maintenance of patient care in distant geographic sites, with
cancer trials. However, many of these ventures have not improved access to tertiary and quaternary facilities, often
been designed to provide all of the key resources, such as via telemedicine.
access to translational trials with laboratory and bio-
repository support, genetic counseling, and patient-family
support, for these geographically isolated patients. Strategies in Play in Michigan
In the United States in recent times, less than 5% of pa- The Michigan Value Collaborative provides 65 hospitals
tients have been enrolled in cancer clinical trials,6,7 and it is statewide with data and tools to help them control costs for
clear that there are noteworthy disparities of access to high- episodes of care, including colorectal cancer resection,
level cancer programs.4 We are now attempting to address esophagectomy, lung cancer resection, and prostatectomy,
these challenging issues in the Carolinas8 and in Michigan, up to 90 days postdischarge. This includes the initial
two areas challenged by considerable geographical and hospitalization plus skilled nursing, rehabilitation, home
demographic constraints. health, transfers/readmissions, etc. The Michigan Value

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VALUE IN ONCOLOGY: BALANCE BETWEEN QUALITY AND COST

SIDEBAR. Criteria for a Symmetrical System of Cancer Care


Multidisciplinary clinics with standard operating procedures and protocols of management, embedded in electronically linked,
evidence-based clinical pathways
System-wide interdisciplinary tumor boards and conferences, augmented by electronic two-way video conferencing to connect
geographically isolated oncology teams
Easy availability of clinical trials, with access close to home throughout North Carolina and South Carolina
A single, central institutional review board for cancer trials covering the whole system, facilitating swift and synchronous, system-
wide activation of studies
Central protocol review and monitoring system, with initial protocol submissions via tumor-specific teams
Central oversight of a tightly controlled clinical trials unit, with central training and monitoring of staff
Centralized connections and data capture for each hospital tumor registry with ability to measure outcomes and costs of care
Extensive patient support services, including patient navigation linked throughout the system, standard operating procedures for
emergency departments throughout the system, palliative care and pain management services, cancer-focused pastoral care, and live
or video-linked genetic counseling and financial counseling
Availability of subspecialty services, such as bone marrow transplantation, phase I clinical trial units, and sophisticated radiation
techniques and equipment in as accessible a fashion as possible
A focus on translational bench research that is focused specifically on the clinical emphases of the instituteearly programs have
focused on cancer pharmacology, stem cell biology of hematologic disorders, and molecular prognostication with availability of a
cost-effective, molecular testing platform where appropriate
Optimal informatics technology support and electronic and video linkage for conferencing, tumor boards, and creation of electronic
pathways in tumor-specific team meetings

Collaborative creates a unique window for hospitals to see discontinuation of these diagnostic or management ap-
charges generated for a patients care outside their four proaches would not result in reduced outcomes and in some
walls, an essential tool for cost-effective care coordination. cases (e.g., screening for prostate cancer in elderly men with
In addition, Collaborative Quality Improvement initia- intercurrent diseases and limited life expectancy) could
tives around the state share clinical process and outcomes actually improve survival and/or morbidity. As can easily be
data to improve outcomes for patients receiving surgical, appreciated from Table 1, nationwide implementation of
radiation, and medical oncology services. Together, these these recommendations has achieved dramatic cost savings,
programs provide clinical and claims-based registries (price- without measurable loss of quality or outcomes.
standardized and risk-adjusted), web-based analytic tools, These items were chosen because they reflected clinical
and forums across the state for practicing physicians and practice among most oncologists and thus would avoid
hospital quality improvement staff to work on individ- partisan subspecialty rivalries and concerns, were broadly
ual improvement and collectively to make Michigan a applicable to large numbers of patients, and also clearly
better place for patients with cancer to receive treatment. reflected the absence of a robust evidence base un-
Combining episode costs (the value equations denominator) derpinning patterns of standard clinical practice.
with clinical outcomes data from collaborative quality im- With the growing evidence on producing high value for
provements (the numerator) gives Michigans hospitals one health expenditure, we will increasingly need to consider
of the countrys best opportunities to improve the value of clinical practices that have evolved without evidence to
cancer care. support a survival or quality-of-life benefit and must focus on
whether the treatments selected have equi-active but less
costly alternatives (e.g., use of generic drugs, biosimilars,
CHOOSING WISELY
and lower doses of cytotoxics, reduced treatment duration
One of the most important aspects to reduction of un-
of radiotherapy, and elimination of heroic but unproven
necessary expenditure in oncology is the consideration of
surgical procedures). In each case, the driver is cost con-
what is gained by the use of the available management
tainment or avoidance of profligate expenditure without
approaches. The Institute of Medicine has encouraged
loss of quality or outcomes.
physicians to carefully consider the benefits and drawbacks
associated, in particular, with expensive management op-
tions in the so-called Choosing Wisely campaign. In line MEASUREMENT OF VALUE
with this philosophy, the American Society of Clinical On- In 2015, the ASCO Value Task Force published the Conceptual
cology (ASCO) created the Value Task Force and developed Framework for Assessing Value in Cancer Care.11 The basic
two consensus documents,9,10 based on the best available construct is as follows:
evidence, that proposed discontinuation of standard
clinical practices that provided no patient benefit (Table 1).
Two major contextual categories are created, advanced
disease (e.g., treatment of metastases) and curative
In each instance, level 1 to 2 evidence clearly showed that intent (e.g., adjuvant therapy).

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RAGHAVAN AND LEGNINI

Clinical benefit is given a score of 1 to 5, and then


numerical weightings are added to reflect the impact of
position paper.12 What is quite remarkable is the extraor-
dinary similarity in concept and execution, achieved by two
treatment on overall survival, progression-free survival, committees working in the United States and in Europe, both
or response rate. The weightings reflect the thought without knowledge of the work in progress of the other
that overall survival is more important than progression- team. The ESMO team also has focused on separate domains
free survival, which is more important than response of curative and palliative settings and attributed levels of
rate when attempting to attribute value for the patient. benefit predicated on absolute or relative increments in
Negative scores are added to reflect the extent of survival and levels of toxicity. Of importance, they have set
toxicity. In the advanced disease setting, bonus points time-dependent criteria, such that the value points allocated
are awarded for palliation of symptoms and for longer for absolute survival increments differ for those with sus-
treatment-free intervals. Finally, the cost of treatment is tained increases versus the less fortunate patients with only
short-term increments in survival.
listed to broaden the context.
Interestingly, both committees used similar sets of level 1
In the adjuvant setting, instead of the response-survival
parameters above, hazard ratio is incorporated into the
data to develop their models and came to quite similar
interpretations of value, notwithstanding different com-
algorithm, and disease-free interval is substituted, but munity pressures, health care costs, and medical traditions
with a slightly lower weighting. on different sides of the Atlantic.
The overall construct of net health benefit is incorpo-
rated to allow the patient to attribute likely value to the
These efforts are important and represent crucial first
steps by members of our profession in attempting to in-
treatment, balancing benefit(s) and toxicities. crease the level of self-discipline and value-based self-
Unbeknownst to the ASCO Task Force, the European criticism of what we do and increased transparency in
Society for Medical Oncology (ESMO) had also created a what we tell our patients about the benefits of treatment.
similar task force, which produced the Magnitude of Clinical We would have preferred a higher bar with regard to at-
Benefit Scale. Led by Dr. Nathan Cherny, the ESMO position tribution of value pointsit is obvious that a patient with a
paper was published at about the same time as the ASCO prognosis of only 3 to 6 months will sustain greater relative

TABLE 1. ASCO Choosing Wisely List

Topic Rationale Level of Cost Savings*


Do not use cancer Rx if PS 3 to 4, no prior benefit, Logical, maximizes QOL, no loss of proven survival Extensive at individual and national level
ineligible for trial, and no evidence to support benefit
more Rx
No extensive staging for low-risk early prostate Overview of published data shows extremely low Extensive at national level
cancer positive yield within false-positive rate.
No extensive staging for low-risk early breast Overview of published data shows extremely low Extensive at national level
cancer positive yield within false-positive rate.
No surveillance via biomarkers or imaging for No survival benefit from early diagnosis of metastatic Extensive at individual and national level
breast cancer after curative Rx (excludes relapse
mammography)
No white cell stimulatory prophylaxis for Risk of febrile neutropenia is predictable for low-risk Extensive at national level
patients with < 20% risk of febrile patients; in high-risk patients, prophylaxis should
neutropenia be considered
Avoid starting antinausea prophylaxis with most Effective options are available for control of regimens Extensive at national level
expensive high-risk drugs for low-risk at low-risk of emesis; crossover can easily be
emetogenic regimens affected if vomiting occurs
Avoid combination chemotherapy for salvage Single-agent Rx is an effective salvage option and Extensive at individual and national level
Rx of metastatic breast cancer unless urgent usually associated with less toxicity
response is required
Avoid post-Rx routine surveillance with PET or No data to support survival benefit of this approach Extensive at individual and national level
CT-PET scanning after completion of Rx unless for most clinical settings
evidence shows survival benefit
Avoid screening asymptomatic men with PSA Randomized data do not support survival benefit Extensive at national level
for prostate cancer if < 10 years of life from screening for prostate cancer and may cause
expectancy harm in elderly
Do not use targeted therapy against specific Very low response rate to most targeted Rx unless Extensive at individual and national level
gene aberration unless biomarker predicts specific target is expressed by tumor
likely response
Abbreviation: Rx, prescription; PS, pain scale; QOL, quality of life; PSA, prostate-specific antigen.
*Individual reflects potential for substantial copays or expensive self-pay. National reflects costs associated with specific service delivery as well as incidence/frequency figures at
national level.

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VALUE IN ONCOLOGY: BALANCE BETWEEN QUALITY AND COST

benefit from a 2-month increment than someone treated professional lives. One way to transform training is to ensure
with curative or aggressive palliative intent; that said, a that teaching programs are located in care settings in which
2-month survival increment, offset by considerable physical residents see high-value care delivered every day. This will
or fiscal toxicity, needs to be taken into context. This is require that funding for graduate medical education be
complex, paradigm-shifting work and will require careful value-based to provide incentives for training programs to
and critical attention and feedback. change. Together, the federal Medicare program and a
majority of state Medicaid programs contribute approxi-
TRAINING THE NEXT GENERATION OF mately $14 billion annually to fund graduate medical edu-
PHYSICIANS TO INCORPORATE THE VALUE cation, based primarily on counts of trainees and residency
PROPOSITION program accreditation. If these payments were value-based,
Training oncology residents to provide high-value care is key that would be a strong incentive for programs to ensure that
to transforming the practice of oncology in the United succeeding cohorts of oncologists emerge from training
States.13 Current policies to improve the performance of imbued with the concept of value in health care and
health care practitioners and the institutions in which they equipped with the tools to provide safe, high-quality, cost-
practice depend primarily on financial incentives aimed at effective cancer care.
changing the behavior of fully-trained physicians. This is
much less effective than intervening earlier in the workforce
pipeline to influence physicians during their training and SUMMARY
professional socialization. The exponential increase in costs of health care is un-
Expressed simply, residents who do not train in high-value necessary and reflects many avoidable factors at a com-
care settings are less likely to become high-value physi- munity level, including poor health practices, unrealistic
cians.13 Residency faculty must be skilled in the organization expectations, corporate profiteering, and a poor medical
and delivery of high-value care and in how to teach those decision process (which often contravenes level 1 to 2 ev-
skills. idence). Physicians must increasingly consider true value
Exhortations without systems transformation will not (outcome/cost ratio) when creating management plans and
break the cycle of teaching each generation of oncologists include these considerations in transparent and realistic
outmoded ways of thinking about safety, quality, and cost- conversations with patients. Attention to these issues will
effectiveness during residency, when their decision making dramatically reduce the burgeoning costs of cancer care in
habits, professional values, ways of interacting with pa- our community while improving the quality and value of
tients and colleagues, etc., are shaped for the rest of their care.

References

1. Soni A. Trends in Use and Expenditures for Cancer Treatment among 8. Raghavan D. Costs of cancer care: rhetoric, value, and steps forward.
Adults 18 and Older, U.S. Civilian Noninstitutionalized Population, 2001 Semin Oncol. 2013;40:659-661.
and 2011. Medical Expenditure Panel Survey, Statistical Brief #443. 9. Schnipper L, Smith TJ, Raghavan D, et al. American Society of Clinical
http://meps.ahrq.gov/mepsweb/data_files/publications/st443/ Oncology identifies five key opportunities to improve care and reduce
stat443.pdf. Accessed February 23, 2016. costs: the top five list for oncology: ASCOs top five list. J Clin Oncol.
2. Porter ME, Teisberg EO. How physicians can change the future of health 2012;30:1715-1724.
care. JAMA. 2007;297:1103-1111. 10. Schnipper LE, Lyman GH, Blayney DW, et al. American Society of Clinical
3. Porter ME, Teisberg EO. Redefining Health Care. Boston, MA: Harvard Oncology 2013 top five list in oncology. J Clin Oncol. 2013;31:
Business School Press; 2006;97-283. 4362-4370.
4. Raghavan D. Slow progress in cancer care disparities: HIPAA, PPACA, 11. Schnipper LE, Davidson NE, Wollins DS, et al; American Society of
and CHEWBACCA... but were still not there! Oncologist. 2011;16: Clinical Oncology. American Society of Clinical Oncology statement:
917-919. a conceptual framework to assess the value of cancer treatment op-
5. Goss E, Lopez AM, Brown CL, et al. American Society of Clinical Oncology tions. J Clin Oncol. 2015;33:2563-2577.
policy statement: disparities in cancer care. J Clin Oncol. 2009;27: 12. Cherny NI, Sullivan R, Dafni U, et al. A standardised, generic, validated
2881-2885. approach to stratify the magnitude of clinical benefit that can be an-
6. Lara PN Jr, Higdon R, Lim N, et al. Prospective evaluation of cancer ticipated from anti-cancer therapies: the European Society for Medical
clinical trial accrual patterns: identifying potential barriers to enroll- Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol.
ment. J Clin Oncol. 2001;19:1728-1733. 2015;26:1547-1573.
7. Raghavan D. An essay on rearranging the deck chairs: whats wrong with 13. Legnini, MW. Can low-performing hospitals train high-performing
the cancer trials system? Clin Cancer Res. 2006;12:1949-1950. residents? Am J Med Qual. 2011;26:408-410.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 13


INVITED ARTICLES COLLECTIVE WISDOM

Womens Health Issues for BRCA Mutation Carriers


Mary E. Sabatini, MD, PhD, and Leif W. Ellisen, MD, PhD

I n 2015, it was estimated that there were 1.6 million new


cases of cancer diagnosed in the United States.1 Remarkably,
more than 86,000 were diagnosed in women under the age
25. Breast screening should begin by age 25 with MRI.
Earlier MRIs are also considered if any family member
was diagnosed with breast cancer before age 25. Annual
of 45. The majority of cancers are thought to be a result of mammography and MRI starts at age 30. Risk-reducing
bad luck; that is, random mutations arising during DNA mastectomy should be offered as an option to all BRCA
replication in normal stem cells,2 whereas inherited muta- mutation carriers, as it has been shown to reduce the risk
tions are thought to be causal in 5%10% of cancers. Thus, of cancer by as much as 90%, although definitive studies
the number of cancer cases that are attributable to inherited showing either an overall or breast cancerspecific sur-
mutations may seem small, however, they are clinically vival advantage are lacking. In contrast, risk-reducing bi-
important. Cancers in patients with hereditary cancer syn- lateral salpingo-oophorectomy (rrBSO) at age 35 to 40
dromes tend to occur at a younger age, and most hereditary or whenever childbearing is completed is associated with a
cancer syndromes are also associated with more than one lower risk of breast cancer and reduces all-cause, ovarian
type of cancer.3 cancerspecific, and breast cancerspecific mortality.9
Approximately 20% of women with inherited breast and/ rrBSO results in an 80% risk reduction for ovarian, fallopian
or ovarian cancers harbor a harmful mutation of one of the tube, and peritoneal cancers. There has been recent interest
breast cancer susceptibility genes 1 or 2, known as BRCA1 and in the possibility of performing salpingectomy only, as it
BRCA2.3,4 Mutations in BRCA1/2 are inherited in an autosomal seems that some ovarian cancers may arise primarily in the
dominant fashion. Families that carry germline mutations may fallopian tube, but this is not recommended other than in
have several women affected by breast and possibly ovarian the setting of a clinical trial. Hysterectomy is not routinely
cancer and men with breast cancer and prostate cancer. These recommended given that the absolute risk of endometrial
mutations also predispose carriers to cancers such as fallopian cancer is low enough that the benefits do not outweigh the
tube cancer, peritoneal cancer, endometrial cancer, pancreatic risks of surgery. For those who do not elect for rrBSO,
cancer, colon cancer, and cancers in other sites. Although there ovarian cancer screening with transvaginal ultrasound and
are many issues for BRCA mutation carriers who have been carbohydrate antigen 125 (CA-125) is suggested every
diagnosed with cancer, this article will focus on the care of 6 months starting at age 30. Notably, however, there are no
women who are known carriers but who have not been di- data to support the efficacy of this practice.
agnosed with cancer. The NCCN guidelines are established by incorporating
For BRCA1 mutation carriers, cumulative estimates of the best evidence available to date. However, in caring for
developing cancer by age 70 vary by population, ranging women who do carry a deleterious BRCA mutation, one of
from 40% to 85% for breast cancer and 10% to 59% for the major challenges is trying to help an individual patient to
ovarian cancer. For BRCA2 mutation carriers, cumulative make decisions using data obtained from studying pop-
estimates of developing cancer are 45% to 57% for breast ulations. Like most autosomal-dominant mutations, pene-
cancer and 11% to 18% for ovarian cancer.5-7 Because of trance of a BRCA mutation is not 100%. The probability of
these risks, the National Comprehensive Cancer Network developing cancer for carriers is alarmingly high, yet the
(NCCN) has established guidelines for women with BRCA morbidity associated with surveillance and/or prevention
mutations to reduce the risk of cancer.8 This includes breast is also not negligible. Furthermore, taking steps toward
awareness and breast self-examinations starting at age 18, prevention does not absolutely eliminate the risk of
with annual to biannual clinical examinations starting at age cancer development. Decision making can be empowering,

From the Department of Obstetrics and Gynecology, Harvard Medical School, Massachusetts General Hospital, Boston, MA; Breast Medical Oncology, Harvard Medical School,
Massachusetts General Hospital Cancer Center, Boston, MA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Mary E. Sabatini, MD, PhD, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114; email: msabatini@mgh.harvard.edu.

2016 by American Society of Clinical Oncology.

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WOMENS HEALTH ISSUES FOR BRCA MUTATION CARRIERS

as indicated by the New York Times opinion article written women with BRCA mutations. One recent survey study
by Angelina Jolie.10 Nonetheless, decisions can be anxiety described the reaction of 25 male partners about their fe-
provoking, particularly when the consequences of the male partners mutation status.16 Twenty of the men were
wrong decision are so large and life altering. married or engaged at the time of the survey, and 19 had
Unfortunately, knowledge of ones mutation and the NCCN been in the relationship at least 5 years. Nine participants
guidelines does not necessarily enable an individual to plan reported changes regarding intimacy levels, and two re-
ones life accordingly. In an ideal world, perhaps every woman spondents reported changes in their level of attraction.
who carried a BRCA mutation would have completed child- Almost all participants noted changes in their commu-
birth prior to age 35. Indeed, younger age at first birth and nication after mutation disclosure, with changes in the
breast-feeding are protective for development of breast and topics discussed and more discussions about the future.
ovarian cancers overall. Additionally, in an ideal world, there Interestingly, of the 14 men whose partners had not un-
would be no repercussions to mastectomy and early surgical dergone a risk-reducing mastectomy, five expressed concerns
menopause. However, these ideals run counter to the realities about their level of attraction to their partner, but of the 11
of life for many. In high-income countries, the median age of men whose partner had had a mastectomy, all said that they
first birth is rising,11 with many women not starting a family were as attracted to their partner after surgery as they were
until after their 35th birthday. Surgery and surgical menopause before surgery. It is difficult to generalize the results of this
can cause morbidity and can be life altering. study broadly, as most of these men were in long-term or
A retrospective study including 305 BRCA mutation carriers committed relationships at the time of the survey.
seen in a California integrated health system between 1995 In general, reproductive options for all women have vastly
and 2012 showed that the uptake of options for BRCA mu- expanded in the past several years, and this may also benefit
tation carriers who were informed of the NCCN guidelines was those who carry a BRCA mutation. For women who are not
lacking in some areas. The median follow-up during the yet ready to have children, in vitro fertilization (IVF) can be
study was 41 months. The median time from diagnosis to risk- used to freeze either oocytes or embryos for future use.
reducing surgery was 6 months, with 74% of patients choosing Embryo cryopreservation has been available since the 1980s,
to undergo rrBSO and 44% of patients choosing to undergo and outcomes have improved dramatically in the last several
risk-reducing mastectomy. Of those choosing surveillance, years. For couples with infertility and a female partner
compliance was 45% in the first year but decreased to younger than age 35, expected pregnancy rates after a single
approximately 10% at 3 years and 2% at 5 years.12 IVF are upwards of 50%.17 For couples with unknown fertility
Decisions about prophylactic surgery are complicated interested in banking embryos for future use, there are no
by concerns about appearance, sexuality, control of re- numbers to guide us, but presumably the success rate would
production, and relationships. A retrospective study by be at least as good if not higher. Oocyte freezing is available
Stukey et al13 highlights that these decisions among carriers to women who are unpartnered, unwilling to use donor
are not, as might be anticipated, based on risk alone. Ninety sperm, or who wish to maintain complete autonomy of their
women, all of whom were carriers of BRCA mutation, were reproductive potential. Historically, oocyte freezing has been
offered prophylactic surgery. Fifty-one percent of the technically more challenging. Although embryo freezing
women underwent surgery, 85% underwent BSO, and 28% remains the gold standard, this will likely change in the near
underwent mastectomy. Women who elected to have future as success rates with frozen oocytes are approaching
surgery were more likely to be parous, married, employed, those of frozen embryos.17
and had a prior history of breast cancer. This implies that Although embryo and oocyte preservation provide op-
those who did not elect for prophylactic surgery may be tions, IVF is expensive, arduous, and time consuming. It
interested in future fertility. BRCA2 mutation carriers were comes with risks including hemorrhagic cysts, ovarian tor-
more likely than BRCA1 carriers to pursue surgery. If sion, ovarian hyperstimulation syndrome, blood clots, in-
avoidance of developing disease were the only factor in- fections, medication reactions, and surgical risks associated
volved in decision making, BRCA1 carriers should be more with oocyte extraction. For these reasons, it is not univer-
likely to undergo surgery. sally available or used. Overall, IVF has not been associated
Hoskins et al14 described 11 cases of unmarried women with an increased risk of development of breast or ovarian
age 26 to 35 who carry a BRCA mutation. These women cancer18-22 in the general population or in BRCA mutation
relayed challenges regarding their perception of their own carriers.23,24 The data for the general population are quite
desirability and anxiety about partners reactions to dis- robust as a result of the length of availability of IVF and the
closure of mutation status. Another web-based survey of 44 number of people who have used IVF. For those with BRCA
women with a BRCA mutation included 13 women who were mutations, however, the numbers are smaller and not as
unmarried, and all of them expressed concerns about how robust, so the conclusions are not as definitive.
and when to disclose their status to future partners. Most of One of the most challenging issues for women who carry
them expressed a sense of urgency to have children.15 a BRCA mutation surrounds the choice about the potential
Considering the anxiety expressed about the effect of their to eliminate this mutation from future offspring. Pre-
own BRCA mutation on their relationships, very little data implantation genetic diagnosis (PGD) is a procedure in which
exist regarding the attitudes of the sexual partners of a cell or cells from a human embryo are removed and tested

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SABATINI AND ELLISEN

for diseases and/or mutations that can result in disease (for surgical menopause happens at an earlier age than does
example, cystic fibrosis, Huntington disease, BRCA mutation). natural menopause. As such, menopausal symptoms, the
PGD requires IVF. The resulting embryos are allowed to grow effects of hormonal changes, and their treatment should be
for 3 to 5 days so there are enough cells to be biopsied for PGD. discussed with women prior to surgery. Menopause is as-
Embryos found by biopsy to be unaffected (on average ap- sociated with hot flashes, sleep disturbances, and changes in
proximately 50%) can be transferred into the womans uterus mood. Women often have a decline in libido and sexual
with the hope that a normal pregnancy will be established. satisfaction and have vaginal changes that result in difficulty
Affected embryos generally are not transferred and can be with intercourse; early menopause may also dramatically
disposed per a couples wishes. impact bone and cardiovascular health.35,36
The topic of PGD can raise a number of social and ethical There are several medical and alternative treatments that
debates. A recent large survey study of the general population can be used to mitigate the effects of menopause; the most
showed that approximately 70% of respondents were sup- effective of these is hormone replacement therapy (HRT)
portive of PGD for diseases that were lethal in early childhood or containing estrogen. The use of HRT in women with BRCA
caused lifelong disability (e.g., cystic fibrosis), yet only 48% mutation can be somewhat of a contentious subject. Currently,
supported it for screening embryos for diseases that strike later most of the literature does not show an increased risk of breast
in life (e.g., BRCA-associated cancers or Huntington disease).25 cancer following rrBSO for BRCA carriers who use HRT.37,38
Another survey assessed the attitudes about PGD among Women who use HRT report less discomfort with intercourse
women with BRCA mutations and/or hereditary cancer syn- and a higher quality of life than nonusers.39 Again, because of
dromes. Of the 52 respondents, 75% thought that PGD was an the absence of long-term studies, the lack of randomization,
acceptable option for those with BRCA mutation.26 Interestingly, and the variations in treatments used, it is still difficult to
though, of the respondents who had completed family building, counsel patients about the safety of HRT. Any woman who
only 37.5% would have used this option for themselves, and for has a uterus should also be counseled about the use of pro-
those who did not yet have children, only 14% stated they would gestin for endometrial protection. This also may impart a higher
consider using PGD. Thirty-five percent of the respondents risk of breast cancer based on previous data,40,41 but how this
stated they worried about the use of PGD because they assume applies to those with BRCA mutations is unclear.
that the effectiveness of screening and prevention for women In a recent article about her BRCA status and medical
with BRCA mutation will improve with time. decisions, Angelina Jolie said, Life comes with many chal-
Choices about the use of birth control and/or any other lenges. The ones that should not scare us are the ones we can
hormone treatments can also be complicated for BRCA take on and take control of.10 In that article, Jolie speaks
carriers. Oral birth control pills (OCPs; containing either much about her family, her partner, and her children, which
estrogen and progestin or just progestin) are the most no doubt gave her clarity on her health decisions. She did not
common form of reversible contraception used world- mention anything about PGD, so we are unclear about her
wide.27 A very large cohort study showed that in the general determination regarding this issue. Jolie also has vast access
population OCPs are not associated with an increased risk to medical care and, thus, has many treatment options. For
overall for cancer, and OCP users had a reduced risk of many women, lifes circumstances do not make decisions so
ovarian, endometrial, and colorectal cancers.28 OCP use has, clear. Decisions can be empowering, but they can also bring
however, also been linked to a trend toward increased risk of about stress and anxiety. Fortunately, most of the studies
breast cancer, but studies are conflicting.29-32 The literature show that women who undergo risk-reducing surgery are
regarding OCP use for BRCA carriers is similar.33,34 Therefore, satisfied with their decision.42,43 Unfortunately, there are
the choice about use of OCPs must be individualized and very few studies that assess womens satisfaction with their
account not only for BRCA status but also other health issues choices about nonintervention or appraise womens feelings
and reproductive goals. over long periods of time. Much additional work is needed to
Surgical menopause causes a more dramatic drop in help patients and the medical community deal effectively
systemic levels of ovarian hormones than the gradual de- with these complex issues. Even with strong data, decision
cline that occurs with natural menopause. Additionally, for making can be complicated; but without data, it is all the
BRCA carriers who undergo rrBSO per NCCN guidelines, more difficult.

References
1. American Cancer Society. Cancer Facts & Figures 2015. www.cancer.org/ 3. American Cancer Society. Family Cancer Syndromes. www.cancer.org/
research/cancerfactsstatistics/cancerfactsfigures2015. Accessed Novem- cancer/cancercauses/geneticsandcancer/heredity-and-cancer. Accessed
ber 12, 2015. January 8, 2016.
2. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk 4. Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting
among tissues can be explained by the number of stem cell divisions. paradigms in personalized cancer care and prevention. Science. 2014;
Science. 2015;347:78-81. 343:1466-1470.

16 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


WOMENS HEALTH ISSUES FOR BRCA MUTATION CARRIERS

5. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and 25. Winkelman WD, Missmer SA, Myers D, et al. Public perspectives on the
ovarian cancer associated with BRCA1 or BRCA2 mutations detected in use of preimplantation genetic diagnosis. J Assist Reprod Genet. 2015;
case series unselected for family history: a combined analysis of 22 32:665-675.
studies. Am J Hum Genet. 2003;72:1117-1130. 26. Menon U, Harper J, Sharma A, et al. Views of BRCA gene mutation
6. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. carriers on preimplantation genetic diagnosis as a reproductive option
J Clin Oncol. 2007;25:1329-1333. for hereditary breast and ovarian cancer. Hum Reprod. 2007;22:
7. Mavaddat N, Peock S, Frost D, et al; EMBRACE. Cancer risks for BRCA1 1573-1577.
and BRCA2 mutation carriers: results from prospective analysis of 27. United Nations. Population Facts. www.un.org/en/development/desa/
EMBRACE. J Natl Cancer Inst. 2013;105:812-822. population/publications/pdf/popfacts/popfacts_2013-9.pdf. Accessed
8. National Comprehensive Cancer Network Clinical Practice Guidelines in January 14, 2016.
Oncology. Genetic/Familial High-Risk Assessment. Version 2. 2015. 28. Hannaford PC, Selvaraj S, Elliott AM, et al. Cancer risk among users of
www.nccn.org/professionals/physician_gls/pdf/genetics_screening. oral contraceptives: cohort data from the Royal College of General
pdf. Accessed January 8, 2016. Practitioners oral contraception study. BMJ. 2007;335:651.
9. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing 29. Oral-contraceptive use and the risk of breast cancer. The Cancer and
surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and Steroid Hormone Study of the Centers for Disease Control and the
mortality. JAMA. 2010;304:967-975. National Institute of Child Health and Human Development. N Engl J
10. Jolie A. My Medical Choice. www.nytimes.com/2013/05/14/opinion/ Med. 1986;315:405-411.
my-medical-choice.html. Accessed February 6, 2016. 30. Hankinson SE, Colditz GA, Manson JE, et al. A prospective study of oral
11. Finer LB, Philbin JM. Trends in ages at key reproductive transitions in contraceptive use and risk of breast cancer (Nurses Health Study,
the United States, 1951-2010. Womens Health Issues. 2014;24: United States). Cancer Causes Control. 1997;8:65-72.
e271-e279. 31. Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and
12. Garcia C, Wendt J, Lyon L, et al. Risk management options elected by the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.
women after testing positive for a BRCA mutation. Gynecol Oncol. 2014; 32. Vessey M, Yeates D. Oral contraceptive use and cancer: final report from
132:428-433. the Oxford-Family Planning Association contraceptive study. Contra-
13. Stuckey A, Dizon D, Scalia Wilbur J, et al. Clinical characteristics and ception. 2013;88:678-683.
choices regarding risk-reducing surgery in BRCA mutation carriers. 33. McLaughlin JR, Risch HA, Lubinski J, et al; Hereditary Ovarian Cancer
Gynecol Obstet Invest. 2010;69:270-273. Clinical Study Group. Reproductive risk factors for ovarian cancer in
14. Hoskins LM, Roy K, Peters JA, et al. Disclosure of positive BRCA1/2- carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet
mutation status in young couples: the journey from uncertainty Oncol. 2007;8:26-34.
to bonding through partner support. Fam Syst Health. 2008;26: 34. Iodice S, Barile M, Rotmensz N, et al. Oral contraceptive use and breast
296-316. or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer.
15. Hamilton R. Being young, female, and BRCA positive. Am J Nurs. 2012; 2010;46:2275-2284.
112:26-31, quiz 46, 32. 35. Mercuro G, Zoncu S, Saiu F, et al. Menopause induced by oophorectomy
16. Mauer C, Spencer S, Dungan J, et al. Exploration of male attitudes on reveals a role of ovarian estrogen on the maintenance of pressure
partnerships and sexuality with female BRCA1/2 mutation carriers. homeostasis. Maturitas. 2004;47:131-138.
J Genet Couns. Epub 2015 Aug 8. 36. Lobo RA. Surgical menopause and cardiovascular risks. Menopause.
17. SART CORS. Clinic Summary Report 2013. www.sartcorsonline.com/ 2007;14:562-566.
rptCSR_PublicMultYear.aspx?ClinicPKID=0. Accessed January 21, 37. Madalinska JB, Hollenstein J, Bleiker E, et al. Quality-of-life effects of
2016. prophylactic salpingo-oophorectomy versus gynecologic screening
18. Rizzuto I, Behrens RF, Smith LA. Risk of ovarian cancer in women treated among women at increased risk of hereditary ovarian cancer. J Clin
with ovarian stimulating drugs for infertility. Cochrane Database Syst Oncol. 2005;23:6890-6898.
Rev. 2013;8:CD008215. 38. Kotsopoulos J, Huzarski T, Gronwald J, et al. Hormone replacement
19. Sergentanis TN, Diamantaras AA, Perlepe C, et al. IVF and breast cancer: therapy after menopause and risk of breast cancer in BRCA1 mutation
a systematic review and meta-analysis. Hum Reprod Update. 2014;20: carriers: a case-control study. Breast Cancer Res Treat. 2016;155:
106-123. 365-373.
20. Gennari A, Costa M, Puntoni M, et al. Breast cancer incidence after 39. Johansen N, Liavaag AH, Tanbo TG, et al. Sexual activity and functioning
hormonal treatments for infertility: systematic review and meta- after risk-reducing salpingo-oophorectomy: impact of hormone re-
analysis of population-based studies. Breast Cancer Res Treat. 2015; placement therapy. Gynecol Oncol. 2016;140:101-106.
150:405-413. 40. Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influ-
21. Zhao J, Li Y, Zhang Q, et al. Does ovarian stimulation for IVF increase ence of estrogen plus progestin on breast cancer and mammography in
gynaecological cancer risk? A systematic review and meta-analysis. healthy postmenopausal women: the Womens Health Initiative Ran-
Reprod Biomed Online. 2015;31:20-29. domized Trial. JAMA. 2003;289:3243-3253.
22. Kessous R, Davidson E, Meirovitz M, et al. The risk of female malig- 41. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of
nancies after fertility treatments: a cohort study with 25-year follow-up. estrogen plus progestin and estrogen alone: analyses of data from 2
J Cancer Res Clin Oncol. 2016;142:287-293. Womens Health Initiative Randomized Clinical Trials. JAMA Oncol.
23. Gronwald J, Glass K, Rosen B, et al; Hereditary Breast Cancer Clinical 2015;1:296-305.
Study Group. Treatment of infertility does not increase the risk of 42. Borreani C, Manoukian S, Bianchi E, et al. The psychological impact of
ovarian cancer among women with a BRCA1 or BRCA2 mutation. Fertil breast and ovarian cancer preventive options in BRCA1 and BRCA2
Steril. Epub 2015 Dec 14. mutation carriers. Clin Genet. 2014;85:7-15.
24. Perri T, Lifshitz D, Sadetzki S, et al. Fertility treatments and invasive 43. Finch A, Narod SA. Quality of life and health status after prophylactic
epithelial ovarian cancer risk in Jewish Israeli BRCA1 or BRCA2 mutation salpingo-oophorectomy in women who carry a BRCA mutation: a re-
carriers. Fertil Steril. 2015;103:1305-1312. view. Maturitas. 2011;70:261-265.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 17


INVITED ARTICLES COLLECTIVE WISDOM

Collective Wisdom: Lobular Carcinoma of the Breast


George W. Sledge, MD, FASCO, Anees Chagpar, MD, and Charles Perou, PhD

B reast cancer researchers have a longstanding fascination


for infiltrating lobular carcinomas. Second in frequency
only to ductal adenocarcinomas, these tumors are charac-
decreased E-cadherin mRNA levels were uniformly observed
in ILC cases. In total, 63% of ILC cases had an E-cadherin
mutation, and 95% of ILC cases had loss when mutation, DNA
terized by unique histopathology and (among breast can- copy number, and low gene and/or protein expression were
cers) distinctive clinical biology, both in the primary and summed together. It is reassuring that this modern study
metastatic settings. Early hints regarding the underlying reaffirmed the primacy of E-cadherin loss in lobular breast
sources of this peculiar cancer, in particular the important cancer, and if a biomarker were to be chosen to identify ILC
role of E-cadherin loss, have now been confirmed through on a molecular level, it would likely be low E-cadherin
comprehensive molecular portraits of the disease. These protein expression and/or DNA mutation of CDH1. Lobu-
molecular observations, in turn, go far to explain how lobular lar carcinomas unique histopathologic features and its
carcinomas play out in the clinic, both as regards local metastatic patterns undoubtedly have their origins in their
control and therapeutic response to systemic therapy. To- impoverished E-cadherin status.
gether, the collective wisdom of the laboratory and the Beyond previously reported CDH1 and PIK3CA mutations
clinic paint an interesting portrait of this fascinating disease. (which occur at a 48% frequency in ILC), the TCGA study
identified a number of novel ILC-enriched recurrent muta-
tions targeting FOXA1, PTEN, RUNX1, and TBX3. FOXA1
MOLECULAR BIOLOGY OF LOBULAR function is particularly intriguing, as it works with the es-
CARCINOMAS trogen receptor (ER) to drive the transcriptional output of
Invasive lobular breast carcinoma (ILC) is the second most ER. Interestingly, FOXA1 also plays a similar role in prostate
prominent histologic form of breast cancer and accounts for cancer, but in these cancers its cofactor is the androgen
10%15% of invasive breast tumors. On a molecular level, receptor.2 In ILC, we find an increased incidence (9% in ILC vs.
lobular breast cancers are a distinct disease type and should 2% in IDC) of FOXA1 mutations, whereas in IDC, we find that
be considered as a unique disease. These molecular un- GATA3 mutations are considerably enriched in IDC luminal
derpinnings were recently intensely studied as part of The tumors (19% IDC vs. 5% ILC). Within ILC tumors, FOXA1
Cancer Genome Atlas (TCGA) effort on breast cancer, mutations were found to cluster into a specific region of the
including a recent publication focused on lobular breast forkhead (FK) domain. A broader analysis of FOXA1 muta-
cancers.1 In this publication, 817 breast tumors from the tions in breast and prostate cancer, in which it is also re-
TCGA project, including 490 invasive ductal cancers (IDCs), currently mutated, confirms two specific hotspots in the FK
127 ILCs, and 88 samples with a mixed IDC-ILC histology, domain and the C-terminal transactivation domain. In-
were molecularly profiled on six genomic platforms to de- terestingly, these mutational classes were associated with
velop a comprehensive portrait of the genetic, epigenetic, higher FOXA1 messenger RNA and protein expression, and
transcriptional, and proteomic landscape of lobular breast with unique transcriptional changes suggesting different
cancers. Comprehensive multiplatform analyses, both su- functional effects.3 More work into why FOXA1 is mutated in
pervised and unsupervised, of ILC tumors and across his- ILC, but GATA3 is mutated in IDC, is needed and could
tologic subtypes were performed to identify genomic possibly reveal some important underlying biology.
drivers of ILC oncogenesis. Another important finding concerning ILC was the in-
As expected, low expression of E-cadherin protein, as creased incidence of phosphatase and tensin homologue
determined by reverse-phase protein array (RPPA), and (PTEN)-inactivating events. When including both mutations

From the Division of Oncology, Stanford University School of Medicine, Stanford, CA; Yale University, New Haven, CT; The University of North Carolina at Chapel Hill, Chapel
Hill, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: George W. Sledge, MD, Stanford University School of Medicine, 269 Campus Dr., CCSR-1115, Stanford, CA 94305; email: gsledge@stanford.edu.

2016 by American Society of Clinical Oncology.

18 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


LOBULAR CARCINOMA OF THE BREAST

and DNA copy number changes, ILC-luminal A showed a 13% TABLE 1. Imaging Concordance With Pathologic
PTEN altered phenotype compared with 3% in IDC-luminal A Tumor Size (Correlation Coefficient)
tumors. This increased mutation frequency of PTEN loss in
ILC correspond with decreased PTEN protein expression and Study MRI Mammography Ultrasound Clinical Exam
was largely mutually exclusive with PIK3CA mutations. Anal- Boetes et al25 0.81 0.34 0.24
yses of RPPA protein and phosphor-protein expression data Francis et al 26
0.87 0.79 0.56 0.89
demonstrated increased phosphoinositide-3 kinase/Akt signal- Kepple et al27 0.88 0.71
ing as evident by increased levels of phosphorylated Akt (pS473 Kneeshaw et al28 0.86 0.47
and pT308) and downstream Akt substrates including p-p27 and 29
Munot et al 0.97 0.66 0.67
p-p70S6 kinase in ILC tumors; these findings may represent a
potential therapeutic opportunity for patients with ILC.
In terms of gene-expression patterns, ILC was found to be conservation are more likely to result in local recurrences13;
of the luminal A subtype in 83% of the cases. Within this ILC- however, this has not been borne out in other studies,9,10,14
luminal A subset, additional expression subtypes were also and long-term survival rates are no different between breast
identified. These included a subset enriched for stromal and conservation and mastectomy.15 Hence, both are consid-
extracellular matrix features, often referred to as the re- ered appropriate in terms of surgical management for this
active subtype.4 Another ILC expression subtype was en- disease. Of note, invasive lobular histology falls into the
riched for immune cell features/infiltrates, whereas the American Society for Radiation Oncologys cautionary
third group showed a more proliferative expression signa- subgroup for the use of accelerated partial breast irradia-
ture and a concomitant worse patient outcome. Finally, a tion,16 given concerns regarding higher ipsilateral breast
multiplatform analysis of the mixed histology tumors tumor recurrences in this population.
showed that approximately 80% of these samples could
clearly be molecularly classified as either ILC or IDC, with Lymph Node Evaluation
only a few showing a possibly hybrid phenotype. This could Besides tumor extirpation from the breast, the other key task
have important implications for treatment of patients with of the breast surgeon is lymph node evaluation. Although it is
mixed ILC-IDC histology, as it suggests they are not a unique clear that sentinel node biopsy is feasible and accurate in
group, but instead that their molecular features could be patients with ILC, the ability to find micrometastatic deposits
used to classify them as either ILC or IDC. particularly on intraoperative evaluation with hematoxylin and
eosin staining alone may be challenging given the discohesive
SURGICAL ASPECTS OF LOBULAR CARCINOMA nature of the neoplastic cells. Some pathologists have not
ILC is a distinct subtype of breast cancer that is deserving of found this to be problematic.17 Others, however, may rec-
particular attention by surgeons. ILCs tend to be insidious ommend deferral of final diagnosis to permanent sections, at
as a result of their lack of E-cadherin, causing noncohesive which time immunohistochemistry can be used to draw at-
neoplastic cells that permeate through tissue in a single-file tention to deposits that otherwise could be missed.18
pattern. Given its biology, a few areas are of particular
concern for surgeons. SYSTEMIC THERAPY FOR LOBULAR CARCINOMA:
CHEMOTHERAPY
Response to Neoadjuvant Therapy
Preoperative Imaging Increasingly, neoadjuvant chemotherapy is part of the mul-
It is clear that the extent of ILCs tend to be underestimated tidisciplinary approach to breast cancer, as more novel ther-
by conventional imaging (Table 1). Some have suggested apeutics are being evaluated in this setting. However,
that MRI may be useful in this context5; however, a recent physicians and patients should be aware that response rates to
meta-analysis found that MRI did not significantly reduce neoadjuvant chemotherapy are lower for ILC than for its ductal
positive margin rates in patients with ILC undergoing breast counterpart, as illustrated by the lower rates of pathologic
conservation.6 The concept that MRI could also find occult complete response and breast conservation (Table 2).
contralateral disease has also been raised; however, ILCs are Why is neoadjuvant chemotherapy relatively ineffective for
no more likely to have a synchronous contralateral cancer lobular carcinomas? Is it something intrinsic to the biology of
than are IDCs.7 MRI is therefore not routinely recommended lobular carcinomas per se? Mathieu et al19 have argued that
in the presurgical workup of patients with ILCs.8 this relative futility is predictable, in that histologic and bi-
ologic factors predicting a poor response to chemotherapy
Breast-Conserving Surgery Versus Mastectomy (low histologic grade, high ER content and bcl-2 expression,
Regardless of whether neoadjuvant chemotherapy is used or and low proliferative rates as measured by Ki67 and negative
not, ILCs are more often associated with positive margins p53 staining) are all more frequent in lobular rather than
after breast-conserving surgery.911 Patients with this his- ductal carcinomas. These, in turn, reflect the luminal A
tologic subtype are more likely to require re-excision, and nature of most lobular carcinomas, discussed above.
potentially mastectomy, for margin clearance.12 Some have There is a much smaller body of data evaluating neoadju-
suggested that invasive lobular cancers treated with breast vant hormonal therapy for lobular carcinoma. Dixon et al20

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 19


SLEDGE, CHAGPAR, AND PEROU

TABLE 2. Response to Neoadjuvant Chemotherapy


Study No. Patients pCR (%) p Value BCS (%) p Value
Truin et al30 IDC: 3,622 20.2 , .0001 39.4 , .0001
ILC: 466 4.9 24.4
Loibl et al31 Non-ILC: 7,969 17.4 , .001 71.1 , .0001
ILC: 1,051 6.2 59.1
Lips et al32 IDC: 601 25 .01 46 .037
ILC: 75 11 33
Wenzel et al33 IDC: 124 20 .009 79 .001
ILC: 37 3 51
Tubiana-Hulin et al34 IDC: 742 9 .002 48 .0004
ILC: 118 1 30
Cocquyt et al35 IDC: 101 15 .0066 50 NS
ILC: 26 0 38
Abbreviations: pCR, pathologic complete response; BCS, breast-conserving surgery; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; NS, not significant.

evaluated the responsiveness of lobular carcinomas to neo- TEAM trial design in that early switch (2 to 3 years of ta-
adjuvant letrozole in 61 patients treated for 3 months. Mean moxifen followed by 2 to 3 years with an aromatase inhibitor)
tumor volume reduction was 66%, with a high rate of breast and up-front (5 years with an aromatase inhibitor) strategies
conservation (81%). Although we lack any head-to-head com- were compared for relative benefit in lobular and invasive
parisons of neoadjuvant endocrine therapy with neoadjuvant ductal cancers. The TEAM analysis suggested that endocrine
chemotherapy (and may never see such a comparison), a pri- therapy efficacy was similar for IDC and ILC once one had
mary endocrine approach does not seem unreasonable. adjusted for ER content. The early switch strategy arm might
well muzzle the treatment interactions seen in the BIG 1-98 trial.
If, as suggested by the BIG 1-98 analysis, lobular carci-
RESPONSE TO HORMONAL THERAPY nomas are relatively less sensitive to tamoxifen than ductal
If lobular carcinoma is relatively resistant to standard chemo- carcinomas, what molecular changes might underlie these
therapeutic agents, and if this is largely as a result of predictable findings? Sikora et al23 have recently evaluated the response
biology (i.e., higher ER and lower proliferative rates), then what of lobular carcinoma cell lines in vitro. Their work suggests
about adjuvant hormonal therapy? Recent data suggest that that the ER drives a unique program of gene expression in
not all hormonal therapies are equal where lobular cancer is lobular cancers when compared with ductal carcinomas.
concerned. In particular, tamoxifen appears to be considerably Indeed, tamoxifen appears to drive the growth of these cell
less effective than aromatase inhibition for lobular cancers. lines, rather than inhibiting them, although this limited cell
Metzger Filho et al21 compared the relative efficacies of line work cannot be safely extrapolated to the clinic.
tamoxifen and letrozole for lobular and ductal carcinomas in In contrast to the preclinical results seen with tamoxifen,
the BIG 1-98 trial. This trial was among the first randomized Arthur et al24 have recently demonstrated in the neo-
controlled trials of aromatase inhibitor therapy in the ad- adjuvant hormonal therapy setting that changes in gene
juvant setting and now has relatively long follow-up (median expression in response to letrozole were highly similar be-
8.1 years). Comparing patients by histologic subtype, patients tween responding ILC and IDC tumors.
with ILC were far more likely to benefit from letrozole than
tamoxifen, regardless of whether patients were luminal A CONCLUSION
or luminal B like. The 8-year disease-free survival estimate Infiltrating lobular carcinoma of the breast represents a bi-
was 66% for tamoxifen compared with 82% for letrozole in ologically distinct subset of breast cancer, a biology defined
the ILC subset (hazard ratio [HR] 0.48) and was 75% for by specific genetic aberrations in E-cadherin, the high
tamoxifen and 82% for letrozole in the IDC subset (HR 0.80). prevalence of ER-positive disease, the relatively low fre-
The test for interaction was significantly positive (p = .006). quency of HER2-positive disease, and specific mutational
These seem, on the face of it, to represent a clinically sig- events revealed by deep sequencing of ILC genomes. This
nificant difference and are paralleled by overall survival distinctive biology, in turn, affects the presentation, treat-
differences (74% for tamoxifen compared with 89% for ment, andpotentiallythe prognosis of ILC. Biology af-
letrozole in the ILC subset [HR 0.40]; 84% for tamoxifen and fects surgery and preoperative chemotherapy results, and,
88% for letrozole in the IDC subset [HR 0.73]). as recent data suggest, it also affects adjuvant hormonal
In contrast, van de Water et al22 have examined the ad- therapy benefits. Ultimately, an improved understanding of
juvant TEAM (Tamoxifen and Exemestane Adjuvant Multi- ILC biology should also lead to novel targeted approaches to
national) trial. This analysis differed considerably in that the the conquest of the disease.

20 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


LOBULAR CARCINOMA OF THE BREAST

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14. Ott OJ, Hildebrandt G, Potter R, et al. Accelerated partial breast 31. Loibl S, Volz C, Mau C, et al. Response and prognosis after neoadjuvant
irradiation with interstitial implants: risk factors associated with chemotherapy in 1,051 patients with infiltrating lobular breast carci-
increased local recurrence. Int J Radiat Oncol Biol Phys. 2011;80: noma. Breast Cancer Res Treat. 2014;144:153-162.
1458-1463. 32. Lips EH, Mukhtar RA, Yau C, et al; I-SPY TRIAL Investigators. Lobular
15. Fodor J, Major T, Toth
J, et al. Comparison of mastectomy with breast- histology and response to neoadjuvant chemotherapy in invasive breast
conserving surgery in invasive lobular carcinoma: 15-year results. Rep cancer. Breast Cancer Res Treat. 2012;136:35-43.
Pract Oncol Radiother. 2011;16:227-231. 33. Wenzel C, Bartsch R, Hussian D, et al. Invasive ductal carcinoma and
16. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast invasive lobular carcinoma of breast differ in response following
irradiation consensus statement from the American Society for Radi- neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF. Breast
ation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:987-1001. Cancer Res Treat. 2007;104:109-114.
17. Horvath JW, Barnett GE, Jimenez RE, et al. Comparison of intraoperative 34. Tubiana-Hulin M, Stevens D, Lasry S, et al. Response to neoadjuvant
frozen section analysis for sentinel lymph node biopsy during breast chemotherapy in lobular and ductal breast carcinomas: a retrospective
cancer surgery for invasive lobular carcinoma and invasive ductal study on 860 patients from one institution. Ann Oncol. 2006;17:
carcinoma. World J Surg Oncol. 2009;7:34. 1228-1233.
18. Cserni G, Bianchi S, Vezzosi V, et al. The value of cytokeratin immu- 35. Cocquyt VF, Blondeel PN, Depypere HT, et al. Different responses to
nohistochemistry in the evaluation of axillary sentinel lymph nodes in preoperative chemotherapy for invasive lobular and invasive ductal
patients with lobular breast carcinoma. J Clin Pathol. 2006;59:518-522. breast carcinoma. Eur J Surg Oncol. 2003;29:361-367.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 21


POINTS OF VIEW
The section, new for 2016, contains articles describing emerging, highly debated, or controversial topics
in cancer research, treatment, and care to benefit patients and the field of oncology.

AUTHORS
Arthur L. Caplan, PhD
NYU Langone Medical Center
New York, NY

Laura Esserman, MD, MBA


University of California, San Francisco
San Francisco, CA

David J. Kerr, MD, PhD


University of Oxford
Oxford, United Kingdom

Ulka N. Vaishampayan, MD
Karmanos Cancer Institute
Detroit, MI
CAPLAN, BATEMAN-HOUSE, AND WALDSTREICHER

Compassionate Use: A Modest Proposal


Arthur L. Caplan, PhD, Alison Bateman-House, PhD, MPH, MA, and Joanne Waldstreicher, MD

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session Expanded Access and the
Right to Try: Navigating the Intersection of Drug Development and Patient Access to Investigational Agents. The authors
present the approach to compassionate use through use of an independent committee to vet and review requests for one
pharmaceutical company.

P atient requests for rapid access to agents that are still in


the research pipeline fall into two categories: requests
from groups of persons with the same malady and requests
who own the drug or agent. Regardless of the approach, this
process is, at best, hit or miss and one that favors patients
with a compelling personal interest story or who are oth-
by individuals. The former are often described as requests erwise well-connected.
for expanded access, the latter as requests for compas- Many have claimed that the key obstacle for patients
sionate use. Regulatory bodies in many countries have seeking compassionate use access is the U.S. Food and Drug
created programs for providing greater access to requests Administration (FDA). However, estimates are that the FDA
from groups including the creation of expanded access approves over 99% of the compassionate use protocols it
programs and emergency use waivers for patients who do receives.1 Furthermore, the FDA plays no role in responding
not qualify for clinical trials. Compassionate use requests for to requests for compassionate use until the company de-
individuals have proven to be more difficult to resolve. veloping the agent has indicated its willingness to provide
Compassionate use requests can come at any time during the product. In contrast, companies encounter multiple
the research processfrom when a drug is being tested in issues when faced with compassionate use requests. These
animals, to its first-in-human studies, to dose-finding trials, include the fact that they have no legal duty to offer access
to when the agent under investigation nears the end of and that they must balance requests with ongoing clinical
clinical trials. Requests can come from patients nearing the development programs. In addition, even if the company
end of life, but they may also come from those facing serious wanted to respond, there may be uncertainty as to what the
disability and pain for which no approved agent has been response should be and how best to respond to all requests
proven effective. Requests can come from around the world fairly, particularly when there are those who are well-
and from parents for their children, patients on their connected and/or using social media campaigns.
deathbeds, those in the midst of lethal disease outbreaks, In this article, we review the approach taken by one of
those newly infected as well as the chronically ill, the very many companies (Janssen) that receives such requests,
poor, and those for whom money is no object. which involved the formation of a third party. Internal
Until very recently, the main strategy for patients seeking discussions at Janssen had focused on how to best handle
compassionate use was to try to locate a possible treatment, compassionate use requests consistent with its commit-
frequently online, and often, though not always, with the ment to obtain regulatory approval for investigational
help (or approval) of their physician. Once a possible treat- agents, thereby making products available to the greatest
ment was found, patients and/or their physicians seeking number of persons. Ultimately, Janssen decided to un-
compassionate use would try to contact the researcher or dertake a first-of-its-kind partnership that enlisted a third
leader of a group involved with testing the agentalmost party to review requests made to the company for com-
always at a company. Some are able to use personal con- passionate use. This novel approach was initiated as a pilot
nections to initiate a request, whereas others reach out program focused on a single investigational medicine,
to their elected officials, shareholders in the company, or daratumumab, which was being evaluated in late-stage
others thought to wield influence. Sometimes patients try to phase III trials at the time and had shown evidence of
interest the traditional media in their plight. Alternatively, efficacy in patients with refractory multiple myeloma.
they may launch campaigns using social media with the hope Janssen approached the director of the Division of Medical
that public pressure might be brought to bear on the parties Ethics at NYU Langone Medical Center, Arthur Caplan, PhD,

From the New York University School of Medicine, New York, NY; NYU Langone Medical Center, New York, NY; Johnson & Johnson, New Brunswick, NJ.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Arthur L. Caplan, PhD, New York University School of Medicine, 227 East 30th St., New York, NY 10016; email: arthur.caplan@nyumc.org.

2016 by American Society of Clinical Oncology.

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COMPASSIONATE USE REQUESTS

to propose a method for reviewing compassionate use re- 1. worked to improve navigation of Janssens worldwide
quests that would be transparent, fair, beneficent, evidence- websites so that those seeking compassionate use for
based, and patient-focused. Drawing upon his prior work multiple myeloma would be able to more easily find
involving the allocation of cadaver organs for transplan- clear information on how to request daratumumab,
tation, Caplan formed a 10-person committee, the Com- 2. insisted that requests came from physicians and be
passionate Use Advisory Committee (CompAC), that consists standardized so that all requests would have the same
of physicians, bioethicists, patients, and patient advocates information, unadorned by letters of support from
from around the world to advise Janssen on compassionate prominent individuals,
use requests for daratumumab. The CompAC was created 3. decided to rotate voting on requests among three of
and staffed by the New York University School of Medicine its 10 members weekly to minimize any effort to lobby
(NYUSOM) and was independent of Janssen. CompAC the committee members,
members contracted with NYUSOM to remain indepen-
4. directed Janssen to redact information pertaining to
dent and reduce the risk of conflicts of interest. Some
the requesters name, location, nationality, and gen-
CompAC members accepted payment for their time;
der to prevent these factors from being taken into
the chair and deputy chair, however, received no direct
consideration by voting members,
compensation.
5. created an appeal process by which a physician whose
request was denied could reintroduce further stan-
HOW THE COMPAC WORKS dardized information about his or her patient (i.e., new
Compassionate use requests for daratumumab are received
laboratory values), and
directly at Janssen through a standardized patient intake
6. committed to respond to all requests within 5 business
form on the companys website. Janssen physicians screen
days, thereby ensuring that appropriate concern was
the intake forms for medical appropriateness, and, if the
shown to all patients and that no one would be left
patient is eligible for a clinical trial, expanded access pro-
gram, or has not yet tried an available drug or program, without an expeditious answerthe opposite of which
Janssen informs the submitting physician of this and is commonly a source of great patient and physician
does not route the request to CompAC. For all other frustration about compassionate use requests.
cases, CompAC receives requests on a weekly basis and Soon after the creation of the CompAC in May 2015, these
returns its recommendation to Janssen within 5 business policies were implemented. Further discussion among
days of receiving each request. CompAC is an advisory CompAC members led to an agreement on a set of principles
committee, and, legally, Janssen must remain in control that would be used to guide the committees recommen-
of the ultimate decision to provide access; however, dations in response to requests. These included: preventing
Janssen made a good faith commitment to follow CompAC harm to patients, requiring that patients had exhausted all
recommendations. available approved treatments before trying unapproved
Although CompAC spent a good deal of time discussing agents, estimating the likelihood of obtaining an efficacious
what, if any, criteria it would use in deciding who to rec- response, and assessing patient functionality, and, at a lower
ommend to receive access, it quickly became evident that order of priority, prior participation in a clinical trial, direct
the key ethical requirement that the CompAC had to achieve support for dependents, suffering from the disease, and age.
was fairness. The existing pathways for making requests of Decision making in response to requests commenced in July
Janssen and other companies were not always fair, some- 2015, with an average of four to five requests per week.
times favoring the rich, celebrities, and those who could Supply varied from week to week including some weeks in
command attention. To work, CompAC had to ensure that it which there was none.
would strengthen the fairness of compassionate use de-
cisions to better meet the needs of patients, doctors, re-
searchers, and the public. To do so, the CompAC: LESSONS TO DATE
Although there is obvious interest both in who was se-
lected, who was rejected, and on what basis, the major
lesson learned from this pilot program is that it is fairness,
KEY POINTS rather than justice, that is the key to the success of the
CompAC. By having a committee with broad expertise that
This article describes the creation of a dedicated is insulated from what ought to be morally irrelevant
committee to respond to compassionate use requests
considerations of wealth, privilege, and media interest,
for an investigational drug for multiple myeloma.
This article describes the importance of creating
the CompAC has been able to institute strategies that
principles of fair opportunity for those making requests minimize the ability of any patient, family, advocacy
for compassionate use. group, or advantaged party to sway decisions. Patients,
This article suggests that this model may have their doctors, and Janssen officials report that they be-
application to other agents and settings. lieve that the pilot approach is more equitable than what
existed beforehand.

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CAPLAN, BATEMAN-HOUSE, AND WALDSTREICHER

The CompAC model may be applied to other novel agents certainly not beyond criticism as to its composition, prin-
across Johnson & Johnson. Other companies, both large and ciples, and decisions. However, the CompAC has identified
small, patient advocacy organizations, and government of- ways to make very hard decisions more equitable. Those
ficials have all expressed interest in learning about or deserve close attention and debate in a world with many
extending the CompAC model to other settings. more unapproved agents that will be sought by the des-
The CompAC pilot program has been resource intensive, perate who face constraints upon the resources available
involving many different groups to support its activities, and is to them.

References

1. Silverman E. The FDA Says Its More Compassionate Than You Think.
Healthcare Blog, The Wall Street Journal. 2014. http://blogs.wsj.com/
corporate-intelligence/2014/05/05/the-fda-says-its-more-compassionate-than-
you-think/. Accessed February 24, 2016.

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THE EVOLVING SURGICAL APPROACH TO BREAST CANCER

Less Is More: The Evolving Surgical Approach to Breast Cancer


Laura Esserman, MD, MBA, Etienne Gallant, and Michael Alvarado, MD

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session Less Is More: A Multi-
disciplinary Conversation on Treatment Options. The authors review the indications for reducing the treatment burden for
women with breast cancer by capitalizing on the emerging opportunity to identify and recognize more indolent forms of the
disease using advanced tools, therapies, and screening methods.

OVERVIEW

Personalized medicine is emerging as an important guiding principle in diagnosis and treatment. This means not just doing
more for some, but safely doing less for others. The lessons learned about the biology of breast cancer over the last 2 decades
have enabled us to understand the incredible heterogeneity of breast cancer and its associated behavior. Although much
work remains, there is an emerging opportunity to identify and recognize more indolent forms of breast cancer, made more
prevalent through the widespread adoption of screening. With our improving systemic therapies and improved molecular
tools, we now have the opportunity to reduce the burden of treatment in women with lower-risk tumors. Our surgical
treatments have evolved, with less morbid and more cosmetic procedures. In this article, we review the indications for
further reducing local therapy, including adjuvant radiation.

T he history of breast surgery is one in which we have gone


from more to less. Radical mastectomies, when first
introduced by Halsted, were an improvement over leaving
reason is that the benefit from an intervention and its side
effects may not outweigh the risk of the disease. Thus, a
postmenopausal woman with favorable-risk hormone
women with fungating masses. However, the field evolved receptorpositive breast cancer has several options after
through a series of randomized trials to minimize the breast conservation. In addition to what has been the gold
morbidity of our surgical procedures. Modified radical standard, standard dose external beam radiation therapy
mastectomies have replaced radical mastectomies. Imme- (EBRT), there are several alternatives including hypo-
diate reconstruction and skin-sparing mastectomy, and now fractionated EBRT, intraoperative radiation therapy (IORT),
total skinsparing mastectomies, have been shown to be or no radiation, which are all supported by the literature as
oncologically safe and cosmetically better.1,2 We have re- at least equivalent, if not superior, strategies to EBRT.5,6 And
duced extended axillary procedures, and sentinel node yet, trial results have not significantly influenced practice in
dissections have fortunately successfully reduced the the United States.
complications of lymphedema. Even in the setting of stage II Over time, the local recurrence rates have been decreasing
and III disease, with axillary disease, surgeons are finding from the original reported risk of 10% EBRT. Recent studies
safe ways to reduce the burden of axillary surgery in the show rates largely less than 5% and even lower when en-
setting of excellent responses to neoadjuvant chemother- docrine therapy is used. Data from four trials with pop-
apy. Especially because we are increasingly more successful ulations of similar biology (postmenopausal women with
in preventing recurrence and death from breast cancer and node-negative, hormone receptorpositive, early-stage breast
as women lead longer lives, we must pay more attention to cancer) are shown in Table 1. Local recurrence rates are very
identifying the opportunities to reduce the burden of low in the EBRT arms or in the complete absence of radiation.
treatment. We now have the opportunity to focus on the Fyles et al found that women over age 50 in the low-risk
advances in molecular biology to help us to identify tumors groupimmunohistochemistry subtype luminal Ahad a
with indolent behavior and to adjust our local therapy local recurrence of 4.9% at 10 years with or without EBRT.7
accordingly.3,4 Intraoperative radiation therapy results, which also show a
Decision making for patients with low-risk disease is often very low locoregional recurrence, are consistent with other
more complicated than for those with high-risk disease. The modern trial results. It should be noted that there was no

From the University of California, San Francisco, San Francisco, CA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Laura Esserman, MD, MBA, University of California, San Francisco, 1600 Divisadero St., 2nd Floor, Box 1710, San Francisco, CA; email: laura.esserman@ucsf.edu.

2016 by American Society of Clinical Oncology.

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ESSERMAN, GALLANT, AND ALVARADO

difference in metastatic rates or overall survival for any of When the CALGB 9343 results were presented in 2002,
the trial arms. they met a similar reaction to the results of the TARGIT-A
The question of how to approach patients with early- results in 2010. Many demanded 10 years of data prior to
stage, favorable-risk breast cancer illustrates the complexity adoption. However, even with 10 years of data demon-
of forces influencing decision making in regard to adoption strating that mortality is not impacted by radiation in women
of new approaches. Whole-breast EBRT remains the stan- over age 70, or even with the publication of the PRIME 2 trial
dard of care following breast-conserving surgery. However, results,13 the standard of care after breast-conserving sur-
multidose partial breast radiation is increasingly offered as gery has remained EBRT.
an alternative for eligible women. Emerging technologies Partial breast radiation as an alternative to EBRT has been
have provided impetus for shifts in radiation approaches on the market for 10 years with variable uptake. There was
despite lack of randomized clinical trial data for these de- a large international randomized trial comparing single
vices. The frequency of brachytherapy use increased from intraoperative radiation using low-energy photons delivered
approximately 1% in 2001 to 10% in 2006, despite concerns by the TARGIT device. The results of the TARGIT A trial were
about long-term efficacy.8 In fact, over 30,000 women had first published in 2010, followed by a second publication in
been treated with accelerated partial breast irradiation 2014.14 The results showed noninferiority, specifically for
(APBI) by the time the American Society for Radiation On- the prepathology stratum (TARGIT given at time of lump-
cology published its first consensus statement.9 ectomy). There was a great deal of criticism and arguments
The finding from a randomized trial (CALGB 9343) that that it was too early to adopt the findings,15 with bias from
older women with hormone receptorpositive breast cancer many radiation oncologists not expecting that a treatment
could be effectively treated with tamoxifen without radia- with low-energy photons would work. Indeed, early adop-
tion therapy has yet to be adopted into clinical practice.10 tion of technology that turns out to be inferior to the status
The results demonstrated that with or without radiation, quo can be harmful, but late adoption of technology that
distant recurrence, breast cancer mortality, and mastectomy turns out to be equivalent or superior to the status quo can
rates are the same and very low in the two arms.11 Despite be a missed opportunity that also harms individuals and
these results with more than 10 years of follow-up and society. Using a framework to evaluate the risks and benefits
corroborating evidence from a similar Canadian trial in all of early versus late adoption, this technology is one where
postmenopausal women,12 as well as the PRIME 2 trial,13 early adoption would be preferable to EBRT for all eligible
radiation is rarely omitted and postlumpectomy radiation is cases.16
considered a quality measure by the American College of Breast cancer is now recognized as being comprised of
Surgeons for older women. Fear of omitting therapy and several distinct diseases. One of the reasons that the
being less aggressive often makes both physicians and pa- locoregional recurrence appears to be so much lower is likely
tients uncomfortable, even in the face of supporting evi- due to the impact of mammography screening and the
dence to the contrary. The cultural bias that more aggressive identification of tumors that are biologically more
treatment of cancer is better, fear of malpractice, and fi- indolent.17-19 The results from older trials in which there
nancial rewards all conspire to encourage intervention. was a 40% locoregional recurrence in the absence of radi-
ation applied to younger women with tumors with more
aggressive biology.20 Thus, reframing risk and options must
occur as we have the ability to better characterize the bi-
ology of newly diagnosed breast cancers21 and offer better
KEY POINTS options for women with low-risk disease. This is even more
Surgery for breast cancer has dramatically changed in
important where local recurrence is not life threatening.
recent years, moving away from extensive surgical The risk for distant breast cancer recurrence for women
resections for all patients to more individualized, limited with hormone receptorpositive disease does extend over a
surgery for early stages of disease. 20-year period.22 This well-known fact leads to an erroneous
Treatment decisions for patients with early-stage conclusion that long-term follow-up for 10 or more years is
disease are complex because decision making typically needed to assess outcomes. However, the peak hazard rate
involves multiple options that likely have little effect on for local recurrence is early, and then is low and stable, thus,
overall survival. the overall conclusions are extremely unlikely to change.
The widespread use of screening has resulted in This has been demonstrated by the overview analyses as
identification of a higher fraction of low-risk cancers. well as many trials,23,24 the Canadian trial, the CALGB trial,
Women undergoing breast-conserving therapy have
and the TARGIT A trial, which showed that early results
numerous options that include surgery alone or surgery
and limited fractionated radiation and IORT.
predicted the later results.12,25-27
Molecular classifiers of indolent tumors can guide a less The demonstration that less-aggressive interventions are
aggressive initial strategy and should inform treatment equally effective for women with lower-risk tumors is a
of both invasive disease and help to reclassify some critical breakthrough for women and a major advance in our
types of DCIS. ability to tailor treatments for women according to the
biology of their tumors. If we can safely accomplish the same

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THE EVOLVING SURGICAL APPROACH TO BREAST CANCER

TABLE 1. Recent Studies of Breast Conservation, Radiation, and Local Therapy Outcomes
Study Accrual Dates No. of Patients Study Arms 5-Year LRR 10-Year LRR 12.6-Year LRR
TARGIT-A14 20002012 2,298 prepathology IORT 2.1% NA NA
EBRT 1.1%
Studies Comparing XRT With No XRT
CALGB C934311 19941999 636 Tam 4% 7% 10%
Tam + RT 1% 1% 2%
Luminal A7 19922000 611 (all T1 patients) Tam 5.5% 13.8% NA
Tam + RT 0.4% 5.3%
114 (subset of G1/2, Tam 2% 4.9% NA
luminal A patients)
Tam + RT 5.5%
PRIME II13 20032009 1,326 No RT 4.1% NA NA
RT 1.3%
Studies Comparing Hypofractionated 3-Week EBRT With 5-Week EBRT
Hypofractionated 19931996 1,234 3-week EBRT 2.33% 6.2% NA
Radiation5
5-week EBRT 2.17% 6.7%
START-B6 19992001 2,215 3-week EBRT 1.9% 5.2% NA
5-week EBRT 3.3% 3.8%
Abbreviations: LRR, locoregional recurrence; NA, not available; IORT, intraoperative radiation therapy; EBRT, external beam radiation therapy; Tam, tamoxifen; RT, radiation therapy.

goal (preventing cancer recurrence) in a much more effi- fraction of tumors with low-risk biology.28 An important way
cient, less invasive, and less personally time-consuming to mitigate that risk is to recognize that lower-risk biology
manner for women, the physician community should be tumors are more likely to be detected with screening and to
the first to embrace this therapy. The complaint about IORT have tools to identify them at the time of diagnosis and
seems to be that the data are immature; however, clinical enable less-aggressive treatment. Using a data set from a
practitioners can switch to IORT and watch the data mature. randomized trial of no treatment compared with treatment
The chance that the results will change has a very small with tamoxifen for 2 years, we sought to leverage a validated
probability, and practitioners could switch back to EBRT or molecular classifier to determine if we could define a group
switch to another treatment that has been shown to be of women whose prognosis was excellent even 20 years after
more effective than EBRT in the interim. As our analysis diagnosis.29 We used a test that was originally designed to
indicates, little will have been lost for any patient who re- identify a population of patients with breast cancer, in the
ceives IORT, as many are also eligible for hormone therapy absence of systemic therapy, with a good prognosis at
alone. 5 years. The 70-gene test (MammaPrint) has been used to
Daily radiation treatments over many weeks are bur- identify women who do not benefit from adjuvant che-
densome to patients, especially those that live far from an motherapy and is currently being evaluated in the MINDACT
adequate radiation treatment center. It is reasonable to clinical trial (6,600 patients; results expected late spring
assume that patients would prefer no radiation, IORT, or 2016). We created a new threshold with the purpose of
shorter courses of EBRT, even simply on the basis of con- specifically evaluating long-term (. 20 years) breast can-
venience. Women concerned only about distant recurrence cerspecific mortality, which we have designated indolent
should be advised about the options of no radiation for threshold.
node-negative disease. If a 5% to 10% difference in local The women in the STO1 study presented with palpable
recurrence is important to avoid, IORT is an excellent al- tumors, so by definition, they had tumors that had come to
ternative to no radiation. clinical attention. These are not cancers detected by
The difficulty in adoption of less-aggressive therapy may screening. When the indolent threshold is applied to the STO
best be approached by using biomarkers that characterize study in which women presented with palpable, clinically
tumors as indolent. One biomarker, specifically adapted for detected tumors, we were able to identify women whose
the express purpose of identifying indolent disease in the tumors, after surgery and a short course (2 to 5 years) of
absence of all treatment, could have the potential to provide tamoxifen, posed no risk for breast cancerspecific death for
reassurance to providers and patients alike that a less- 15 years.29
aggressive initial treatment is appropriate. An indolent tumor should signal that a more minimal
The widespread prevalence of screening has resulted in a treatment approach would be sufficient. Although there
shift in the kinds of cancers detected. The objective of may be a small fraction of patients who progress, that
screening is to identify cancers at a lower stage, however, a progression is many years later, and early treatments are
consequence of screening is the identification of a higher unlikely to impact that progression. The critical distinction is

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ESSERMAN, GALLANT, AND ALVARADO

FIGURE 1. Indolent Threshold of the 70-Gene Assay The indolent threshold could therefore be used to identify
women for whom lumpectomy alone and a short course
of adjuvant endocrine therapy is sufficient. Many women
are unable to tolerate 5 years of endocrine therapy, and as
many as 60% have discontinued aromatase inhibitors by
3 years.30,31 The ability to identify a population of women
with little benefit of extended endocrine risk-reducing
therapy would be of huge benefit. The indolent threshold
does not allow us to say that women would never experience
recurrence over their lifetime (we have not found the
classification for truly IDLE [indolent lesions of epithelial
origin] conditions), but we can say that the chance of any
recurrence is low and that more aggressive therapy can
be administered at the time of recurrence, sparing many
women treatments that will not be of benefit.
It is estimated that over a 10-year period, five to seven
cancers per 1,000 might be diagnosed that might not oth-
An indolent threshold of the 70-gene assay has been validated in a randomized erwise come to clinical attention.32 These represent ap-
trial of postmenopausal women with node-negative palpable tumors.29 These proximately 17% of the patients diagnosed with breast
tumors are essentially curable at the time of presentation. Thus, there would be no
value to identifying the precursors of such tumors. Such precursors would therefore cancer. Interestingly, approximately 15% of the STO1 trial
fit the definition of IDLE conditions18 and should not be called cancer nor be the target population had tumors that met the indolent threshold. In
of screening. The most likely candidates for these precursors are low-grade ductal
carcinoma in situ lesions. Studies are ongoing to investigate the relationship of the MINDACT study, a modern cohort of patients in which
low-grade ductal carcinoma in situ and indolent invasive breast cancer. over 80% of women are screened, the fraction of women
Abbreviations: IDLE, indolent lesions of epithelial origin; DCIS, ductal carcinoma in
situ; Dx, diagnosis; TAM, tamoxifen. with screen-detected tumors with indolent cancers may be
in the range of 37%, or about 20% more than what was
that additional treatment should be reserved for when and observed in the STO trial, which was conducted prior to the
if that disease progresses, and additional treatment should widespread use of screening. This is consistent with the
be administered at the time of progression (Fig. 1). additional low-risk cancers diagnosed with screening. Over a
We can reflect on the three randomized studies that 10-year period in the United States, where 50 million women
demonstrate that women with relatively low-risk biology are screened for 10 years, this might amount to 300,000
have a low risk of recurrence in the setting of hormone cancers with extremely low-risk of recurrence. Character-
therapy alone and without radiation.11-13 The risk of local ization of all screen-detected cancers could provide critical
recurrence, as stated earlier, has dropped over the years information about how to further personalize treatment.
likely because of the dramatic increase in the number of Even in the setting of presentation of palpable disease,
women diagnosed who have indolent cancers.16 In the about 10% of tumors fit the molecular definition of indolent
CALGB 9343 trial of women treated with lumpectomy alone
and 5 years of tamoxifen, local recurrence was uncommon
and successfully treated at the time of diagnosis without an FIGURE 2. Identification and Therapy of the Indolent
impact on mortality or the mastectomy rate. Recurrence Spectrum of Breast Cancers
rates in the absence of radiation are low,11-13 and, in par-
ticular, the event of recurrence appears to be salvageable
without an adverse impact on mastectomy rates or mor-
tality. In particular, the Canadian trial of radiation compared
with no radiation demonstrates that luminal A tumors have
only a 5% risk of local therapy with 5 years of tamoxifen
therapy and absence of radiation. The indolent threshold
described here is more stringent than the luminal A cate-
gory, with only 31% of luminal A tumors meeting the in-
dolent designation. Importantly, in all of the radiation versus
no radiation studies, the chance of dying of other causes is
considerably higher than the chance of dying of breast
cancer. The analysis of the Stockholm 1 study confirms the
existence of a tumor type that has an indolent course, which
can be treated less aggressively at the time of diagnosis. In
this population of women, the indolent threshold did not
Identification of the indolent spectrum of breast cancers and tailoring therapy
identify women who had zero risk absent therapy, but al- accordingly (local and systemic) should be considered part of the evolution
most no risk with a minimal course of tamoxifen. toward personalized breast cancer treatment.

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THE EVOLVING SURGICAL APPROACH TO BREAST CANCER

disease. In the setting of screening, that number is more Such precursors would better be reclassified as IDLE, instead
likely to be in the range of 35% or higher33 in keeping with of carcinoma in situ.18 If the indolent invasive tumors can be
observations from screening trials.34 If the biology of these treated without radiation, then certainly women with risk
tumors can be recognized at the time of diagnosis, and factors or precursors of IDLE conditions such as low and
women can be reassured that their prognosis is excellent, intermediate DCIS should not be routinely offered radia-
simpler interventions can be used such as excision alone, tion.35 Evidence to support this concept was recently
sentinel node, and hormone therapy for 2 to 5 years. published by Sagara et al.36 The investigators looked at
Registry studies for using less intervention for post- surgery or no surgery for DCIS in a large SEER database of
menopausal women with lower-risk tumors are under 57,000 patients. For low-grade DCIS, the 10-year breast
development. The University of Michigan is leading a multi- cancerspecific survival for no surgery was 98.8% whereas
institutional study of surgical excision alone for women age the survival for the surgery group was 98.6%. Surely, we can
50 to 69 with T1NO tumors with Oncotype Dx results lower start advocating for less treatment for these women.
than 18. LUMINA is a Canadian Ontario Cancer Group study Learning how to safely do less should be considered part of
of lumpectomy alone for women older than age 55 with the evolution of personalized breast cancer treatment
T1NO tumors that are luminal A. There are several ductal (Fig. 2).
carcinoma in situ (DCIS) trials starting, two in Europe, in- All treatments have side effects. Mastectomy, even with
cluding the LORD trial and the LORIS trial, and three in the reconstruction, can be disfiguring and debilitating to
United States (a registry trial through the ATHENA network, women. They can experience postmastectomy pain. Radi-
the COMET trial recently funded by PCORI, and the ECOG- ation also has side effects.37,38 Extended endocrine therapy
ACRIN MRI and Oncotype prospective study) exploring op- can also be challenging to take for women, and it has been
tions of using less intervention. reported that over 40% of women stop taking their medicine
Overdiagnosis is much less of a problem if we accept and after 3 years.30,31 The STO data suggest that 2 years of ta-
recognize that we will identify indolent disease with moxifen should be sufficient for women with tumors that
screening and if we have tools to characterize it and be less meet the molecular definition of indolent disease. Although
aggressive with our interventions. To do so, we have to have it would be difficult to test, the persistence of a small risk for
confidence in the tools that we use to identify such indolent recurrence after 15 years over so many years suggests that
conditions. perhaps 2 years of hormonal therapy could be repeated 7 to
These data should also make us reflect on the dilemma of 10 years after diagnosis if we are able to identify those
DCIS. If there are indolent cancers that can be successfully women with late risk for recurrence. The opportunity to
treated upon diagnosis, then certainly there would not be know when such treatments are not necessary would be a
any value to finding the precursors of these indolent cancers. great boon to patients.

References
1. Wang F, Peled AW, Garwood E, et al. Total skin-sparing mastectomy and 7. Fyles A, McCready D, Pintilie M. Luminal A subtype predicts radiation
immediate breast reconstruction: an evolution of technique and as- response in patients with T1N0 breast cancer enrolled in a randomized
sessment of outcomes. Ann Surg Oncol. 2014;21:3223-3230. trial of tamoxifen with or without breast radiation. Cancer Res. 2011;71:
2. Peled AW, Wang F, Foster RD, et al. Expanding the indications for total S2-2.
skin-sparing mastectomy: is it safe for patients with locally advanced 8. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast
disease? Ann Surg Oncol. 2016;23:87-91. irradiation consensus statement from the American Society for Ra-
3. Boughey JC, Suman VJ, Mittendorf EA, et al; Alliance for Clinical Trials in diation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009;74:
Oncology. Sentinel lymph node surgery after neoadjuvant chemo- 987-1001.
therapy in patients with node-positive breast cancer: the ACOSOG 9. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast
Z1071 (Alliance) clinical trial. JAMA. 2013;310:1455-1461. irradiation consensus statement from the American Society for Radi-
4. Caudle AS, Yang WT, Krishnamurthy S, et al. Improved axillary ation Oncology (ASTRO). J Am Coll Surg. 2009;209:269-277.
evaluation following neoadjuvant therapy for patients with node- 10. Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative
positive breast cancer using selective evaluation of clipped nodes: group trial on breast cancer care in the medicare population. J Clin
implementation of targeted axillary dissection. J Clin Oncol. Epub Oncol. 2012;30:1601-1607.
2016 Jan 25. 11. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen
5. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypo- with or without irradiation in women age 70 years or older with early
fractionated radiation therapy for breast cancer. N Engl J Med. 2010; breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol. 2013;
362:513-520. 31:2382-2387.
6. Haviland JS, Owen JR, Dewar JA, et al; START Trialists Group. The UK 12. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without
Standardisation of Breast Radiotherapy (START) trials of radiotherapy breast irradiation in women 50 years of age or older with early breast
hypofractionation for treatment of early breast cancer: 10-year follow- cancer. N Engl J Med. 2004;351:963-970.
up results of two randomised controlled trials. Lancet Oncol. 2013;14: 13. Kunkler IH, Williams LJ, Jack WJ, et al; PRIME II investigators. Breast-
1086-1094. conserving surgery with or without irradiation in women aged 65 years

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ESSERMAN, GALLANT, AND ALVARADO

or older with early breast cancer (PRIME II): a randomised controlled 26. Vaidya JS, Wenz F, Bulsara M, et al. Targeted intraoperative radio-
trial. Lancet Oncol. 2015;16:266-273. therapy for early breast cancer: TARGIT-A trial- updated analysis of local
14. Vaidya J, Wenz F, Bulsara M, et al; TARGIT trialists group. Risk- recurrence and first analysis of survival. Cancer Res. 2012;72:S4-2.
adapted targeted intraoperative radiotherapy versus whole-breast 27. Hughes KS, Schnaper LA, Berry D, et al; Cancer and Leukemia Group B;
radiotherapy for breast cancer: 5-year results for local control and Radiation Therapy Oncology Group; Eastern Cooperative Oncology
overall survival from the TARGIT-A randomised trial. Lancet. 2014;383: Group. Lumpectomy plus tamoxifen with or without irradiation in
603-613. women 70 years of age or older with early breast cancer. N Engl J Med.
15. Woloshin S, Schwartz LM. Whats the rush? The dissemination and adoption 2004;351:971-977.
of preliminary research results. J Natl Cancer Inst. 2006;98:372-373. 28. Esserman LJ, Thompson IM, Reid B, et al. Addressing overdiagnosis and
16. Esserman LJ, Alvarado MD, Howe RJ, et al. Application of a decision overtreatment in cancer: a prescription for change. Lancet Oncol. 2014;
analytic framework for adoption of clinical trial results: are the data 15:e234-e242.
regarding TARGIT-A IORT ready for prime time? Breast Cancer Res Treat. 29. Esserman LJ, Thompson CK, Yau C, et al. Identification of tumors with an
2014;144:371-378. indolent disease course: MammaPrint ultralow signature validation in a
17. Esserman LJ, Shieh Y, Rutgers EJ, et al. Impact of mammographic retrospective analysis of a Swedish randomized tamoxifen trial. Cancer
screening on the detection of good and poor prognosis breast cancers. Res. 2016;76:P6-09-01.
Breast Cancer Res Treat. 2011;130:725-734. 30. Cuzick JF, Sestak I, Howell A, et al. Anastrozole versus tamoxifen for the
18. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer prevention of loco-regional and contralateral breast cancer in post-
and prostate cancer. JAMA. 2009;302:1685-1692. menopausal women with locally excised ductal carcinoma in-situ (IBIS-II
19. Bleyer A, Welch HG. Effect of three decades of screening mammography DCIS). Lancet. 2016;387:866-873.
on breast-cancer incidence. N Engl J Med. 2012;367:1998-2005. 31. Ganz PA, Cecchini RS, Julian TB, et al. Patient-reported outcome (PRO)
20. Fisher B, Montague E, Redmond C, et al. Findings from NSABP Protocol results, NRG Oncology/NSABP B-35: a clinical trial of anastrozole (A) vs
No. B-04-comparison of radical mastectomy with alternative treat- tamoxifen (tam) in postmenopausal patients with DCIS undergoing
ments for primary breast cancer. I. Radiation compliance and its relation lumpectomy plus radiotherapy. Cancer Res. 2016;76:S6-04.
to treatment outcome. Cancer. 1980;46:1-13. 32. Marmot MG, Altman DG, Cameron DA, et al. The benefits and harms of
21. Buyse M, Loi S, vant Veer L, et al; TRANSBIG Consortium. Validation and breast cancer screening: an independent review. Br J Cancer. 2013;108:
clinical utility of a 70-gene prognostic signature for women with node- 2205-2240.
negative breast cancer. J Natl Cancer Inst. 2006;98:1183-1192. 33. Drukker CA, Schmidt MK, Rutgers EJ, et al. Mammographic screening
22. Esserman LJ, Moore DH, Tsing PJ, et al. Biologic markers determine both detects low-risk tumor biology breast cancers. Breast Cancer Res Treat.
the risk and the timing of recurrence in breast cancer. Breast Cancer Res 2014;144:103-111.
Treat. 2011;129:607-616. 34. Miller AB, Wall C, Baines CJ, et al. Twenty five year follow-up for breast
23. Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of cancer incidence and mortality of the Canadian National Breast
chemotherapy and hormonal therapy for early breast cancer on re- Screening Study: randomised screening trial. BMJ. 2014;348:g366.
currence and 15-year survival: an overview of the randomised trials. 35. Narod SA, Iqbal J, Giannakeas V, et al. Breast cancer mortality after a
Lancet. 2005;365:1687-1717. diagnosis of ductal carcinoma in situ. JAMA Oncol. 2015;1:888-896.
24. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists Col- 36. Sagara Y, Mallory MA, Wong S, et al. Survival benefit of breast surgery
laborative Group (EBCTCG). Effects of radiotherapy and of differences in for low-grade ductal carcinoma in situ: a population-based cohort
the extent of surgery for early breast cancer on local recurrence and study. JAMA Surg. 2015;150:739-745.
15-year survival: an overview of the randomised trials. Lancet. 2005; 37. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in
366:2087-2106. women after radiotherapy for breast cancer. N Engl J Med. 2013;368:
25. Liu F, Shi W, Done SJ, et al. Identification of a low-risk luminal A breast 987-998.
cancer cohort that may not benefit from breast radiotherapy. J Clin 38. Esserman L, Yau C. Rethinking the standard for ductal carcinoma in situ
Oncol. 2015;33:2035-2040. treatment. JAMA Oncol. 2015;1:881-883.

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STRATEGIES FOR SUSTAINABLE CANCER CARE

Strategies for Sustainable Cancer Care


David J. Kerr, MD, Anant Jani, PhD, and Sir Muir Gray, CBE, FRCPSGlas, FCLIP

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session NICE or Not? Evaluating
Global Strategies for Sustainable Cancer Care. The authors review strategies for sustainable cancer care and the National
Institute for Health and Care Excellences role in the assessment of clinical and cost-effectiveness of new pharmaceutical and
biopharmaceutical products in the United Kingdom.

OVERVIEW

There is an increasing focus on the relative cost-effectiveness and sustainability of delivering high-quality cancer care,1 with
most emphasis, debatably, given to cost control of innovative treatments. It is difficult to calculate all the direct and indirect
contributors to the total cost of cancer treatment, but it is estimated that cancer drugs constitute 10% to 30% of the total cost
of cancer care. A 2007 study in France2 showed the contribution of drug costs was less than 20%, with approximately 70% of
the total expenditure on cancer accounted for by health care resource use, such as hospitalization. The U.K. government
established the National Institute for Health and Care Excellence (NICE)the dominant function of which is technology
appraisalto assess the clinical and cost-effectiveness of new pharmaceutical and biopharmaceutical products. This is to
ensure that all National Health Service (NHS) patients have equitable access to the most clinically effective and cost-effective
treatments that are viable. NICE has developed a transparent, public process to judge incremental cost-effectiveness using
the quality-adjusted life year (QALY), which allows comparisons of cost-effectiveness across medical specialties. NICE has
been both lauded and criticizedespecially when it passes judgment on marginally effective but expensive anticancer
drugsbut it provides a route to rational rationing and, therefore, may contribute to sustainable cancer care by
highlighting the issue of affordable medicine. This implies a challenge to the wider oncology community as to how we might
cooperate to introduce the concept of value-driven cancer care.

M ichael Porter, a leading professor at the Harvard


Business Institute, has developed the following defi-
nition of value:
and the resources used. In turn, the outcome is determined
by the quality and safety of the intervention or service.

Value in any field must be defined around the customer, not STRATEGIES FOR SUSTAINABLE CANCER CARE:
the supplier. Value must also be measured by outputs, not VALUE
inputs. Hence it is patient health results that matter, not the Value Versus Quality
volume of services delivered. But results are achieved at some Services become high quality for several reasons, many of
cost. Therefore, the proper objective is patient health which are factors that have been shown to reduce the in-
outcomes relative to the total cost (inputs). Efficiency, then, cidence of errors, notably: (1) good leadership, (2) devel-
is subsumed in the concept of value.3(p. 12) opment of systems, and (3) the creation of a strong culture.
To maximize the probability of benefit and minimize the
Porter and Teisberg put this another way: Achieving high
probability of harm and errors, professionals need standard
value for patients must become the overarching goal of
operating procedures (SOPs), commonly defined as a pro-
health care delivery, with value defined as the health out- cedure, or set of procedures, to perform a given operation
comes achieved per dollar spent.4 Value, therefore, de- or evolution in reaction to a specific event. To improve
pends on results, not input, and so value in health care is quality and safety, it is necessary to have a style of gen-
measured by the outcomes achieved, not the volumes de- eral management that will increase effectiveness and re-
livered, and the relative costs of achieving those outcomes.5 duce harmfor example, promotion of safety culture; use
Put simply, value is the relationship between the outcome of systems, including clinical guidelines; clear lines of

From the Nuffield Division of Clinical and Laboratory Science, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: David J. Kerr, MD, Nuffield Division of Clinical and Laboratory Sciences, Level 4, Academic Block, John Radcliffe Infirmary, Headington, Oxford, OX3 9DU
United Kingdom; email: david.kerr@ndcls.ox.ac.uk.

2016 by American Society of Clinical Oncology.

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KERR, JANI, AND GRAY

accountability for risk management and safety; and data The second problem is underuse of effective and cost-
collection about risk factors, errors, and near misses. effective interventions for cancer, principally because of poor
Certainly there is concern about low-value, low-quality organization in the management of cancer services. One other
cancer care, and the Institute of Medicine report, Crossing aspect of underuse that should be considered is inequity, where
the Quality Chasm, on improving the quality of health care certain subgroups of the populationfor example, distin-
has been welcome, but high-quality health care need not be guished by age, ethnic background, or classreceive lower
synonymous with high-value health care. Low-quality health levels of high-value treatment than the general population.
care is certainly of lower value, but there are many examples Therefore, a focus on value is needed. Three aspects of
of health care providing high quality that is of low value. The value are:
semantics of this are important because consumers often
associate value (e.g., in supermarkets) at the lower end of
allocative value, determined by how the assets are
distributed to different subgroups in the population;
the market (e.g., Attention Kmart shoppers, as Beetlejuice
once said!).
technical value, determined by how well resources are
used for all the people in need in the population; and
The assessment of cost-effectiveness by organizations
such as NICE is of vital importance, but cost-effectiveness
personalized value, determined by how well the de-
cisions relate to the values of each individual.
refers to an intervention, whereas value refers to a pop-
ulations services. Perhaps populations will have to make
decisions between different degrees of cost-effectiveness, Triple-Value Health Care
worrying not about the financial cost of one particular in- Practitioners providing cancer care should continue to cam-
tervention but about its opportunity costnamely what else paign for more resources for cancer, but they should also be
can be done with resources within a finite health budget. If prepared to defend the allocative value of everything they are
there is an investment in cancer drugs, there may have to be currently doing. There are ways in which reallocation can be
disinvestment elsewhere within the cancer program or the facilitated. For example, in Spain, there was a bid for immu-
wider health service. notherapy resources for malignant melanoma, the total cost
being about V2 million for the population served. The payers
said they were unable to find this resource, but actually, in that
Choosing Wisely same population, the annual expenditure on skin disease was
There is increasing recognition of unwarranted variation not approximately V170 million per year. Practitioners in cancer
only in investment in cancer care but also in quality, cost, and care should learn to argue that consideration should be given
outcome. This variation highlights two other problems that to shifting V2 million from lower-value care for other skin
should be addressed not only by policy makers but also by diseases to malignant melanoma.
every clinician providing cancer services. The main challenge for people providing cancer services is
The first of these is overuse, highlighted in the Choosing to consider the allocation of resources between different
Wisely Campaign in the United States and in the Too Much cancer groups or between different modalities. The balance
Medicine campaign of the British Medical Journal. Overuse of investment in different patient groups is often a matter of
always wastes resources and sometimes does harm (e.g., historical accident, with one particular clinical group having
prescribing chemotherapy to patients when palliative care been more successful than others, but this should be
would be more appropriate, where the concern is not to save reviewed to see if the balance is optimal between the dif-
costs, but that the prescription of chemotherapy can be ferent types of common cancer, not excluding rare cancers.
classified as inappropriate or futile). As the path becomes more difficult, providers of cancer care
and patient representatives should consider whether the
balance is right; for example, should the interval between
KEY POINTS breast cancer screening be increased to free up resources
that can be switched to chemotherapy for women with
There is a need to balance cost-effectiveness and breast cancer?
sustainability of delivering high-quality cancer care. Technical value is different from efficiency. Technical value
It is estimated that cancer drugs constitute 10% to 30% has to take into account not only the use of resources for
of the total cost of cancer care. the patients seen, but also the possibility of overuse and
The U.K. government established NICE to assess the underuse. Every cancer service should conduct a review of
clinical effectiveness and cost-effectiveness of new inappropriate or futile care, which relates to the third type of
pharmaceutical and biopharmaceutical products.
value, personalized value
NICE has been praised as well as criticized, but it
contributes to sustainable cancer care by highlighting
In making decisions about personalized value, the model
the issue of affordable medicine. of decision making at the Centre of Evidence-Based Medi-
The worldwide oncology community must cooperate to cine is useful (Fig. 1). Cancer services should ensure that
introduce the concept of value-driven cancer care for every patient is fully informed about not only the benefits of
patients. treatment, but also the risks, and help them reflect on how
these odds reflect on values.

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STRATEGIES FOR SUSTAINABLE CANCER CARE

FIGURE 1. Center of Evidence-Based Medicines of course plays to the current model of precision med-
Personalized Value Model of Decision Making icine, selecting the right drug for the right patient.
Payers also should be explicit about health care condi-
tions that will or will not be given treatment from
publicly/insurance-funded health services.
In addition, services must make explicit decisions and
publish the decisions to not provide interventions they
deem to be of low value, such as expensive but mar-
ginally effective cancer therapeutics.
Management of demand may not be possible if left
solely to individual clinicians faced with the distress of
the individual patient. Funders should make decisions
at a population level. This is the implicit tension be-
tween the practice of population and clinical medicine
should practicing clinicians always stand outside of
decisions on drug rationing to maintain the integrity of
Managing Clinical Demand their relationship with the patients entrusted to their
There is a fashion in operations, as there is in sleeves and care?
skirts: the triumph of some surgeon who has at last found out
how to make a once desperate operation fairly safe is usually
followed by a rage for that operation not only among the National Institute for Health and Care Excellence
doctors, but actually among their patients. Since 1999, NICE has provided the United Kingdoms NHS
and those who rely on it for their care, with an increasing
George Bernard Shaw, preface to The Doctors Dilemma, 1906 range of advice on effective, good-value health care, and
Enthusiastic medical professionals, altruistic as we are and it has gained a reputation for rigor, independence, and
keen to do good, are armed with information provided by objectivity (Fig. 3). This has been described by some as
enthusiastic promoters of new technology, expressed in terms rational rationing. Available guidance takes several forms:
of relative benefit rather than absolute benefit, and are, not
surprisingly, the people who may fuel the growth in demand.
NICE guidelines make evidence-based recommenda-
tions that aim to promote integrated care.
Clinical demand may be overtly expressedfor example by
clinicians leading a campaign for a new drug or a new facility
Technology appraisal guidance to assess the clinical and
cost-effectiveness of health technologies, such as new
such as a PET scanneror demand can arise through what pharmaceutical and biopharmaceutical products, but
is called creep (i.e., an inexorable increase in testing and
treatment). Innovation should decrease cost as well as increase
it, and there is now a drive to innovate for better value, FIGURE 2. Causes of Cost Inflation
harnessing the power of new technology and improved ways
of organizing services. A classic study by Eddy6 in the United
States showed that, in a health care system in which ex-
penditure is not finite, changes in the volume and intensity
of clinical practice are the main factors driving increases
in the cost of care that can be controlled by those who
pay for or manage health care. The other causes of in-
creasing costsaging population, medical and general price
inflationare beyond the power of health service managers
to control (Fig. 2).
Managing innovation usually focuses on a small number of
potentially high-cost interventions; however, the conclusion
from the work of Eddy,6 which is as true today as when it was
published, is that every innovation, no matter how small, should
have its introduction to, or removal from, the health care system
carefully managed, particularly if it is for a common disease.
Managing demand is not easy, but some steps can be
taken; for example:
Be very clear and explicit about the subgroups of cancer
patients most likely to benefit from an intervention and,
as a corollary, those who are least likely to benefit. This

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KERR, JANI, AND GRAY

FIGURE 3. Kerr Led a Review of Scotlands Health care. These are derived from the best available evi-
ServiceThe Resemblance Is Evident! dence, particularly NICEs own guidance.

Technology Appraisals
NICE recommendations review clinical and economic evi-
dence, balancing the clinical data in relation to how much it
costs the NHSdoes it represent value for money? This advice
ends the uncertainty and helps to standardize access to health
care across the country. This is reflected in the NHS Consti-
tution, which states that patients have the right to drugs and
treatments that have been recommended by NICE for use in
the NHS, if their doctor believes they are clinically appropriate.
Sir Andrew Dillon, Chief Executive of NICE, said:
also include procedures, devices, and diagnostic agents. We support the general principle that the NHS should pay a
This is to ensure that all NHS patients have equitable price which reflects the additional therapeutic benefit of new
drugs. We also share the Governments ambition to ensure
access to the most clinically effective and cost-effective
that the option exists for all new licensed drugs to be offered
treatments that are viable. to those patients who can benefit from them, provided the
Quality standards are concise sets of statements with
accompanying metrics designed to drive and measure
price is a fair reflection of their value. We are confident that
the Government will want to take advantage of NICEs
priority quality improvements within a particular area of expertise and experience as it develops value-based pricing.

FIGURE 4. Estimating Cost and Cost-effectiveness

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STRATEGIES FOR SUSTAINABLE CANCER CARE

The dominant drivers of NICEs approach are incremental


cost-effectiveness and the QALY, which allows comparisons
The use of information technology to seamlessly in-
tegrate clinical and translational research and patient
of cost-effectiveness across all of medicine. How else would care.
we compare the relative benefits of cataract or hip surgery
with cancer therapy? The following hypothetical example
Greater use of adaptive (Bayesian) design techniques in
the design and analysis of randomized controlled trials
gives a clear idea of how the arithmetic is worked out. could reduce trial duration and the number of patients
As is described in Fig. 4, the model is dependent on inputs. needed.
If drug A had an incremental QALY of only 0.2 with an in-
cremental cost of 6,500, then the incremental cost- Oncologists and patient advocacy organizations should
challenge regulatory authority data requirements.
effectiveness would be 32,500 and possibly outside the
value range. Rather than criticize organizations such as NICE for de-
clining reimbursement on grounds of cost-effectiveness,
clinicians and patient advocates should start challenging
Operationalizing Strategies for Sustainable Cancer pharmaceutical companies about the high prices they
Care: Affordable Drugs seek for products with modest benefits.
Almost every time that NICE makes a negative pro-
nouncement on a new cancer drug, there is a volubly
Address the difficulties facing low- and middle-income
countries in accessing affordable cancer care, rather
negative press reaction, often driven, understandably, by than only focusing on problems facing high-income
disease-oriented interest groups. The NICE leadership has countries.
pushed back on this somewhat and has set a series of
challenges for the wider oncology community,7 namely: (1) CONCLUSION
the industry must operate in a much more efficient manner, Research and technologic innovation continue to produce
(2) the costs of drug development should be slashed, and (3) novel therapies, but these are often of marginal clinical
oncologists and patient advocacy groups must ask tough value, while managing to be very costly. Similarly, there is
questions of regulators and the pharmaceutical industry. increasing dependence on expensive new imaging modali-
They also made suggestions for practical implementation ties to assess tumor burden throughout treatment, despite
of effective solutions: the seeming paradox that patients in the United Kingdom, at
They suggest that clinical trial costs could be decreased
by 40%60% without detriment to their quality using
least, present with later-stage disease. There is no doubt
that a programmatic approach to budgeting the totality of
measures such as electronic data capture, reduction in cancer care for a specific population will highlight areas that
the length of case management forms, and modified represent low value and that, therefore, could be targets for
site management practices. disinvestment to make way for more effective treatment.

References

1. Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer care 4. Porter ME, Teisberg EO. Redefining Health Care. Creating value-based
in high-income countries. Lancet Oncol. 2011;12:933-980. competition on results. Boston, MA: Harvard Business School Press;
2. Amalric F. Analyse e conomique des Couts de Cancer en France. Impact Sur 2006.
la Qualite de Vie, Prevention, Depistage, Soin, Recherche. Paris: Institut 5. Porter ME. What is value in health care? N Engl J Med. 2010;363:
National Du Cancer; 2007. 2477-2481.
3. Porter ME. Defining and introducing value in health care. In Evidence- 6. Eddy DM. Clinical decision making: from theory to practice. Three battles
based Medicine and the Changing Nature of Health Care: 2007 Institute to watch in the 1990s. JAMA. 1993;270:520-526.
of Medicine (IOM) Annual Meeting Summary. Washington, DC: Institute 7. Rawlins MD, Chalkidou K. The opportunity cost of cancer care: a state-
of Medicine; 2008. ment from NICE. Lancet Oncol. 2011;12:931-932.

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ULKA VAISHAMPAYAN

The Role of Nephrectomy for Kidney Cancer in the Era of


Targeted and Immune Therapies
Ulka N. Vaishampayan, MD

Editors Note: The following article is based on the 2016 ASCO Annual Meeting Education Session Cytoreductive Nephrectomy in
Renal Cell Carcinoma: A Debate. The author reviews the pros and cons of cytoreductive nephrectomy and whether recent
advances in systemic therapy warrant physicians to proceed directly to systemic therapy as in other metastatic solid tumors,
without the integral step of cytoreductive nephrectomy.

OVERVIEW

Although two phase III trials support the recommendation of nephrectomy followed by interferon alpha in metastatic renal
cell carcinoma (RCC), this procedure cannot be applied to every patient with this condition. Systemic therapy has changed
from interferon alpha to antiangiogenic-targeted therapy, and the clinical impact of nephrectomy in the era of targeted
therapy has not been proven. The SEER database shows that only 35% of patients with advanced RCC undergo nephrectomy
as their initial treatment. Retrospective studies showed improved overall survival (OS) outcomes with nephrectomy and
interleukin-2 (IL-2) therapy; however, the inherent selection bias of younger and healthier patients receiving IL-2 likely
accounts for this finding. Neoadjuvant therapy has demonstrated only modest efficacy in unresectable disease, and if
remission is obtained with systemic therapy, it is unclear whether nephrectomy has any incremental benefit. In the absence
of proven benefit of nephrectomy in the setting of targeted therapy, it seems advisable for patients with RCC with severely
symptomatic disease, competing comorbidities, poor performance status, or unresectable disease to avoid nephrectomy
and proceed directly to systemic therapy. The clinical implications of deferred cytoreductive nephrectomy for patients with
metastatic RCC are poorly understood, and patient cohorts that do not undergo this procedure are likely to be comprised of
patients with unfavorable disease characteristics. Unfortunately, the completed trials of targeted therapy were 90%
comprised of patients with prior nephrectomy (the majority of trials incorporate prior nephrectomy as an eligibility re-
quirement) and hence may not reflect the outcomes of the majority of the patients with advanced RCC who have not
undergone nephrectomy. Newer therapies such as nivolumab and cabozantinib have also been evaluated for a population in
which 90% of the patients underwent nephrectomy. Future clinical trials and registry studies must focus on the therapeutic
treatment and overall outcome of patients without nephrectomy and treated with contemporary systemic therapy.

K idney cancer is one of the few malignancies in which


surgical resection of the primary disease, or cytore-
ductive nephrectomy, has held tremendous importance.
without the integral step of cytoreductive nephrectomy.
The pros and cons of this procedure are summarized in
Table 1.
Historically, systemic therapy was underdeveloped and in-
effective, and surgical resection was considered the only
hope of remission. However, an analysis of the Surveillance, NEPHRECTOMY IN THE CONTEXT OF IMMUNE
Epidemiology, and End Results Program (SEER) database THERAPY
revealed that only 539 of the 1,537 (35%) cases diagnosed Renal cell carcinoma is unique in the fact that randomized
with advanced RCC between 2000 and 2013 had nephrec- trials have actually been conducted to establish the role of
tomy as their initial therapy.1 nephrectomy in metastatic disease.24 The results revealed
The major advances in systemic therapy of RCC in recent that patients subjected to nephrectomy followed by in-
years beg the fundamental question whether a large enough terferon alpha in the presence of metastatic disease ex-
impact has been made to consider proceeding directly to perienced OS benefit (Table 2). The reasons for this
systemic therapy as in other metastatic solid tumors, benefit remain unclear. It does not appear that nephrectomy

From the Karmanos Cancer Institute, Wayne State University, Detroit, MI.

Disclosures of potential conflicts of interest provided by the author are available with the online article at asco.org/edbook.

Corresponding author: Ulka N. Vaishampayan, MD, Karmanos Cancer Institute 4100 John R St., 4233 HWRC, Detroit, MI 48201; email: vaishamu@karmanos.org.

2016 by American Society of Clinical Oncology.

e16 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


ROLE OF NEPHRECTOMY IN THE TARGETED THERAPY ERA

TABLE 1. Pros and Cons of Nephrectomy in Metastatic nephrectomy; median OS was 6.9 months in the cytore-
Renal Cell Carcinoma ductive nephrectomy arm and 4.8 months in the interferon-
alone arm.5
Pros of Nephrectomy in Cons of Nephrectomy in There are numerous reports indicating that cytoreductive
Metastatic RCC Metastatic RCC
nephrectomy improves host immune reaction to the
Control of symptoms from Complications of surgery metastases and is likely to decrease the levels of immu-
primary tumor
nosuppressive factors. It also normalized the nuclear factor-
Phase III trials showing OS benefit No benefit proven with targeted
therapy
kappa B and various other immune defects.6,7 Clinically
No change in response to systemic spontaneous regressions have been observed. A peri-
therapy operative (neoadjuvant) checkpoint inhibitor trial has
Resection of resistant clones Delay of systemic therapy been proposed based on the finding that peripheral
Long-term remissions noted with Impaired creatinine clearance, blood PD-1 expression is reduced significantly after cyto-
surgical resection of metastatic increased risk of hypertension reductive nephrectomy.8 Expression of PD-1 in tumor-
RCC
infiltrating lymphocytes was associated with a more
Nephrectomy patients comprise Unlikely to benefit patients with aggressive phenotype of RCC (larger tumors, higher nu-
90% of clinical trial patient comorbidities and impaired
population performance status clear grade, and sarcomatoid differentiation) and increased
Abbreviations: RCC, renal cell carcinoma; OS, overall survival risk of cancer-specific death, as reported in a study led
by the Mayo Clinic (risk ratio of 2.24; p = .004).9 However,
a recent report evaluating tumor PD-L1 expression in
boosted the response rates to interferon therapy, as the 417 cases of clear cell RCC from The Cancer Genome
response rate remained at a dismal 3.3% and 3.6% in the Atlas database reported a lack of association between
cytoreductive nephrectomy and interferon-alone arms, PD-L1 expression and unfavorable tumor characteristics
respectively, regardless of whether the patients were and an improved OS outcome (hazard ratio [HR] 0.59;
randomly selected to undergo nephrectomy or not. Retro- p = .006).10
spective case series have been reported favoring cytore- Unfortunately, modern immunotherapy trials cannot in-
ductive nephrectomy prior to immune therapy, such as IL-2, form the benefits of treatment for patients who have not
because of OS benefit.5 However, the inherent biases of a undergone nephrectomy. For immune checkpoint inhibitors,
retrospective study are prominently prevalent in the IL-2 the recently reported randomized trial of nivolumab versus
population, as this is a stringently selected group of patients everolimus mainly included patients who had undergone
with excellent cardiopulmonary status and no brain me- nephrectomy.11 Similarly for patients on antiangiogenic or
tastases, which predicts a better OS regardless of choice or mTOR inhibitor therapies, approximately 90% of the patients
sequence of therapy. In fact, even the patients with a included had nephrectomy prior to study enrollment.1216
performance status of 1 within the IL-2treated patient co- Studies are ongoing to evaluate the impact of PD-1 inhibition
hort had a minimal benefit in OS favoring cytoreductive on biomarkers of immune response pre- and post-nephrectomy.
Phase II trials such as ADAPTeR (NCT02446860) are assessing
the response and changes in immune-related markers after
the neoadjuvant administration of nivolumab for 8 weeks
KEY POINTS followed by nephrectomy.
Two phase III trials support the recommendation of
nephrectomy in metastatic renal cancer when
compared with interferon therapy alone; however, the
NEPHRECTOMY IN THE CONTEXT OF VEGF
clinical applicability of this finding is not clear in the era INHIBITOR THERAPY
of targeted therapy. The clinical implications of deferred nephrectomy for pa-
A delay in systemic therapy (because of nephrectomy) tients with metastatic renal cancer are not well understood.
can have deleterious effects on the survival of patients As in the case of immunotherapy trials, the percentage of
with metastatic renal cancer. patients who had undergone nephrectomy in a majority of
Patients with poor-risk disease or predicted survival less clinical trials evaluating VEGF inhibitors is greater than 90%.
than 12 months are unlikely to benefit from The report by Choueiri et al,17 which suggested that patients
nephrectomy. The clinical implications of deferred treated with targeted therapy had a Karnofsky performance
nephrectomy for patients with metastatic renal cancer status less than 80% or poor-risk disease as gauged by the
are not well understood.
Memorial Sloan Kettering Cancer Center criteria, experi-
Surveillance, Epidemiology, and End Results Program
database analysis revealed that 65% of patients with
enced no benefit from cytoreductive nephrectomy (p = .08
advanced renal cancer do not undergo nephrectomy as and .06, respectively; Table 2). A separate report used data
their initial treatment. This patient population warrants from the International Metastatic Renal Cell Carcinoma
further study, especially as it is not included in current Database Consortium database, which included 982 patients
clinical trials. treated with nephrectomy and targeted therapy and 676
patients treated with targeted therapy alone.18 Although

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ULKA VAISHAMPAYAN

TABLE 2. Summary of Study Data on Nephrectomy and Systemic Therapy


First Author, Reference Type of Study No. of Patients Results
Flanigan and Yonover2 Phase III 241 Median OS: CN + IFN: 11.1 months; IFN: 8.1 months; PFS 0; p = .05;
Median OS: CN + IFN: 17.4 months; IFN: 11.7 months; PFS 1; p = .08;
Median OS: CN + IFN: 6.9 months; IFN: 4.8 months
Mickisch et al3 Phase III 84 Median OS: CN + IFN: 17 months; IFN: 7 months (HR 0.54; 95% CI, 0.310.94)
4
Flanigan et al Meta-analysis 331 Median OS: CN + IFN: 13.6 months; IFN: 7.8 months (HR 0.69; p = .002)
Pantuck et al5 Retrospective 89 CN + IL-2: median OS, 16.7 months; 5-year OS, 19.6%
Choueiri et al17 Retrospective 314 (CN: 201; Median OS: 19.8 months (CN) vs. 9.4 months (no CN); HR 0.44; p , .01;
targeted-therapy era no CN: 113) multivariate analysis: no benefit; p = .08; poor risk: no benefit; p = .06
Heng et al18 Retrospective 1,658 (CN: 982; Median OS: 20.6 months (CN) vs. 9.5 months (no CN); p , .0001
targeted-therapy era no CN: 676)
Abbreviation: CN, cytoreductive nephrectomy; OS, overall survival; IFN, interferon; PFS, progression-free survival; N/A, not applicable.

patients treated with cytoreductive nephrectomy had sig- those without nephrectomy.5 Neoadjuvant therapy has also
nificantly better OS compared with those treated with shown only modest benefit in advanced RCC.19 In summary,
targeted agents (median OS, 20.6 vs. 9.5 months, re- until the results of randomized trials are available, no
spectively; HR 0.60; 95% CI, 0.520.69), it is important to synergy has been proven to date between targeted
recognize that selection bias is at play; patients with poor- antiangiogenic therapy and cytoreductive nephrectomy
risk disease comprised only 28% of those treated with in RCC.
cytoreductive nephrectomy versus 54% of the group who did
not undergo the procedure. In addition, only 1% of patients
who did not undergo cytoreductive nephrectomy had fa- THE IMPORTANCE OF MULTIDISCIPLINARY
vorable risk characteristics. TEAM INPUT: COLLECTIVE WISDOM AND THE
Several trials are seeking to prospectively evaluate the role FUTURE OF PATIENT-CENTERED CARE AND
of cytoreductive nephrectomy for patients being treated RESEARCH
with targeted therapy. The CARMENA trial studying ne- Typically, patients who are not offered cytoreductive ne-
phrectomy followed by sunitinib versus sunitinib alone phrectomy have poor performance status, major comor-
will likely shed light on the question of whether cyto- bidities, and limited access to care. Racial disparity in rates of
reductive nephrectomy remains relevant in the context nephrectomy has also been shown to have an impact on
of anti-VEGF therapy for metastatic renal cancer. The patient outcomes. In a SEER database analysis of advanced
primary endpoint is OS, and secondary endpoints are RCC, patients of African-American origin were noted to
progression-free survival and operative complication rates. have a worse OS outcome as compared with white patients
The study has completed accrual, and results are awai- with metastatic RCC, and an interaction effect was noted
ted. The SURTIME study is randomly selecting patients with the disparity in rates of nephrectomy.20 However,
with metastatic RCC to receive sunitinib followed by whether this finding reflects other inherent biases noted
nephrectomy versus sunitinib alone. The study will ad- above is unknown. This observation highlights the need for
dress whether patients with adequate response to sys- data collection regarding the factors commonly considered
temic therapy should receive surgical consolidation with toward the decision-making process of nephrectomy.
nephrectomy. In addition, cytoreductive nephrectomy carries a certain
risk that has to be factored into the decision. The major
complication rates of cytoreductive nephrectomy have been
SYNERGY BETWEEN NEPHRECTOMY AND reported to be about 5%, and 11% of the patients did not
SYSTEMIC THERAPY: REALITY OR PERCEPTION? start systemic therapy within 60 days after nephrectomy
Despite a hypothesized synergy between systemic therapy because of surgical complications. Overall, 61% of patients
and nephrectomy, it has not been borne out in clinical did not start systemic therapy in a timely fashion. The
practice. For example, the randomized trials of nephrectomy presence of liver metastases, intraoperative transfusion, and
and interferon versus interferon alone reported identical pathologic nodal involvement were noted to be predictors of
response rates of approximately 3% in both arms. An ad- delay of systemic therapy more than 60 days after cytore-
juvant trial of sunitnib versus sorafenib versus placebo ductive nephrectomy.21
(ASSURE/ECOG 2805) reported lack of benefit for either of It is not advisable to reflexively send the patient for ne-
the agents postnephrectomy.18 The only data that suggest phrectomy upon diagnosis of advanced kidney cancer.
potential synergy come from retrospective trials of patients Multidisciplinary evaluation to carefully weigh the risk and
treated with IL-2 showing an improved outcome achieved benefit ratio factoring in whether the bulk of the patients
for patients who underwent nephrectomy as compared with symptoms are related to the cancer or to other comorbidities

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ROLE OF NEPHRECTOMY IN THE TARGETED THERAPY ERA

would be important. Renal cancer is a heterogeneous dis- Risk of Surgical Complications


ease,22 and to date, the resection of resistant clones is still Patients with impaired performance status and comorbid-
considered an ideal way to manage the problem. Stage IV ities are likely to have a higher complication rate from
disease within RCC spans a wide spectrum of outcomes, and cytoreductive nephrectomy.
risk prognostication is critically important before nephrec-
tomy is considered.
The reported efficacy of targeted therapy for patients with CASE ILLUSTRATIONS
metastatic renal cancer is mainly known only in the setting of Deferral of Nephrectomy as a Result of Disease
cytoreductive nephrectomy. This means that current clinical Symptoms and Burden
trialbased data regarding efficacy of systemic therapy in Case 1. A 68-year-old man presented with malena, anemia
RCC do not apply to a large magnitude of the patient (hemoglobin of 4.0 g/dL), and hip pain. Imaging revealed
population treated. As systemic therapy options and effi- a large renal mass, hip metastases, and lung metastases.
cacies evolve, the role of nephrectomy requires re-evaluation. Colonoscopy showed large mucosal lesions, the biopsy of
It does not seem appropriate to subject every patient with which revealed clear cell RCC. This patient, given the life-
metastatic renal cancer to the morbidity, adverse events, threatening nature of his metastatic disease, would not be a
cost, and potential delay of systemic therapy that result candidate for nephrectomy. The patient was started on an
from the nephrectomy procedure. In addition, special oral anti-VEGF tyrosine kinase inhibitor. His hemoglobin
efforts must be made to collect information regarding the improved within 2 weeks of starting therapy, and his lesions
efficacy of specific systemic therapies for the patients who were clinically responding. Clearly, this case needed to
are not candidates for nephrectomy. It is likely that the proceed to systemic therapy rapidly, and attempting cyto-
presence of nephrectomy is an objective measure that reductive nephrectomy for this patient was likely to have
reflects a subgroup within RCC that has a distinctly favorable a deleterious effect. This case also raises the dilemma of
outcome. whether to consider a nephrectomy at a later date after initial
response to targeted therapy. There is no evidence to support
FACTORS TO BE CONSIDERED PRIOR TO that cytoreductive nephrectomy would be beneficial at this
CYTOREDUCTIVE NEPHRECTOMY time in this case. The concerns comprise discontinuing VEGF
Histology (Clear Cell or Non-clear Cell) inhibitor therapy, the regrowth potential of his disease, and
Non-clear cell histology has suboptimal systemic therapy patient safety during surgery. In a clinical trial of preoperative
options, and hence cytoreductive nephrectomy maybe a sunitinib followed by cytoreductive nephrectomy, about 36%
more important component of the management. However, (17 of 47) of patients had disease progression during the
poor prognostic characteristics such as liver metastases, break from systemic therapy, confirming the concerns re-
impaired performance status, and the unresectable nature garding this approach.19 The patient continues to be treated
of the disease should be considered as relative contrain- without nephrectomy and with systemic therapy alone.
dications to cytoreductive nephrectomy.
Case 2. A 58-year-old man presented with severe dyspnea,
noted to be related to pleural effusion. A 6-cm left-sided
Patient Performance Status renal mass was noted. Thoracentesis was performed, and
Retrospective studies show that patients with impaired lung and pleural metastases were noted. Cytology revealed
performance status failed to benefit from cytoreductive malignant cells, and biopsy of kidney revealed clear cell
nephrectomy. cancer. The patient was treated with targeted therapy and
demonstrated a response with complete resolution of the
Current/Impending Symptoms From Disease pleural effusion and stable renal mass. In this case, ne-
Delay in systemic therapy because of cytoreductive ne- phrectomy was considered advisable to render the patient in
phrectomy is a concern for symptomatic patients with RCC. clinical complete remission. However, there were valid
concerns of holding systemic therapy and risking progres-
sion of disease during cytoreductive nephrectomy and the
Burden of Metastatic Disease healing period after the procedure.
Patients with liver metastases or nodal involvement were
likely to have a higher complication rate with cytoreductive
Case 3. A 52-year-old man was hospitalized with hyper-
nephrectomy that resulted in more than a 60-day delay in
calcemia; his corrected calcium was 15 mg/dL, and workup
systemic therapy.
revealed a renal mass and bilateral lung and bone lesions,
including one in the sacrum. Biopsy of bone showed clear cell
Memorial Sloan Kettering Cancer Center Risk Criteria cancer consistent with renal primary. This patient needs to
Multivariate analysis revealed no benefit from cytoreduc- proceed directly to systemic therapy, as attempting a ne-
tive nephrectomy for patients with poor risk characteristics phrectomy in the presence of uncontrolled metastatic dis-
per the Memorial Sloan Kettering Cancer Centers risk ease would result in worsening patient condition and
classification. compromise survival outcome.

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ULKA VAISHAMPAYAN

Deferral of Nephrectomy as a Result of Comorbid CONCLUSION


Conditions Absence of cytoreductive nephrectomy is a very common oc-
Case. An 85-year-old woman with coronary artery dis- currence in advanced RCC (65% of cases) and warrants further
ease and angioplasty with stent placement 4 months clinical and research investigation. The efficacy and toxicity
ago presented with microscopic hematuria. Workup reports from clinical trials of targeted and immune therapy
revealed a 7-cm right renal mass and bilateral lung predominantly represent the patient population that has had
masses. Biopsy of the lung lesion demonstrated clear cytoreductive nephrectomy and need to be interpreted and
cell carcinoma consistent with renal primary. Cytore- applied in the appropriate context. The complication rates of
ductive nephrectomy was considered risky because of nephrectomy range from 7% to 21%19 and may have impli-
the patients cardiac condition, and, hence, systemic cations in the delay of or inability to administer systemic therapy.
therapy was started with clinical response. Currently, Outcome-based research and interventional trials focusing on
the patient remains free of progression for the last the clinical treatment of patients with metastatic RCC not un-
10 months. dergoing nephrectomy represent a critical unmet need.

References

1. National Cancer Institute. SEER*Stat Databases: November 2014 Submission. 13. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon
http://seer.cancer.gov/data/seerstat/nov2014/. Accessed March 21, 2016. alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:
2. Flanigan RC, Yonover PM. The role of radical nephrectomy in metastatic 115-124.
renal cell carcinoma. Semin Urol Oncol. 2001;19:98-102. 14. Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus,
3. Mickisch GH, Garin A, van Poppel H, et al; European Organisation for interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med.
Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical 2007;356:2271-2281.
nephrectomy plus interferon-alfa-based immunotherapy compared with 15. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or
interferon alfa alone in metastatic renal-cell carcinoma: a randomised metastatic renal cell carcinoma: results of a randomized phase III trial.
trial. Lancet. 2001;358:966-970. J Clin Oncol. 2010;28:1061-1068.
4. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy 16. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus
in patients with metastatic renal cancer: a combined analysis. J Urol. interferon alfa versus interferon alfa monotherapy in patients with
2004;171:1071-1076. metastatic renal cell carcinoma: final results of CALGB 90206. J Clin
5. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrectomy and interleukin-2 for Oncol. 2010;28:2137-2143.
metastatic renal-cell carcinoma. N Engl J Med. 2001;345:1711-1712. 17. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytore-
6. Dadian G, Riches PG, Henderson DC, et al. Immunological parameters in ductive nephrectomy on survival of patients with metastatic renal cell
peripheral blood of patients with renal cell carcinoma before and after carcinoma receiving vascular endothelial growth factor targeted
nephrectomy. Br J Urol. 1994;74:15-22. therapy. J Urol. 2011;185:60-66.
7. Uzzo RG, Clark PE, Rayman P, et al. Alterations in NFkappaB activation in 18. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients
T lymphocytes of patients with renal cell carcinoma. J Natl Cancer Inst. with synchronous metastases from renal cell carcinoma: results from
1999;91:718-721. the International Metastatic Renal Cell Carcinoma Database Consor-
8. MacFarlane AW IV, Jillab M, Plimack ER, et al. PD-1 expression on tium. Eur Urol. 2014;66:704-710.
peripheral blood cells increases with stage in renal cell carcinoma 19. Haas NB, Manola J, Uzzo R, et al. Initial results from ASSURE (E2805):
patients and is rapidly reduced after surgical tumor resection. Cancer adjuvant sorafenib or sunitinib for unfavorable renal carcinoma, an
Immunol Res. 2014;2:320-331. ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol. 2015;33;(suppl; abstr
9. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor- 403).
infiltrating immune cells and is associated with poor outcome for 20. Vaishampayan U, Vankayala H, Vigneau FD, et al. The effect of targeted
patients with renal cell carcinoma. Clin Cancer Res. 2007;13:1757-1761. therapy on overall survival in advanced renal cancer: a study of the
10. Peters I, Tezval H, Kramer MW, et al. Implications of TCGA network data national surveillance epidemiology and end results registry database.
on 2nd generation immunotherapy concepts based on PD-L1 and PD-1 Clin Genitourin Cancer. 2014;12:124-129.
target structures. Aktuelle Urol. 2015;46:481-485. 21. Gershman B, Moreira DM, Boorjian SA, et al. Comprehensive charac-
11. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 In- terization of the perioperative morbidity of cytoreductive nephrec-
vestigators. Nivolumab versus everolimus in advanced renal-cell car- tomy. Eur Urol. 2016;69:84-91.
cinoma. N Engl J Med. 2015;373:1803-1813. 22. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and
12. Escudier B, Eisen T, Stadler WM, et al; TARGET Study Group. Sorafenib in branched evolution revealed by multiregion sequencing. N Engl J Med.
advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134. 2012;366:883-892.

e20 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


BREAST CANCER

Breast Cancer Survivorship:


Strategies for Optimal Care

CHAIR
Beverly Moy, MD, MPH
Massachusetts General Hospital Cancer Center
Boston, MA

SPEAKERS
Debra L. Barton, PhD, AOCN, RN
University of Michigan
Ann Arbor, MI

William J. Gradishar, MD
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Chicago, IL

Michelle E. Melisko, MD
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, CA
MELISKO, GRADISHAR, AND MOY

Issues in Breast Cancer Survivorship: Optimal Care, Bone


Health, and Lifestyle Modifications
Michelle E. Melisko, MD, William J. Gradishar, MD, and Beverly Moy, MD, MPH

OVERVIEW

There are an estimated 3.1 million survivors of breast cancer in the United States. The predominant reasons for this
substantially large population are that breast cancer is the most common noncutaneous malignancy among women and that
5-year survival rates after breast cancer treatment are approximately 90%. These patients have many medical consid-
erations, including the need to monitor for disease recurrence and to manage complications of their previous cancer
treatments. Most patients remain at risk indefinitely for local and systemic recurrences of their breast cancers and have an
increased risk of developing contralateral new primary breast cancers. Therefore, optimizing care for this patient population
is critical to the overall health care landscape in the United States. Here, we summarize survivorship care delivery and its
challenges, the optimization of bone health in breast cancer survivors, and opportunities for risk reduction through lifestyle
modifications.

T here are an estimated 3.1 million survivors of breast


cancer in the United States.1 The predominant reasons
for this substantially large population are that breast cancer
From an economic perspective, breast cancer is the
costliest of all cancers, with an estimated $18.1 billion of
national expenditures in the United States in 2014. Almost
is the most common noncutaneous malignancy among $8 billion of these expenditures are for the costs of survi-
women and that 5-year survival rates after breast cancer vorship care.3 This proportional cost of breast cancer care
treatment are approximately 90%.2 In recognition of the exceeds the annual expenditures for the entire treatment of
importance of breast cancer survivorship care, multiple other types of cancer, such as leukemia and ovarian, brain,
medical organizations, including the Institute of Medicine, head and neck, or pancreatic cancer.
American Society of Clinical Oncology (ASCO), American Despite the calls for action from multiple prestigious
Cancer Society, and the Commission on Cancer, have high- medical societies and the reality of the various medical and
lighted the importance of addressing the many issues and economic challenges, to date, there is no universally agreed
concerns of breast cancer survivors following treatment. The upon standardized follow-up model for patients with early-
medical community recognizes the multiple challenges for stage breast cancer who have completed active cancer therapy.
breast cancer survivors that follow-up care creates. In addi- Barriers to survivorship care implementation are well docu-
tion to the significant logistics required to care for a large mented and include challenges with staffing and resources.4,5
population of breast cancer survivors, reasons for these Many societies have recommended that every patient receive a
challenges include the long course of disease, a relentless risk survivorship care plan that details follow-up care plans, a sur-
of recurrence even 15 to 20 years after the original diagnosis, veillance plan, and general health recommendations.6 However,
the need for endocrine therapy for 5 to 10 years in most survivorship care plan adoption in oncology clinics is highly
patients, and the need to continue screening because of a 1% variable, and there is insufficient evidence that the plans
risk per year of new contralateral primary breast cancers. improve outcomes for patients.4,7
Clinicians must address the physical, emotional, social, and There are three models of comprehensive survivorship
long-term effects faced by many breast cancer survivors after care delivery found in academic medical centers.8 The first
they complete active treatment. These long-term effects model consists of consultative clinics that offer a one-time
include anxiety and depression, vasomotor symptoms, cog- survivorship visit for patients when active therapy is com-
nitive dysfunction, fatigue, pain, sexual dysfunction, loss of plete. The second model consists of advanced care
bone density, infertility, neuropathy, and cardiac toxicity. practitionerled survivorship clinics, during which patients

From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mas-
sachusetts General Hospital Cancer Center, Boston, MA.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Beverly Moy, MD, Massachusetts General Hospital Cancer Center, 55 Fruit St., Boston, MA 02114; email: bmoy@partners.org.

2016 by American Society of Clinical Oncology.

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ISSUES IN BREAST CANCER SURVIVORSHIP

meet with nurse practitioners or physician assistants either reassurance, and, oncologists, driven by a sense of duty to
in a stand-alone clinic or embedded within the oncology their patients, may be unwilling to relinquish control of their
practice. The patient is then transitioned back to primary care patients medical care after developing close relationships
as appropriate. The third model is a multidisciplinary survivor during active cancer treatment. Furthermore, primary care
program that relies on collaboration between oncologists, physicians may be uncomfortable taking the lead in caring for
advanced care practitioners, social workers, and psychologists these patients because they may feel ill-prepared to manage
to provide comprehensive care. the many issues faced by breast cancer survivors. Regarding
Some policymakers would argue that follow-up care of these specific guidance for medical care, we lack evidence about
patients can be transitioned to primary care physicians on the whether certain types of breast cancer, such as locally ad-
basis of randomized trial results that show equivalent out- vanced or hormone receptornegative disease, would benefit
comes with follow-up by either the oncologist or primary care from more intensive follow-up and imaging. Finally, with the
physician.9-12 The most compelling data are from a study in lack of interinstitutional standards, providers may worry about
which 968 women with early-stage breast cancer were ran- the risk of being sued if they decrease their follow-up visits or
domly assigned to follow-up care with either a family physician imaging studies.
or an oncologist.9 Recurrence rates, mortality rates, and rates There have been multiple efforts to provide clinical
of serious clinical events, such as spinal cord compression, guidance on how best to care for breast cancer survivors.
pathologic fractures, brachial plexopathy, or hypercalcemia, The National Comprehensive Cancer Network (NCCN) issued
were equivalent in both the family physician and the oncol- guidelines for the treatment of breast cancer, which in-
ogist groups. Health-related quality of life was also similar in cluded information on recommended surveillance for cancer
both groups. Lending additional support to simplifying follow- recurrence or new cancers.17 Both ASCO and NCCN have
up for breast cancer survivors, a British study revealed that symptom-specific survivorship care guidelines to address
twice as many patients preferred simpler, less frequent follow- issues such as cardiac toxicity and neuropathy.18,19 Recently,
up by telephone.13 Finally, patients are less likely to demand ASCO and the American Cancer Society jointly issued a
medically inappropriate testing, such as imaging or tumor breast cancer survivorship care guideline to provide con-
markers, if they are educated about the specificity, sensitivity, crete recommendations to assist clinicians, both oncologists
and usefulness of the available tests.14 and primary care physicians, in the care of these patients.20
These studies beg the question: Are we providing exces- Among the concrete recommendations, there is a recom-
sively redundant care to breast cancer survivors? In the current mendation patients receive a history and physical every 3 to
health care climate with finite resources, are oncology pro- 6 months for the first 3 years after primary therapy, every 6
viders obligated to be more discriminating about the to 12 months for the next 2 years, and annually thereafter.
amount of care we provide?15,16 There are myriad reasons Supported by the recommendations made by the ASCO
why oncology providers are not prepared to relinquish the Choosing Wisely campaign, clinicians should not offer rou-
care of breast cancer survivors. Providers and patients often tine laboratory tests or imaging, except mammography if
feel emotionally attached to each other. It is not uncommon indicated, for the detection of disease recurrence in the
for patients to want to see their oncologists more often for absence of symptoms.21 The guideline also recommends that
the cancer treatment team provides a treatment summary
and survivorship care plan to primary care clinicians.
These and other similar guidelines are helpful. However,
KEY POINTS they still provide ambiguity about the ideal models for care
and the appropriate intervals between follow-up exami-
Care for the estimated 3.1 million survivors of breast
cancer is logistically and medically complex, given the
nations. A history and physical every 3 to 6 months amounts
long course of disease, continued risk of recurrence, and to a difference of two to four clinician visits per year. Can
treatment-related side effects. these visits be shared between primary care physicians,
Additional research to provide evidence about the medical oncologists, surgical oncologists, and radiation
optimal way to deliver survivorship care to this large and oncologists? Would patients benefit more from increased
growing population is needed. care coordination? From a purely economical point of view,
To date, there is no uniform consensus about the role of one could argue that biannual visits by any oncology pro-
bone-modifying agents in the treatment of early-stage vider or by a primary care physician in an otherwise healthy
breast cancer. asymptomatic patient would be supported by the evidence
Data on breast cancer risk reduction are based on and may provide the most value in terms of containing
multiple epidemiologic studies.
medical costs. However, certain higher-risk patient pop-
Independent of the potential for reducing risk of breast
cancer recurrence, strong evidence exists that lifestyle
ulations may benefit from more intensive follow-up care.
factors, such as modification of diet, increasing physical Unfortunately, we lack clear evidence to be able to identify
activity, weight management, and smoking cessation, these patient subgroups. There is a pressing need for ad-
influence other medical comorbidities that ultimately ditional research to provide evidence about the optimal way
impact overall survival. to deliver care to a large and growing breast cancer survi-
vorship population.

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MELISKO, GRADISHAR, AND MOY

BONE HEALTH AGENTS IN BREAST CANCER The phase III ABSCG-18 trial was presented by Gnant et al at
The role of bone agents in the treatment of patients with the 2015 San Antonio Breast Cancer Symposium, in which
early-stage breast cancer has fallen under two broad cate- postmenopausal women with nonmetastatic breast cancer
gories: the established role of preventing loss of bone density were randomly assigned to receive the RANK ligand inhibitor,
and the more contentious role of reducing the risk of re- denosumab, or placebo in addition to aromatase inhibitor
currence of breast cancer.22-25 The two classes of bone agents therapy. 37 Previous results from the ABCSG-18 trial de-
used are bisphosphonates, of which several agents currently monstrated a reduced fracture rate with adjuvant denosumab
are in use, and RANK ligand inhibitors, of which there is one, compared with placebo in postmenopausal women with
denosumab. Cancer treatmentinduced bone loss is an iat- hormone receptorpositive breast cancer who were treated
rogenic disease, a condition created by breast cancer treat- with aromatase inhibitors.16 In the most recent presentation,
ments. It is well known that various cancer therapies (e.g., the primary outcomes were related to bone health, and the
aromatase inhibitors, chemotherapy, and surgery) decrease secondary outcomes included DFS. In an intention-to-treat
bone mineral density and increase the risk of fracture.26 analysis, the impact of denosumab on DFS reached borderline
Treatment-related fractures lead to decreased quality of life significance (hazard ratio [HR] 0.82; 95% CI, 0.661.00). The
and shorter survival times, which translate into clinical, social, benefit was approximately 1% after 3 years, 2% after 5 years,
and economic consequences.27,28 and 3% after 7 years of follow-up. Exploratory subgroup an-
The ABCSG-12,26,29,30 Z-FAST,31,32 and ZO-FAST33,34 trials alyses suggested that the benefit increases when denosumab
have shown that bone-targeted agents can prevent cancer is started early, along with aromatase inhibitor therapy, and
that the benefit is greater in patients who have larger tumors
treatmentinduced bone loss in early breast cancer. In the
and ductal histology. Overall, the DFS benefit seen with
ZO-FAST trial,29,33,34 up-front zoledronic acid increased bone
denosumab was comparable to that reported in the meta-
mineral density in both the lumbar spine and hip. Gnant
analysis of bisphosphonates.16
et al26,29,30 reported that the addition of zoledronic acid to
The debate about these data largely revolves around how
both tamoxifen and anastrozole yielded no treatment-
to translate the apparent benefit into day-to-day manage-
induced bone loss compared with treatment without the
ment decisions. Different bone agents were used in the
bone-strengthening agent. Additionally, denosumab pro-
trials, the trial designs were meant to evaluate primarily
duced similar results, with increases in bone mineral density
bone health endpoints with DFS as a secondary endpoint,
seen over 24 months in trabecular and cortical bone in women
duration of therapy is an open question, and which post-
with nonmetastatic breast cancer and low bone mass who
menopausal patients should be considered for this type of
were receiving adjuvant aromatase inhibitor therapy.35 adjuvant therapy remains unclear. To date, though the data
The issue of adjuvant bisphosphonate therapy in breast
are compelling, the NCCN guideline panel could not reach
cancer has been an area controversy. The results from several
consensus for supporting these bone agents as a compo-
long-term, large clinical trials have added to the confusion. nent of adjuvant therapy of breast cancer. That said, indi-
Improvements in disease-free survival (DFS) were reported vidual patients who have any issues with bone density or
in postmenopausal women who were treated with letrozole increased risks of fracture may reap the benefits on bone
and zoledronic acid compared with letrozole alone (ZO- health as well as some additional reduction in the risk of
FAST).29,33,35 In contrast, the findings of the AZURE trial35 did disease recurrence.
not support the routine use of zoledronic acid in the ad-
juvant management of breast cancer; no significant benefits
in DFS and overall survival (OS) were reported. In both the RISK REDUCTION THROUGH LIFESTYLE
ABCSG-1226,30 and AZURE35 trials, adjuvant bisphosphonates MODIFICATIONS
offered an advantage to postmenopausal women, regardless of After a breast cancer diagnosis, most patients have great
whether their postmenopausal status occurred naturally or was interest in adoption of lifestyle changes that might reduce
drug induced. In the results of the 9-year update of the ABCSG- their risk of cancer recurrence. Despite significant advances
12 trial, there was a persistent benefit in DFS with zoledronic in breast cancer therapies that are supported by randomized
acid in a low-estrogen environment (e.g., a postmenopausal clinical trials demonstrating benefits in DFS and OS, the data
state). The meta-analysis of 36 trials by Coleman et al,36 which on risk reduction through lifestyle modifications are more
evaluated nearly 23,000 women, focused on the use of limited and are primarily based on epidemiologic studies.
bisphosphonates in the adjuvant setting. Although no effects on Patients, the lay press, and physicians alike often confuse the
disease outcomes in premenopausal women were observed, data about which lifestyle factors may impact risk of de-
adjuvant bisphosphonates reduced bone metastases and im- veloping breast cancer compared with those factors that
proved survival in women who had low levels of reproductive have an influence on recurrence after diagnosis. Strong
hormones (which included women older than age 55 if men- evidence exists that, independent of the potential for re-
opausal status was unknown). There was a 34% reduction in the ducing risk of breast cancer recurrence, lifestyle factors that
risk of bone recurrence (p = .00001) and a 17% reduction in the include modification of diet, increasing physical activity,
risk of breast cancer death (p = .004). No significant reduction weight management, and smoking cessation influence other
was reported in first distant tumor recurrence outside of bone. medical comorbidities that ultimately impact OS. Similarly,

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ISSUES IN BREAST CANCER SURVIVORSHIP

lifestyle and treatment factors also contribute to an in- maintenance (# 5.0% weight change) was associated with
creased risk of second primary malignancies seen among increased all-cause mortality (HR 1.12). In a secondary
breast survivors.38 analysis to evaluate effects of the amount of weight gain,
moderate-level weight gain (5%10% compared with main-
Management of Comorbidities tenance of baseline weight) was not associated with a hazard
Cancer survivors face many health challenges, including of overall mortality (HR 0.97; 95% CI, 0.861.11; p = .70), but
morbidity from residual treatment toxicity and increased higher weight gain (. 10% from baseline compared with
mortality from cardiovascular and respiratory diseases. The maintenance) was associated with increased mortality (HR
impact of comorbidities on survival after a diagnosis of 1.23; 95% CI, 1.091.39; p , .001). Among studies for which
breast cancer cannot be underestimated. Among 63,566 data were available, weight gain among patients who were
women diagnosed with breast cancer who were older than already overweight at baseline (body mass index [BMI] .
age 66 and identified through the Surveillance, Epidemiol- 25.0 kg/m2) did not result in worse mortality. In terms of breast
ogy, and End Results database, age and comorbidities at the cancer outcomes, moderate weight gain (5%10%) was not
time of diagnosis had the largest effects on mortality from associated with breast cancerspecific mortality, whereas
causes other than breast cancer.39 The presence of car- there was a suggestion that weight gain of greater than 10%
diovascular disease, chronic obstructive pulmonary disease, was associated with breast cancerspecific mortality (HR 1.17;
or diabetes increased breast cancerspecific mortality by 95% CI, 1.001.38; p = .05). Interestingly, in the studies within
between 10% and 24%. Among this study population, car- this meta-analysis that included data, no amount of weight
diovascular disease was the primary cause of death in 15.9% gain was associated with an increase in breast cancer recur-
of women, followed closely by breast cancer in 15.1%. Al- rences.47,48 The reason for this may be that a larger number of
though this study focused on an older population with breast patients would be required to demonstrate a relatively small
cancer, exposure to radiation, anthracyclines, and trastu- contribution of weight gain on breast cancer recurrences.
zumab are all associated with a small risk of cardiac toxicity Alternatively, the negative impact of weight gain on mortality
that may subsequently result in excess morbidity and, in and possibly breast cancerspecific mortality after diagnosis of
some cases, mortality.39 In addition, the long-term impacts breast cancer may not be due to increased rate of recurrence
of inducing premature menopause and of treatment with but, rather, to the overall health, comorbidities, treatment
an aromatase inhibitor on cardiovascular health in younger patterns, and responses to treatment after recurrence among
breast cancer survivors are still unknown. Studies to in- patients with significant weight gain.
vestigate beta blockers, angiotensin-converting enzyme
inhibitors, and statins to reduce the risk of cardiac toxicity Weight Loss Interventions
during and after treatment with anthracyclines and tras- No matter what the underlying cause, avoidance of signif-
tuzumab have shown some promise, but none of these icant weight gain after a diagnosis of breast cancer is a de-
pharmacologic interventions have become standard of sirable goal to improve OS. The challenge of avoiding weight
care.40-42 Attention to reducing the risk of subsequent gain is substantial for breast cancer survivors, many of whom
cardiovascular disease should be a priority after the di- enter menopause abruptly as a result of chemotherapy and
agnosis and treatment of breast cancer. some of whom remain on hormonal therapy as long as 10
years. Additionally, many patients suffer ongoing toxicities
Weight Gain from their treatment, including fatigue, sleep disturbance,
Weight gain is common during and after treatment of breast neuropathy, and arthralgias, all which may interfere with the
cancer and may be even more pronounced in patients who ability to initiate and maintain an exercise program supportive
are overweight or obese prior to diagnosis.43 Factors con- of weight control.
tributing to weight gain include use of corticosteroid pre- There have been numerous weight loss intervention
medications with chemotherapy, decreased physical activity studies among breast cancer survivors. A recent systematic
during treatment, transition into menopause, and ongoing review included 15 studies, among which were eight ran-
hormonal therapy.44 Weight gain after diagnosis has been domized controlled trials, four single-cohort experimental
associated with a higher rate of breast cancer recurrences intervention studies, two randomized parallel-intervention
and with worse OS. In an analysis of a cohort of 3,993 women trials, one randomized crossover trial, and one controlled
identified through state registries who were diagnosed with nonrandomized trial.49 The primary objective of each of
stage I to III breast cancer, each 5-kg gain was associated these studies was weight loss intervention with a focus on
with a 12% increase in all-cause mortality, a 13% increase in changing body weight (measured as change in weight, BMI,
breast cancerspecific mortality, and a 19% increase in percentage body fat, or percent overweight). Studies de-
cardiovascular disease mortality.45 A systematic review and signs included multicomponent interventions that in-
meta-analysis that included a total of 12 cohort studies and corporated diet, physical activity, and behavior modification,
clinical trials with a total of 23,832 patients measured weight whereas other studies combined personalized lifestyle
change after breast cancer diagnosis and investigated breast telephone counseling with face-to-face group-based edu-
cancerspecific mortality, all-cause mortality, and recur- cation. Several studies used a commercial weight loss
rence outcomes.46 Weight gain ($ 5.0%) compared with programs, such as Weight Watchers and/or Curves,50,51 and

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MELISKO, GRADISHAR, AND MOY

one study incorporated group teleconferencing for breast The Womens Healthy Eating and Living (WHEL) randomized
cancer survivors in rural locations.52 trial tested whether increasing vegetable, fruit, and fiber intake
Of the 15 studies included in this systematic review, 14 and decreasing dietary fat intake could reduce the risk of re-
resulted in significant weight loss; weight loss of 5% or greater currence or new primary breast cancer and impact mortality in
from baseline was reported in 10 of the studies (p , .001). patients with early-stage breast cancer.55 A total of 3,088
Unfortunately, weight regain was observed in some women were randomly assigned to an intervention arm to
studies that included longer follow-up. For example, in the receive telephone counseling, cooking classes, and newsletters
Exercise and Nutrition to Enhance Recovery and Good promoting high fruit and vegetable intake, increasing fiber, and
Health for You (ENERGY) study, 692 overweight or obese reducing energy intake from fat, or to a comparison group that
breast cancer survivors were randomly assigned to either a was provided only with print materials. Analysis validated by
group-based behavioral intervention, supplemented with plasma carotenoid concentrations indicated that the inter-
telephone counseling and tailored newsletters, or to a less- vention group maintained significant differences compared
intensive control intervention to encourage weight loss. with the control group for increased fruit, vegetable, and fiber
Greater weight loss was observed in the intervention than in intake and reduction in fat through 4 years of follow-up. After a
the control group at 12 months (6% vs. 1.5%) and was still mean follow-up time of 7.3 years, there were no differences
maintained but was less pronounced at 24 months (3.7% vs. between the intervention and control groups for recurrence of
1.3%). Improvements in blood pressure control and physical invasive or noninvasive breast cancer or death. Explanations of
activity were also observed in the intervention arm.53 this lack of treatment effect included the fact that many WHEL
participants had already changed their dietary patterns after
Dietary Interventions diagnosis of breast cancer, so 75% of patients were already
The evidence to support specific dietary recommendations consuming at least five servings of vegetables and fruit a day at
after a diagnosis of breast cancer is surprisingly limited and is baseline; results suggest that intake of fruits and vegetables
backed by only a handful of randomized clinical trials, few of beyond that amount may not be beneficial. Multiple sub-
which achieved the desired endpoints of either reduction in sequent endocrinologic and behavioral findings and subset
breast cancer recurrences or improvement in DFS or OS. analyses have been reported from the data collected from this
The Womens Intervention Nutrition Study (WINS) was a very well-conducted trial, which demonstrates the importance
randomized prospective multicenter clinical trial that of this study despite its negative results.
included a total of 2,437 patients with early-stage breast
cancer to test the effect of a dietary intervention designed to Exercise
reduce fat intake.54 The goal of the dietary intervention was Physical activity has been shown to improve quality of life
to reduce percentage of calories from fat to 15%, such that after a breast cancer diagnosis.56 Multiple cohort studies
there would actually be a sustained reduction in fat intake to have investigated the impact of physical activity after di-
approximately 20% of calories in the intervention arm. The agnosis on breast cancerspecific and overall mortalities.
low-fat eating plan included self-monitoring (fat gram Most of these studies describe exercise frequency and in-
counting and recording), goal setting, modeling, and relapse tensity in metabolic equivalent (MET) hours, for which 3 MET
support and involved multiple in-person counseling sessions hours is equivalent to walking at average pace of 2 to 2.9 mph
initially and then subsequent contact with a dietician every for 1 hour. Among 2,987 patients with early-stage breast cancer
3 months. The patients in the control group had a baseline in the Nurses Health Study, the relative risk of death from
dietician visit and then visits every 3 months, during which breast cancer, compared with women who engaged in fewer
general dietary guidelines were reviewed. At a median than 3 MET hours per week of physical activity, for patients with
follow-up time of 60 months, an interim analysis demon- 9 to 14.9 MET hours per week of exercise was 0.50 (95% CI,
strated that dietary fat intake was significantly lower in the 0.310.82); for patients with 15 to 23.9 MET hours per week
intervention than in the control group (p , .001), and the was 0.56 (95% CI, 0.380.84); and for patients with 24 or more
effect was maintained out to 60 months. Additionally, there MET hours per week was 0.60 (95% CI, 0.400.89). Absolute
was a 6-pound lower mean body weight in the intervention mortality risk was also reduced by 6% at 10 years for women
group. The hazard of relapse events (local, regional, distant, who engaged in 9 or more MET hours per week.57
or ipsilateral breast cancer recurrence or new contralateral In the Collaborative Womens Longevity Study (CWLS),
breast cancer) in the intervention group compared with the 4,482 women completed questionnaires on postdiagnosis
control group was 0.76 (95% CI, 0.600.98). Subgroup an- physical activity and other lifestyle factors. Compared
alyses were conducted on the basis of BMI, hormone re- with women engaging in fewer than 2.8 MET hours per
ceptor status, and nodal status, and the dietary intervention week of physical activity, women who engaged in greater
had a greater effect on relapse-free survival in women with levels of activity ($ 21 MET hours per week) had a sig-
estrogen receptornegative cancer (HR 0.58; 95% CI, nificantly lower risk of dying as a result of breast cancer
0.370.91) than in women with estrogen receptorpositive (HR 0.51; 95% CI, 0.290.89; p = .05) and had improved OS
disease (HR 0.85; 95% CI, 0.631.14). In this analysis, with a (HR 0.44; 95% CI, 0.320.60; p , .001). These results were
60-month median follow-up time, there was no difference in consistent independent of age, stage of disease, and
OS between the dietary intervention and control groups. BMI.58

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In two smaller-sized cohorts (1,970 women in The Life After with no drinking was associated with an increased risk of
Cancer Epidemiology [LACE] study and 933 women in the breast cancer recurrence (HR 1.35; 95% CI, 1.001.83) and
Health, Eating, Activity and Lifestyle [HEAL] study), greater death as a result of breast cancer (HR 1.51; 95% CI,
physical activity after diagnosis was associated with a de- 1.002.29). The increased risk of recurrence was most
crease in overall mortality but not in breast cancerspecific pronounced in postmenopausal and overweight/obese
mortality.59,60 women. Alcohol intake was not associated with overall
A longitudinal study of 4,643 women diagnosed with in- mortality, possibly because of a cardioprotective effect
vasive breast cancer after entry into the Womens Health and a reduction in noncancer deaths.61
Initiative study evaluated the association between change in In contrast to the findings in the LACE cohort, alcohol
physical activity from before diagnosis to after diagnosis with intake was not significantly associated with breast cancer
all-cause and breast cancerspecific mortalities. Physical ac- recurrence in 3,088 patients participating in the WHEL
tivity was reported at baseline (before breast cancer diagnosis) trial.62 Among this group of patients, moderate alcohol
and after diagnosis (3 or 6 years after baseline visit). Women intake (. 300 g/month or seven drinks a week) was as-
who engaged in moderate levels of physical activity (fast walking sociated with improved all-cause mortality (HR 0.69; 95%
for 3 hours/week) before diagnosis had lower all-cause mortality CI, 0.490.97) when analysis was adjusted for obesity. One
(HR 0.61; 95% CI, 0.440.87; p = .01) than inactive women. explanation for this may be that obese women were more
Women engaging in similar moderate physical activity levels likely to be nondrinkers, and patients with moderate al-
after diagnosis had both lower breast cancer mortality (HR 0.61; cohol consumption may engage in protective behaviors,
95% CI, 0.350.99; p = .049) and lower all-cause mortality (HR such as increased physical activity.
0.54; 95% CI, 0.380.79; p , .01). Women who increased or In the After Breast Cancer Pooling Project, which included
maintained physical activity of 9 or more MET hours per week 9,329 patients with breast cancer (more than half of whom
after diagnosis had lower all-cause mortality (HR 0.67; 95% CI, were part of the LACE and WHEL cohorts), regular alcohol
0.460.96) even if they were inactive before diagnosis.59 intake ($ 6.0 g/day) had no effect on breast cancer recurrence
With the abundance of epidemiologic data demonstrating or overall mortality among the entire population. However,
the benefit of exercise after diagnosis of breast cancer, nu- among women who were postmenopausal, alcohol con-
merous randomized prospective trials are ongoing to better sumption of 6.0 or more g/day was associated with increased
understand which interventions are most effective to increase breast cancer recurrence (HR 1.19; 95% CI, 1.011.40).61
physical activity, what levels and types of physical activity are
optimal, and if associated lifestyle factors have an interaction
with the benefit of exercise. CONCLUSION
Breast cancer survivorship care has emerged as a high-
Alcohol Consumption priority issue in the oncology community, given its large
There is reasonably strong evidence that moderate alcohol and growing population. Breast cancer survivors face
consumption increases the risk of developing breast cancer, multiple complex issues, including optimization of bone
but the effect of ongoing alcohol intake after diagnosis is health and lifestyle considerations. Clinicians caring for
less clear. In the LACE cohort consisting of 1,897 patients this substantial population must be knowledgeable on
with early-stage breast cancer who enrolled on average 2 many medical issues and must be prepared to counsel
years after diagnosis, self-reported drinking of 6 g/day or their patients on the best health promotion strategies to
more of alcohol (approximately 2.5 ounces of wine, 6 minimize risks of recurrence and long-term side effects of
ounces of beer, or 1.5 ounces of hard liquor) compared their treatments.

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24. Strobl S, Korkmaz B, Devyatko Y, et al. Adjuvant bisphosphonates and 2474-2481.
breast cancer survival. Annu Rev Med. 2016;67:1-10. 41. Seicean S, Seicean A, Plana JC, et al. Effect of statin therapy on the risk
25. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al; Austrian Breast for incident heart failure in patients with breast cancer receiving
and Colorectal Cancer Study Group (ABCSG). Adjuvant endocrine anthracycline chemotherapy: an observational clinical cohort study.
therapy plus zoledronic acid in premenopausal women with early-stage J Am Coll Cardiol. 2012;60:2384-2390.
breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density 42. Pituskin E, Mackey JR, Koshman S, et al. Prophylactic beta blockade
substudy. Lancet Oncol. 2008;9:840-849. preserves left ventricular ejection fraction in HER2-overexpressing
26. Ezat SW, Syed Junid SM, Noraziani K, et al. Skeletal-related events breast cancer patients receiving trastuzumab: primary results of the
among breast and prostate cancer patients: towards new treatment MANTICORE randomized controlled trial. Presented at: San Antonio
initiation in Malaysias hospital setting. Asian Pac J Cancer Prev. 2013; Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX.
14:3357-3362. Abstract S1-05.
27. Hagiwara M, Delea TE, Chung K. Healthcare costs associated with 43. Chlebowski RT, Aiello E, McTiernan A. Weight loss in breast cancer
skeletal-related events in breast cancer patients with bone metastases. patient management. J Clin Oncol. 2002;20:1128-1143.
J Med Econ. 2014;17:223-230. 44. Goodwin PJ, Ennis M, Pritchard KI, et al. Adjuvant treatment and onset
28. Gnant M, Eidtmann H. The anti-tumor effect of bisphosphonates ABCSG- of menopause predict weight gain after breast cancer diagnosis. J Clin
12, ZO-FAST and more. Crit Rev Oncol Hematol. 2010;74:S2-S6 (suppl 1). Oncol. 1999;17:120-129.
29. Gnant M, Mlineritsch B, Stoeger H, et al; Austrian Breast and Colorectal 45. Nichols HB, Trentham-Dietz A, Egan KM, et al. Body mass index before
Cancer Study Group, Vienna, Austria. Adjuvant endocrine therapy plus and after breast cancer diagnosis: associations with all-cause, breast
zoledronic acid in premenopausal women with early-stage breast cancer, and cardiovascular disease mortality. Cancer Epidemiol Bio-
cancer: 62-month follow-up from the ABCSG-12 randomised trial. markers Prev. 2009;18:1403-1409.
Lancet Oncol. 2011;12:631-641. 46. Playdon MC, Bracken MB, Sanft TB, et al. Weight gain after breast
30. Brufsky AM, Bosserman LD, Caradonna RR, et al. Zoledronic acid ef- cancer diagnosis and all-cause mortality: systematic review and meta-
fectively prevents aromatase inhibitor-associated bone loss in post- analysis. J Natl Cancer Inst. 2015;107:djv275.
menopausal women with early breast cancer receiving adjuvant 47. Caan BJ, Emond JA, Natarajan L, et al. Post-diagnosis weight gain and
letrozole: Z-FAST study 36-month follow-up results. Clin Breast Cancer. breast cancer recurrence in women with early-stage breast cancer.
2009;9:77-85. Breast Cancer Res Treat. 2006;99:47-57.

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ISSUES IN BREAST CANCER SURVIVORSHIP

48. Jeon YW, Lim ST, Choi HJ, et al. Weight change and its impact on prognosis 55. Pierce JP, Natarajan L, Caan BJ, et al. Influence of a diet very high in
after adjuvant TAC (docetaxel-doxorubicin-cyclophosphamide) chemo- vegetables, fruit, and fiber and low in fat on prognosis following
therapy in Korean women with node-positive breast cancer. Med Oncol. treatment for breast cancer: the Womens Healthy Eating and Living
2014;31:849. (WHEL) randomized trial. JAMA. 2007;298:289-298.
49. Playdon M, Thomas G, Sanft T, et al. Weight loss intervention for breast 56. Daley AJ, Crank H, Saxton JM, et al. Randomized trial of exercise therapy
cancer survivors: a systematic review. Curr Breast Cancer Rep. 2013;5: in women treated for breast cancer. J Clin Oncol. 2007;25:1713-1721.
222-246. 57. Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival
50. Djuric Z, DiLaura NM, Jenkins I, et al. Combining weight-loss counseling after breast cancer diagnosis. JAMA. 2005;293:2479-2486.
with the weight watchers plan for obese breast cancer survivors. Obes 58. Holick CN, Newcomb PA, Trentham-Dietz A, et al. Physical activity and
Res. 2002;10:657-665. survival after diagnosis of invasive breast cancer. Cancer Epidemiol
51. Greenlee HA, Crew KD, Mata JM, et al. A pilot randomized controlled Biomarkers Prev. 2008;17:379-386.
trial of a commercial diet and exercise weight loss program in minority 59. Irwin ML, McTiernan A, Manson JE, et al. Physical activity and survival in
breast cancer survivors. Obesity (Silver Spring). 2013;21:65-76. postmenopausal women with breast cancer: results from the womens
52. Befort CA, Klemp JR, Austin HL, et al. Outcomes of a weight loss in- health initiative. Cancer Prev Res (Phila). 2011;4:522-529.
tervention among rural breast cancer survivors. Breast Cancer Res 60. Sternfeld B, Weltzien E, Quesenberry CP Jr, et al. Physical activity and
Treat. 2012;132:631-639. risk of recurrence and mortality in breast cancer survivors: findings from
53. Rock CL, Flatt SW, Byers TE, et al. Results of the Exercise and Nutrition to the LACE study. Cancer Epidemiol Biomarkers Prev. 2009;18:87-95.
Enhance Recovery and Good Health for You (ENERGY) trial: a behavioral 61. Kwan ML, Chen WY, Flatt SW, et al. Postdiagnosis alcohol consumption
weight loss intervention in overweight or obese breast cancer survivors. and breast cancer prognosis in the after breast cancer pooling project.
J Clin Oncol. 2015;33:3169-3176. Cancer Epidemiol Biomarkers Prev. 2013;22:32-41.
54. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction 62. Flatt SW, Thomson CA, Gold EB, et al. Low to moderate alcohol intake is
and breast cancer outcome: interim efficacy results from the Womens not associated with increased mortality after breast cancer. Cancer
Intervention Nutrition Study. J Natl Cancer Inst. 2006;98:1767-1776. Epidemiol Biomarkers Prev. 2010;19:681-688.

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BREAST CANCER

Less Is More: A Multidisciplinary


Conversation on Treatment
Options

CHAIR
Fatima Cardoso, MD
Champalimaud Cancer Centre
Lisbon, Portugal

SPEAKERS
Eun-Sil Shelley Hwang, MD, MPH
Duke University
Durham, NC

Laura Esserman, MD, MBA


University of California, San Francisco
San Francisco, CA
TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER

Tailoring Chemotherapy in Early-Stage Breast Cancer: Based


on Tumor Biology or Tumor Burden?
Domen Ribnikar, MD, and Fatima Cardoso, MD

OVERVIEW

The question of whether to offer adjuvant chemotherapy to patients with early-stage breast cancer has always been
challenging to answer. It is well known that a substantial proportion of patients with early-stage breast cancer are over
treated, especially when staging and hormonal and HER2 receptors are solely taken into consideration. The advances in our
knowledge of breast cancer biology and its clinical implications were the basis for the discovery of additional reliable
prognostic markers to aid decision making for adjuvant treatment. Gene expression profiling is a molecular tool that more
precisely defines the intrinsic characteristics of each individual tumor. The application of this technology has led to the
development of gene signatures/profiles with relevant prognosticand some predictivevalue that have become im-
portant tools in defining which patients with early-stage breast cancer can be safely spared from chemotherapy. However,
the exact clinical utility of these tools will only be determined after the results of two large prospective randomized trials,
MINDACT and TailorX, evaluating their role become available. Notwithstanding the existence of these genomic tools, tumor
burden (defined as tumor size and nodal status) still has independent prognostic value and must be incorporated in decision
making. In addition, these gene signatures have limited predictive value, and new biomarkers and new targets are needed.
Therefore close collaboration between clinicians and scientists is crucial. Lastly, issues of cost-effectiveness, reimbursement,
and availability are crucial and widely variable around the globe.

H istorically, breast cancer was viewed as one disease with


different histopathological characteristics and responses
to systemic treatment. The choice of treatment was solely
The advent of genomic signatures allowed us to better
understand the heterogeneity of breast cancer and led to
more individualized systemic treatment approaches. In this
based on clinicopathologic parameters that are prognostic, article, we describe traditional clinicopathologic factors and
such as tumor size, nodal status, and histologic grade, and the new molecular tools that may be used to more accurately
three predictive markers of response to either endocrine tailor adjuvant treatment decisions for patients with early-
therapy and/or trastuzumab therapy (estrogen and pro- stage breast cancer. Additionally, we discuss some studies
gesterone receptor expression for endocrine therapy and showing that response to a specific type of treatment is
HER2 for trastuzumab). These factors are combined with mainly determined by the intrinsic molecular characteristics
different algorithms for treatment decision making, such as of each individual tumor rather than by anatomic prognostic
those used by Adjuvant! Online1 and the Nottingham parameters. However, these anatomic parameters have
Prognostic Index, and represent the basis of international important risk implications and effects on the relative
treatment guidelines, including those from the National magnitude of benefit of treatment.
Comprehensive Cancer Network,2 National Cancer Institute,
and European Society for Medical Oncology 3 as well as TRADITIONAL FACTORS FOR ADJUVANT
St. Gallens consensus statements.4 The major disadvantage of CHEMOTHERAPY DECISION MAKING
this approach is that nearly 60% of all patients with early-stage The Early Breast Cancer Trialists Collaborative Group (EBCTCG)
breast cancer receive adjuvant chemotherapy, but only 2% to meta-analyses (also called Oxford Overview) have demon-
15% of these patients derive an important benefit and others strated substantial evidence of the efficacy of adjuvant
only experience its toxic effects.5 chemotherapy in early-stage breast cancer.6,7 The last pub-
Fortunately, breast cancer was one of the first cancers with lished results in 2005 report on data from 60 randomized
advances in molecular profiling technologies, leading to a trials initiated before 1995 comparing polychemotherapy to
deeper understanding of its biology and molecular subtypes. no chemotherapy (29,000 patients of whom 10,000 died).7

From the Department of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia; Breast Unit, Champalimaud Cancer Center, Champalimaud Foundation, Lisbon, Portugal.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Fatima Cardoso, MD, Champalimaud Cancer Center, Av. De Brasilia, Doca De Pedroucos, 1400-048, Lisbon, Portugal; email: fatimacardoso@fundacaochampalimaud.pt.

2016 by American Society of Clinical Oncology.

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RIBNIKAR AND CARDOSO

At 15-year follow-up, there was a substantial reduction in Generally, decisions regarding adjuvant chemotherapy are
the absolute risk of recurrence and death from breast cancer based on prognosis, that is, risk of disease recurrence, and on
for polychemotherapy compared with no chemotherapy. the likelihood of benefit from the treatment. The threshold
Among women younger than age 50, polychemotherapy of 10% risk for distant relapse is often used to make rec-
reduced the annual risk of relapse and death by 37% and ommendation for adjuvant chemotherapy.10
30%, respectively, and the absolute gain in survival was twice Clinicopathological prognostic factors for survival of early-
as great at 15 years as it was at 5 years (10% vs. 4.7%). Among stage breast cancer include tumor size, nodal status, his-
older women (age 5069), at 15-year follow-up, the annual tologic grade, and estrogen receptor, progesterone re-
risk of relapse and breast cancer mortality were reduced by ceptor, and HER2 expression as well as the presence of
19% and 12%, respectively, and translated into an absolute lymphovascular invasion. Several consensus and evidence-
gain of 4.1% and 3%, respectively.7,8 The proportional re- based guidelines3,4,11,12 provide recommendations on the
ductions in both recurrence and breast cancer mortality use of adjuvant chemotherapy in early-stage breast cancer.
were similar in node-negative and node-positive patients, The St. Gallen guidelines,4 for instance, suggest that patients
although the absolute benefit was greater in those with with early-stage breast cancer at low enough risk to avoid
node-positive disease. Furthermore, it was demonstrated adjuvant chemotherapy are characterized by node-negative
that the greatest effect of adjuvant chemotherapy occurs in disease with all of the following features: pathologic tumor
the initial few years after therapy. size of 2 cm or smaller, grade 1, estrogen receptor and pro-
Additional subgroup analyses showed that adjuvant che- gesterone receptor positive, HER2 negative, age older than
motherapy was effective in both estrogen receptornegative 35, and no vascular invasion. All other patients who do not
and estrogen receptorpositive disease, albeit the magnitude meet these criteria are considered to derive sufficient benefit
of the absolute benefit was larger in estrogen receptor from adjuvant chemotherapy because their risk of distant
negative disease. Data from multiple Cancer and Leukemia relapse is considered higher than 10%.
Group B (CALGB) trials among women with node-positive Adjuvant! Online is an independently validated, widely
breast cancer reveal greater chemotherapy benefit in es- used web-based tool for assessment of the risk of recurrence
trogen receptornegative disease compared with estrogen and mortality. It combines multiple clinical and pathologic
receptorpositive disease.7,9 Substantial reductions were factors and produces estimates for recurrence and death
observed in the absolute risk of recurrence and cancer- from early-stage breast cancer. It incorporates the effect of
specific mortality of 12.3% and 9.2% for patients younger comorbidities in the determination of prognosis and benefit
than age 50 and 8.6% and 6.1% for patients age 5069, from different therapeutic strategies.13 However, there are
respectively. data suggesting that it generally overestimates prognosis
and it lacks some crucial elements such as HER2 status.
The guidelines described above and Adjuvant! Online can-
not reveal the substantial heterogeneity that exists between
KEY POINTS patients with similar stages and grades of disease. Several
independent groups have conducted comprehensive gene
In the past, breast cancer was perceived to be one expression profiling studies using microarray technology to
disease with different anatomical extents and different develop new tools that are more effective at an individual
expressions of estrogen and progesterone receptors and level and that can assess risk of relapse to improve decision
HER2. making for adjuvant treatment.
Gene expression analysis has revealed distinct intrinsic
subtypes of breast cancer with different natural
behaviors and responses to treatment.
First-generation gene signatures have the common INTRINSIC MOLECULAR SUBTYPING
ability to further subdivide estrogen receptorpositive Over 10 years ago, Perou et al14 and Sorlie et al15 dem-
HER2-negative breast cancers into subgroups that differ onstrated that estrogen receptorpositive and estrogen
in regards to their expression of proliferation-related receptornegative breast cancers are completely distinct
genes. Additional biomarkers, particularly those with diseases on a molecular level. In addition, hierarchical
predictive value, are urgently needed. cluster analyses of genes that vary more between tumors
Classic clinicopathologic tools and new molecular than between repeated samples of the same tumor, the so-
tools should be integrated in and complementary to called intrinsic genes, revealed at least four molecular
adjuvant treatment decision making for individual subtypes of breast cancer, namely, luminal, HER2-enriched,
patients with breast cancer, in particular for cases where
basal-like, and normal breastlike.14 Multiple independent
the benefit of chemotherapy is uncertain.
Treatment of patients with low-risk tumor biology
datasets have shown the prognostic effect of intrinsic sub-
and high tumor burden is challenging since, despite typing of breast cancer with luminal A cases (high expression of
being at considerable high risk for distant relapse, the estrogen receptor and estrogen receptorregulated genes) to
expected benefit of chemotherapy might not be enough be at low risk of early recurrence. Apart from its prognostic
in terms of the low proliferative biology. implication, the intrinsic molecular subclassification seems to
predict responsiveness to chemotherapy.16 Studies evaluating

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TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER

the association between molecular subtype and path- of common clinicopathologic features traditionally used
ologic complete response (pCR) rate to preoperative for determining prognosis of early-stage breast cancer;
(neoadjuvant) chemotherapy have reported the highest important meta-analyses have shown that they com-
rate of pCR in basal-like (30%45%) and HER2-enriched plement but do not replace traditional factors since both
(33%55%) subtypes, while pCR rates for luminal B tumor size and nodal status provide independent prog-
(1%15%) and luminal A disease (0%7%) were substantially nostic information in multivariate analyses.25 In addition,
lower. the accuracy of the outcome prediction of all first-
It is important to highlight that molecular classifica- generation prognostic signatures is time-dependent,
tion is not without its inherent limitations because up with more accurate prediction during the first 5 years
to 30% of breast cancers do not fit into any of the four after diagnosis and less accurate predictions for late
molecular categories. 17 The exact number of true mo- relapses.26 Finally, there is some evidence that the
lecular subclasses of breast cancer is currently unknown, prognostic information provided by first-generation
and it is expected that the molecular classification will signatures may be comparable with that offered by
further evolve with new technological platforms and semiquantitative and centralized (high-quality) assess-
improved understanding of tumor biology. In particular, ment of estrogen and progesterone receptors, HER2, and
the immunohistochemistry-defined triple-negative sub- Ki-67.27
type is currently being subdivided into several molecularly
distinct subtypes with potential future clinical and thera-
peutic implications.18 70-Gene Profile
The 70-gene profile, also known as MammaPrint, was the
first microarray-based prognostic signature to be approved
PROGNOSTIC GENE EXPRESSION SIGNATURES by the U.S. Food and Drug Administration. The 70-gene
Concomitant to the discovery of heterogeneity of breast profile may be used for determining the prognosis of pa-
cancers, microarray-based gene expression profiling was tients with stage I and/or II, node-negative, invasive breast
used to predict the outcomes of individual patients with cancer28 as well as for nodes 1 to 3 positive disease.29 This
breast cancer and aimed to identify those patients who gene profile was first established using RNA from fresh,
could be safely omitted from adjuvant chemotherapy.19 First frozen tumor tissues; however, from 2012 onward, it is also
attempts were empirical, whereby tumors from patients evaluable in formalin-fixed, paraffin-embedded tumor
with good and poor outcomes were profiled, and collections tissue.28 The assay was based on an empirical microarray
of candidate genes that could discriminate between patients analysis of 78 patients who did not receive adjuvant systemic
with disease of good and poor prognosis were identified.19,20 therapy for their breast cancer. They were younger than age
Later, studies in which a multigene predictor was generated 55, had tumors up to 5 cm, and were node-negative. If these
on the basis of a hypothesis derived from in vivo or in vitro patients developed distant metastases within the first 5
experiments and then applied to breast cancer samples were years after primary diagnosis, they were classified as poor
conducted.21 prognosis or good prognosis in the event there were no
There are many gene-expression prognostic signatures distant metastases during this timeframe. A list of 70 genes
that were used during the past decade.22 The so-called first- that could accurately predict poor versus good prognosis for
generation signatures have several common features. De- these patients was identified by a supervised analysis of
spite the different gene sets that compose each of the 25,000 genes included in the microarrays. Subsequent studies
signatures, they characterize a unique population with a high in breast cancer cohorts that were retrospectively accrued
expression of proliferation-related genes associated with demonstrated the potential of the MammaPrint assay to
poor prognosis.23 Because the levels of expression of determine prognosis of both node-negative and node-
proliferation-related genes are usually high in estrogen positive disease29 and also for patients with HER2-positive
receptornegative disease, these signatures almost always disease.30 The prognostic subgroups, which were identified
classify estrogen receptornegative cancers as being a poor by the MammaPrint assay, correlate sensitivity to che-
prognosis disease. In estrogen receptorpositive breast can- motherapy in general: patients with high-risk signatures
cer, the strongest prognostic factor is the degree of ex- derive the greatest absolute benefit from adjuvant chemo-
pression of proliferation-related genes. Based on these therapy.31 However, it has no ability to differentiate sensi-
features, it seems that most of these signatures generally tivity to different types of chemotherapy regimens. One of
correlate with response to conventional chemotherapy main disadvantages of the MammaPrint assay is its small
regimens,24 that is, high proliferative tumors respond better discriminatory power for patients with estrogen receptor
to chemotherapy; however, they are not predictive of one negative disease (only up to 5% of patients with estrogen
type of chemotherapy agent over another and cannot be receptornegative disease are classified as having good
used to define the best chemotherapy agent/regimen for prognosis disease).32 The true clinical utility of MammaPrint is
each individual patient. being tested in a randomized prospective phase III trial EORTC
In the early years of their development, some defended 10041/BIG 3-04 MINDACT,33 the results of which will be
that these signatures would be a more objective replacement presented in April 2016.

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RIBNIKAR AND CARDOSO

Recurrence Score or Oncotype DX 76-Gene Signature


In parallel with the development of microarray-based prog- The 76-gene signature, also known as the Veridex signature,
nostic signatures, Paik and et al34 developed Oncotype DX, a was developed on the basis of a supervised analysis of
quantitative reverse transcription polymerase chain reaction microarray data in a set of 115 breast cancers, of which 80%
based signature that measures the expression of 21 genes were estrogen receptorpositive. Contrary to MammaPrint,
(16 cancer-related genes and five reference genes). It can estrogen receptorpositive and estrogen receptornegative
be performed with RNA extracted from formalin-fixed, cancers were analyzed separately, and this enabled the
paraffin-embedded tissue samples. Oncotype DX calcu- identification of 60 genes that could predict the develop-
lates the recurrence score (RS) to predict the risk of distant ment of distant metastases within 5 years among patients
relapse within 10 years for patients with estrogen receptor with estrogen receptorpositive disease and 16 genes that
positive, lymph nodenegative breast cancers. It was de- could predict distant dissemination in estrogen receptor
veloped on the basis of analysis of clinical samples from the negative disease.42 All 76 genes together were applied to an
National Surgical Adjuvant Breast and Bowel Project (NSABP) independent test set of 171 patients with node-negative
B-20 clinical trial. Later, it was validated with material from disease only. The 76-gene predictor was a strong prognostic
the B-14 trial. The RS is a continuous variable, ranging factor for development of metastases within the first 5 years
from 0 to 100, and is an independent prognostic factor for after diagnosis. The main disadvantages of this signature are
patients with estrogen receptorpositive, node-negative time dependency, requirement of fresh or frozen samples,
breast cancer treated with adjuvant tamoxifen. Patients prognostic power supported by level III evidence only, and,
are classified into three categories, including low risk last but not the least, that the 16-gene signature developed
(RS , 18), intermediate risk (RS 18-31), and high risk (RS . 31), for estrogen receptornegative disease might not predict
which correlate with 10-year relapse rates of 7%, 14%, the outcome of patients with triple-negative breast
and 30%, respectively. The optimal management of the cancer.23
intermediate-risk group is uncertain and is being studied
in the TailorX trial, in which patients with estrogen
Genomic Grade Index
receptorpositive, node-negative breast cancer were assessed
In 2006, Sotiriou et al developed the Genomic Grade Index
for risk of distant relapse after surgery and assigned
(GGI). It was based on the expression of 97 genes that were
to low-risk (RS , 11), intermediate-risk (RS 11-25), and
selected by comparing the gene expression of histologic
high-risk groups (RS . 25). Patients with intermediate-risk
grade 2 tumors with that of grade 1 tumors by means of a
disease were randomly assigned to either endocrine
DNA microarray.43 Importantly, this signature was able to
therapy alone or in combination with chemotherapy. In
divide estrogen receptorpositive grade 2 cancers into grade
2015, the results of the low-risk patients (RS , 11) were
1-like with a low frequency of distant relapse and grade
presented and demonstrated excellent outcome at
3-like with an aggressive clinical behavior that is similar to
5 years with endocrine therapy alone, irrespective of age,
that of histologic grade 3 tumors. Similar to MammaPrint,
tumor size, and grade. The authors concluded that these
GGI also correlates with the benefit from chemotherapy in
patients can be safely treated without chemotherapy.35
general: GGI grade 3 cancers seem to derive higher absolute
The main results of the intermediate-risk score group are
benefit from conventional chemotherapy versus GGI grade 1
eagerly awaited.
tumors.44 The main common limitations of first generation
Further analyses also demonstrated that RS generally
prognostic signatures also apply to GGI.22
correlates with benefit from chemotherapy in estrogen
receptorpositive disease.36 However, it does not provide
predictive value to differentiate between different che- PAM 50
motherapy agents/regimens. It is also not useful to dis- PAM 50, also known as Prosigna, was originally developed
criminate between subgroups of HER2-positive breast for intrinsic subtyping of breast cancer,45 but later it started
cancer because HER2 is one of the 21 genes that constitute to be used to predict recurrence.46 It was developed for
the test. patients receiving adjuvant tamoxifen. Its score, PAM 50
During the last few years, the Oncotype DX assay was ROR (PAM 50 risk of recurrence), is calculated by using the
validated among patients who had up to three positive expression profile of 50 selected genes from four intrin-
lymph nodes37 and for those who are supposed to be treated sic subtypes, a proliferation score (18-gene subset), and
with an aromatase inhibitors.38 pathologic tumor size47; it classifies patients into those at
Although the prognostic effect of the Oncotype DX assay low, intermediate, and high risk of recurrence, but it also
has been extensively validated, there is some evidence provides the score as a continuous variable. It can be used
that RS correlates with some clinicopathologic parame- with formalin-fixed, paraffin-embedded tissue samples and
ters, and, some of them, such as tumor size, nodal status, was approved by the U.S. Food and Drug Administration in
and even histologic grade, remain independent of RS.39,40 2013. An important finding was the ability of the PAM 50
Hence, a model that combines RS with traditional ana- ROR score to effectively divide patients into the three risk
tomic pathologic factors may be more prognostic than groups according to risk for recurrence between 5 and 15
RS alone.41 years after the primary diagnosis, using the samples from the

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TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER

Austrian Breast and Colorectal Cancer Study Group 8 trial DX, and wound response models. Of the five models that Fan
(ABCSG-8). It is, therefore, a more useful signature to et al analyzed in their study, only the two-gene ratio (H/I)
predict late distant relapses compared with Oncotype DX failed to identify substantial differences in outcome within
or MammaPrint. that data set.
There are two additional reports evaluating the accu-
Breast Cancer Index racy of prediction of BCI among patients with estrogen
The Breast Cancer Index (BCI) is another second-generation receptorpositive, node-negative breast cancer. One report
gene signature that was found to be a prognostic marker for by Reid et al showed that the two-gene model failed to
patients with early-stage estrogen receptorpositive breast detect differences in outcome,53 and the other study,
cancer who have or who have not received tamoxifen. It conducted by Goetz et al, showed that the H/I ratio was a
is a quantitative reverse transcription polymerase chain substantial predictor of relapse-free survival and disease-
reactionbased method that measures the expression of free survival.54 The possible explanation for these contra-
two genes, HOXB13 and IL17BR (H/I), and classifies patients dictory findings is that a model based on the analysis of only
into three recurrence risk categories (low, intermediate, and two genes is much more likely to be sensitive to technical
high).48 The BCI was found to be useful for the assessment of differences in analysis platforms than one based on many
both early and late distant recurrence, according to the genes.
Stockholm study. This study included 317 patients with Findings from multiple analyses incorporating first- and
estrogen receptorpositive node-negative disease, treated second-generation gene signatures among patients with
with adjuvant tamoxifen only, and showed that recurrence early-stage breast cancer suggest that even though there is
rates for the low-risk group based on the BCI were very low, very little gene overlap and different algorithms are used,
not only in the first 5 years after the surgery, but also in years the prediction of outcome for the majority of patients is
5 to 10. similar. One may therefore conclude that, even though
different gene sets are being used as predictors of outcome,
the signatures identify a common set of biologic charac-
EndoPredict teristics that allow for a good distinction between different
The most recently developed second-generation gene sig- subgroups of patients with breast cancer who have distinct
nature is EndoPredict. Just like the majority of first- and prognoses.
second-generation signatures, it is also used for estrogen
receptorpositive and HER2-negative breast cancers. It was
developed based on the analysis of 964 breast cancer GENE EXPRESSION SIGNATURES AND RESPONSE
samples, from which eight genes and four control genes TO CHEMOTHERAPY
were selected. The expression of these 12 genes is analyzed The predictive value of genomic signatures has been eval-
with the quantitative reverse transcription polymerase chain uated mostly in the neoadjuvant setting. Several small
reactionbased method for the classification of patients into studies suggested that the gene expression profiles of
two recurrence risk groups.49 The assay was validated in the cancers that are highly sensitive to chemotherapy differ
ABCSG-6 and ABCSG-8 trials that included patients with from those of less responsive tumors. For example, Ayers
estrogen receptorpositive, HER2-negative, lymph node et al conducted a prospectively designed study in which
positive or negative breast cancers who were treated with needle-biopsy samples from 133 patients with stage I, II, and
adjuvant tamoxifen only.50 Additionally, EndoPredictClin, III breast cancers were collected before systemic therapy.55
which combines the EndoPredict score with tumor size and Patients were then treated with preoperative chemotherapy
nodal status in a linear model, identified a subgroup of with weekly paclitaxel and a combination of fluorouracil,
patients with an excellent long-term prognosis after a doxorubicin, and cyclophosphamide. A 30-gene predictor
standard 5 years of endocrine therapy,51 thus making it was developed from the data from the first 82 patients, and
useful for evaluating risk of late relapse. it was shown to have a higher sensitivity for prediction of
pCR than a clinical predictor that included age, nuclear
grade, and estrogen receptor status (92% vs. 61%). These
CONCORDANCE AMONG GENE results need further validation and confirmation in in-
EXPRESSIONBASED PREDICTORS FOR BREAST dependent and larger studies.
CANCER Currently no multigene predictor is ready to be used in
Fan et al analyzed a single data set of 295 tumor samples and
clinical practice with the aim of predicting response to
applied five gene expressionbased models including in-
specific chemotherapy agents or regimens.
trinsic subtypes, MammaPrint assay, wound response,
Oncotype DX, and the two-gene ratio (BCI) for patients who
had been treated with tamoxifen.52 Four of these models CONCLUSION
were similar in prediction for particular risk groups. For Undoubtedly, the era of molecular oncology has brought a
instance, tumors classified as HER2-enriched, basal-like, and deeper insight into the complex biology of breast cancer
luminal Blike by intrinsic subtyping were almost all clas- and its crucial clinical and therapeutic implications. A new
sified as having a poor outcome by MammaPrint, Oncotype molecular-based classification of breast cancer exists, going

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RIBNIKAR AND CARDOSO

TABLE 1. Most Common Commercially Available Prognostic Gene Signatures for Breast Cancer
MammaPrint Oncotype DX Breast Cancer Index Mapquant DX PAM 50 ROR EndoPredict
Provider Agendia Genomic Health Biotheranostics Ipsogen NanoString Sividon
Type of 70-gene assay 21-gene 2-gene ratio (H/I) Genomic grade 50-gene assay 12-gene assay
Assay recurrence score and molecular
grade index
Type of Fresh or frozen FFPE FFPE Fresh or frozen FFPE FFPE
Sample or FFPE or FFPE
Technique DNA microarray qRT-PCR qRT-PCR DNA microarray qRT-PCR qRT-PCR
or qRT-PCR or qRT-PCR
Clinical Prognosis of Prediction of Prognostic in ER+, Molecular Originally for Recurrence
Application N0, , 5 cm, recurrence risk prediction of grading for intrinsic subtyping, prediction for
stage I/II, in ER+ and N0 response to TAM ER+, histologic recurrence prediction ER+ HER2
age , 61 treated with TAM grade II disease
Results Dichotomous, Continuous variable Continuous variable Dichotomous, Continuous variable Dichotomous, low
Presentation good or poor GGI I or GGI III or high risk
prognosis
Level of II I III III I I
Evidence
FDA Approval YES NO NO NO YES NO
Abbreviations: ER+, estrogen receptorpositive; FDA, U.S. Food and Drug Administration; FFPE, formalin-fixed, paraffin-embedded; GGI, Genomic Grade Index; qRT-PCR, quantitative
reverse transcription polymerase chain reaction; TAM, tamoxifen.

beyond traditional morphologic oncology. It is, however, While we wait for the results of the large prospective ran-
indispensable to use the new molecular tools in conjunction domized trials, MINDACT, TailorX, RxPONDER, and OPTIMA,
with classic clinicopathologic parameters because the latter all major international guidelines recommend the use of
retain their independent prognostic value for early-stage genomic tools in cases for which the potential benefit of
breast cancer in multivariate models. adjuvant chemotherapy is difficult to estimate based only
All available tools have advantages and limitations, both of using on clinicopathologic factors.
which must be discussed with patients. First-generation Currently, one of the greatest challenges for the medical
prognostic gene signatures consistently demonstrate that oncologist is determining the treatment strategy for patients
about half of the patients with estrogen receptorpositive, with favorable tumor biology and high tumor burden. These
HER2-negative disease are at low risk for early distant re- patients are at substantial risk for distant relapse with en-
lapse and are likely to obtain minimal, if any, benefit from docrine therapy alone.37,56 However, they do not seem to
adjuvant chemotherapy, but do not provide information derive a substantial benefit from adjuvant chemotherapy
about late relapses. Novel second-generation multigene and are at risk for the acute and long-term toxicities of this
prognosticators have some additional advantages, such as a therapy.
better prediction of late distant relapses, a common situation In summary, adjuvant treatment decision making in
in estrogen receptorpositive, HER2-negative breast cancer. breast cancer involves an integration of the available
Combination tools, such as EndoPredictClin and Prosigna, may clinicopathologic factors and new genomic tools, when-
be even more accurate in determining short- and long-term ever appropriate, as well as a detailed and compre-
prognoses for this subgroup of breast cancer. Therefore, hensible discussion with each individual patient regarding
tumor biology and tumor burden must be complementary risk of recurrence, risk of adverse events, comorbidities,
and not mutually exclusive, so that more individualized ad- performance status, and, very importantly, patient
juvant treatment decision making can occur (Table 1). preferences.

References
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TAILORING CHEMOTHERAPY IN EARLY-STAGE BREAST CANCER

6. Early Breast Cancer Trialists Collaborative Group. Polychemotherapy for 27. Cuzick J, Dowsett M, Pineda S, et al. Prognostic value of a combined
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352:930-942. growth factor receptor 2 immunohistochemical score and comparison
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649-668. 31. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene
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Guidelines in Oncology. Breast Cancer, V.I. 2010. http://www.nccn.org/ Cancer Res Treat. 2010;120:655-661.
professionals/physician_gls/PDF/breast.pdf. Accessed January 19, 2010. 32. Buyse M, Loi S, vant Veer L, et al; TRANSBIG Consortium. Validation and
12. National Institutes of Health Consensus Development Panel. Adjuvant clinical utility of a 70-gene prognostic signature for women with node-
therapy for breast cancer. NIH Consens Statement. 2000;17:1-35. negative breast cancer. J Natl Cancer Inst. 2006;98:1183-1192.
13. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based validation of 33. Bogaerts J, Cardoso F, Buyse M, et al; TRANSBIG consortium. Gene
the prognostic model ADJUVANT! for early breast cancer. J Clin Oncol. signature evaluation as a prognostic tool: challenges in the design of the
2005;23:2716-2725. MINDACT trial. Nat Clin Pract Oncol. 2006;3:540-551.
14. Perou CM, Srlie T, Eisen MB, et al. Molecular portraits of human breast 34. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of
tumours. Nature. 2000;406:747-752. tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;
15. Srlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of 351:2817-2826.
breast carcinomas distinguish tumor subclasses with clinical implica- 35. Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-
tions. Proc Natl Acad Sci USA. 2001;98:10869-10874. gene expression assay in breast cancer. N Engl J Med. 2015;373:2005-
16. Hu Z, Fan C, Oh DS, et al. The molecular portraits of breast tumors are 2014.
conserved across microarray platforms. BMC Genomics. 2006;7:96. 36. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemo-
17. Pusztai L, Mazouni C, Anderson K, et al. Molecular classification of therapy in women with node-negative, estrogen receptor-positive
breast cancer: limitations and potential. Oncologist. 2006;11:868-877. breast cancer. J Clin Oncol. 2006;24:3726-3734.
18. Curtis C, Shah PS, Chin SF, et al. The genomic and transcriptomic ar- 37. Albain KS, Barlow WE, Shak S, et al; Breast Cancer Intergroup of North
chitecture of 2,000 breast tumours reveals novel subgroups. Nature. America. Prognostic and predictive value of the 21-gene recurrence
2012;486:346-352. score assay in postmenopausal women with node-positive, oestrogen-
19. Weigelt B, Baehner FL, Reis-Filho JS. The contribution of gene ex- receptor-positive breast cancer on chemotherapy: a retrospective
pression profiling to breast cancer classification, prognostication and analysis of a randomised trial. Lancet Oncol. 2010;11:55-65.
prediction: a retrospective of the last decade. J Pathol. 2010;220: 38. Dowsett M, Cuzick J, Wale C, et al. Prediction of risk of distant re-
263-280. currence using the 21-gene recurrence score in node-negative and
20. Van;t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling node-positive postmenopausal patients with breast cancer treated with
predicts clinical outcome of breast cancer. Nature. 2002;415:530- anastrozole or tamoxifen: a TransATAC study. J Clin Oncol. 2010;28:
536. 1829-1834.
21. Kim C, Paik S. Gene-expression-based prognostic assays for breast 39. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor
cancer. Nat Rev Clin Oncol. 2010;7:340-347. gene expression and risk of breast cancer death among lymph node-
22. Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. negative patients. Breast Cancer Res. 2006;8:R25.
N Engl J Med. 2009;360:790-800. 40. Tang G, Shak S, Paik S, et al. Comparison of the prognostic and predictive
23. Wirapati P, Sotiriou C, Kunkel S, et al. Meta-analysis of gene expression utilities of the 21-gene Recurrence Score assay and Adjuvant! for
profiles in breast cancer: toward a unified understanding of breast women with node-negative, ER-positive breast cancer: results from
cancer subtyping and prognosis signatures. Breast Cancer Res. 2008;10: NSABP B-14 and NSABP B-20. Breast Cancer Res Treat. 2011;127:
R65. 133-142.
24. Iwamoto T, Bianchini G, Booser D, et al. Gene pathways associated with 41. Tang G, Cuzick J, Wale C, et al. Recurrence risk of node-negative and ER-
prognosis and chemotherapy sensitivity in molecular subtypes of breast positive early-stage breast cancer patients by combining recurrence
cancer. J Natl Cancer Inst. 2011;103:264-272. score, pathologic and clinical information: a meta-analysis approach. J
25. Desmedt C, Haibe-Kains B, Wirapati P, et al. Biological processes as- Clin Oncol. 2010;28 (suppl; abstr 509).
sociated with breast cancer clinical outcome depend on the molecular 42. Wang Y, Klijn JG, Zhang Y, et al. Gene-expression profiles to predict
subtypes. Clin Cancer Res. 2008;14:5158-5165. distant metastasis of lymph-node-negative primary breast cancer.
26. Desmedt C, Piette F, Loi S, et al; TRANSBIG Consortium. Strong time Lancet. 2005;365:671-679.
dependence of the 76-gene prognostic signature for node-negative 43. Sotiriou C, Wirapati P, Loi S, et al. Gene expression profiling in breast
breast cancer patients in the TRANSBIG multicenter independent cancer: understanding the molecular basis of histologic grade to im-
validation series. Clin Cancer Res. 2007;13:3207-3214. prove prognosis. J Natl Cancer Inst. 2006;98:262-272.

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44. Liedtke C, Hatzis C, Symmans WF, et al. Genomic grade index is as- patients with endocrine-responsive early breast cancer from the
sociated with response to chemotherapy in patients with breast cancer. Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012;
J Clin Oncol. 2009;27:3185-3191. 30:722-728.
45. Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of breast 51. Dubsky P, Brase JC, Jakesz R, et al; Austrian Breast and Colorectal Cancer
cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160-1167. Study Group (ABCSG). The EndoPredict score provides prognostic in-
46. Gnant M, Filipits M, Greil R, et al; Austrian Breast and Colorectal Cancer formation on late distant metastases in ER+/HER2- breast cancer pa-
Study Group. Predicting distant recurrence in receptor-positive breast tients. Br J Cancer. 2013;109:2959-2964.
cancer patients with limited clinicopathological risk: using the PAM50 52. Fan C, Oh DS, Wessels L, et al. Concordance among gene-expression-
Risk of Recurrence score in 1478 postmenopausal patients of the based predictors for breast cancer. N Engl J Med. 2006;355:560-569.
ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann 53. Reid JF, Lusa L, De Cecco L, et al. Limits of predictive models using
Oncol. 2014;25:339-345. microarray data for breast cancer clinical treatment outcome. J Natl
47. Filipits M, Nielsen TO, Rudas M, et al; Austrian Breast and Colorectal Cancer Inst. 2005;97:927-930.
Cancer Study Group. The PAM50 risk-of-recurrence score predicts risk 54. Goetz MP, Suman VJ, Ingle JN, et al. A two-gene expression ratio of
for late distant recurrence after endocrine therapy in postmenopausal homeobox 13 and interleukin-17B receptor for prediction of recurrence
women with endocrine-responsive early breast cancer. Clin Cancer Res. and survival in women receiving adjuvant tamoxifen. Clin Cancer Res.
2014;20:1298-1305. 2006;12:2080-2087.
48. Zhang Y, Schnabel CA, Schroeder BE, et al. Breast cancer index identifies 55. Ayers M, Symmans WF, Stec J, et al. Gene expression profiles predict
early-stage estrogen receptor-positive breast cancer patients at risk for complete pathologic response to neoadjuvant paclitaxel and fluoro-
early- and late-distant recurrence. Clin Cancer Res. 2013;19:4196-4205. uracil, doxorubicin, and cyclophosphamide chemotherapy in breast
49. Filipits M, Rudas M, Jakesz R, et al; EP Investigators. A new molecular cancer. J Clin Oncol. 2004;22:2284-2293.
predictor of distant recurrence in ER-positive, HER2-negative breast 56. Saghatchian M, Mook S, Pruneri G, et al. Combining genomic profiling
cancer adds independent information to conventional clinical risk (70-gene MammaPrint) with nodal status allows to classify patients
factors. Clin Cancer Res. 2011;17:6012-6020. with primary breast cancer and positive lymph nodes (1-9) into very
50. Dubsky PC, Jakesz R, Mlineritsch B, et al. Tamoxifen and anastrozole as a distinct prognostic subgroups that could help tailor treatment strate-
sequencing strategy: a randomized controlled trial in postmenopausal gies. Cancer Res. 2009;69:a102.

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BREAST CANCER

Targeted Therapies in Hormone


ReceptorPositive Breast Cancer

CHAIR
Hope S. Rugo, MD
University of California, San Francisco
San Francisco, CA

SPEAKERS
Cynthia Ma, MD, PhD
Washington University School of Medicine
St. Louis, MO

Dejan Juric, MD
Massachusetts General Hospital Cancer Center
Boston, MA
RUGO, VIDULA, AND MA

Improving Response to Hormone Therapy in Breast Cancer:


New Targets, New Therapeutic Options
Hope S. Rugo, MD, Neelima Vidula, MD, and Cynthia Ma, MD, PhD

OVERVIEW

The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without
concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to
hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of
resistance mechanisms leading to estrogen-independent growth of hormone receptorpositive (HR+) breast cancer as a
result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired
mutations in ER-alpha (ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK)
4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor
receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by
histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of
these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-
stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer,
including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of
treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia
(treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel
combinations are under active investigation.

T he estrogen-dependent nature of breast cancer has been


well established since the historical observation that
removal of the ovaries was effective in treating breast tumors.1
CDK4/6, and epigenetic and immune checkpoints as resis-
tance mechanisms and therapeutic targets in ER+ breast
cancer (Fig. 1).
A number of pharmacological agents, referred to as endocrine
therapy, are now available in the clinic. These include aro- UNDERSTANDING THE BIOLOGY OF HORMONE
matase inhibitors (AI) and gonadotropin-releasing hormone RECEPTORS AND POTENTIAL MECHANISMS OF
(GnRH) agonists that reduce estrogen biosynthesis, the RESISTANCE
selective estrogen receptor modulators (SERM) tamoxifen, Mechanisms of Action of Estrogen Receptors
and the selective ER down regulator (SERD) fulvestrant. The Estrogen receptors belong to the family of steroid hormone
clinical application of these agents has led to substantial receptors and its main mechanism of action is a transcription
improvements in survival outcomes for patients with ER+ factor (Fig. 2). There are two different forms of ER, ER-alpha
breast cancer.2 However, despite standard therapy, over and ER-beta, encoded by ESR1 and ESR2, respectively. There
20% of patients with early-stage disease experience relapse, is substantial sequence homology between ER-alpha and
and, essentially, all patients with metastatic disease suc- ER-beta, although the function of ER-beta is less known.
cumb to their illness.2,3 Although the mechanisms of en- Upon activation by estrogen, the cytosolic ER forms dimers
docrine resistance are not fully understood, significant and translocates to the nucleus where ER binds directly to
progress has been made in recent years in uncovering the estrogen response elements (ERE) or is tethered to
several key molecular pathways that promote ligand- the promoter regions of target genes via its interaction
independent activation of ER and tumor growth. In this with SP1. 4 Additional coregulators are then recruited
article, we will focus on evidence for ER-alpha (ESR1) mu- to the complex to regulate the transcription levels of
tation, growth factor receptor signaling, PI3K/Akt/mTOR, target genes, including cyclin D, to promote cell cycle

From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of San Francisco School of Medicine, San Francisco, CA; Department of Medicine,
Washington University School of Medicine in St. Louis, St. Louis, MO.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero St., San Francisco, CA 94115; email: hope.rugo@ucsf.edu.

2016 by American Society of Clinical Oncology.

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IMPROVING RESPONSE TO HORMONE THERAPY

FIGURE 1. Key Pathways of Endocrine Resistance

Pink and blue color code activating and suppression signals, respectively, for pathway activation.
Abbreviations: HDAC, histone deacetylase; RTK, receptor tyrosine kinase.

progression.4,5 In addition to this classic genomic action of leading to estrogen-independent cell proliferation and resistance
ER, growth factor receptor tyrosine kinases and a variety of to endocrine therapy.6-10
proximal signaling molecules, such as G protein, Ras, Src,
PI3K, and Shc, could activate ER in the absence of estrogen,
ESR1 Mutation
Although initially discovered in the 1990s, the ESR1 mutation
was largely overlooked until recent years when recurrent,
rather than primary, breast cancers were studied. In contrast
KEY POINTS
to the extremely low incidence in treatment-naive primary
Resistance to endocrine therapy in HR+ breast cancer is breast cancers, mutations in ESR1 have been reported in
associated with diverse molecular mechanisms, 11%55% of recurrent or metastatic cancers that progressed
including acquired mutations in ESR1 in response to after long-term endocrine therapy (Fig. 3).11-14 The hot-spot
endocrine deprivation, constitutive activation of CDK4/6, mutations cluster in the ligand-binding-domain of ER, which
cross talk between the ER and growth factor receptor induce a constitutive agonist conformation. Compared with
signaling, epigenetic modifications by HDAC, and the wild-type ER, mutant ER is resistant to estrogen dep-
interactions with tumor microenvironment and host rivation and much less responsive to tamoxifen or fulves-
immune response. trant. Successful treatment of ESR1-mutant breast cancer
Increased understanding of endocrine resistance
therefore requires the development of newer generation
mechanisms has led to the development of targeted
SERMs or SERDs, or other strategies, that are effective in
agents, including two agents which are approved for
clinical use in the United States, that have improved targeting the mutated ER.
progression-free survival in combination with standard
hormone agents.
PI3K is the most commonly altered pathway in HR+ HER2 Gene Amplification
breast cancer; multiple agents that target this pathway HER family members, including HER1 (EGFR), HER2, HER3,
or related growth factor receptors are being studied. To and HER4, are tyrosine kinase receptors important in
date, markers of PI3K pathway activation have not promoting cell growth and survival.15 Cross talk between
identified a specific population most likely to benefit ER and HER family members has been well recognized in
from this therapy. preclinical and clinical studies. HER2 amplification occurs
Toxicities of targeted therapies and impact on quality of in about 10% of ER+ breast cancers and is an established
life must be taken into account and managed mechanism of endocrine resistance.16 Compared with ER+
expectantly when treating patients; common toxicities HER2- disease, ER+ HER2+ breast cancer is associated with a
are stomatitis (everolimus) and neutropenia
higher risk of relapse on adjuvant endocrine therapy17 and
(palbociclib).
Ongoing trials are evaluating inhibitors of the PI3K
incomplete cell cycle arrest to neoadjuvant endocrine
pathway, CDK4/6, and HDAC, primarily in combination therapy.18 Adjuvant trastuzumab reduces relapse in ER+
with hormone therapy in the metastatic, adjuvant, and HER2+ breast cancer and is the standard of care.19 In the
neoadjuvant settings; combination therapy targeting metastatic setting, hormonal therapy in combination with
two or more pathways is also under investigation. HER2-targeted agents provides an alternative to chemo-
therapy regimens.20-22

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RUGO, VIDULA, AND MA

FIGURE 2. Estrogen Receptor Pathway and Cross Talk With Growth Factor Receptor, PI3K/AKT/mTOR, and
CDK4/6 Pathways

Estrogen-bound estrogen receptor (ER), in complex with coactivators (CoA) or corepressors (CoR), regulates target gene expression via the estrogen response element (ERE)
or the AP1 binding sites via its interaction with other transcription factors. Additionally, ER can interact with receptor tyrosine kinases (FGFR, EGFR/HER), which promote
estrogen-independent ER phosphorylation through pathways such as PI3K/Akt/mTOR and MAPK (a and b). The G1 to S phase transition is controlled by CDK4/6, which is
activated by the ER downstream target cyclin D. Constitutive activation of CDK4/6 is associated with endocrine resistance.

HER2 Mutation interaction with other HER family members. In preclinical


Somatic mutations in HER2 in otherwise HER2-negative models, many of these mutations have shown to be on-
breast cancer have attracted much attention in recent years. cogenic and are sensitive to treatment with the irreversible
Although the overall HER2 mutation rate is approximately tyrosine kinase inhibitor of HER1/HER2, neratinib.23 Results
2% in primary breast cancers,23 it reaches over 20% in in- of the breast cancer cohort of the SUMMIT study, a mul-
vasive lobular cancers.24 These mutations cluster in the ticenter, open-label, multihistology phase II basket trial of
kinase domain and the extracellular domain important for its neratinib for patients with HER2-mutant, nonamplified,

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IMPROVING RESPONSE TO HORMONE THERAPY

FIGURE 3. ESR1 Mutation as an Acquired Mechanism survival signals, and acquired endocrine resistance is often
of Endocrine Resistance accompanied by upregulation of PI3K pathway signaling.29-32
Gain of function mutations in the alpha catalytic subunit of PI3
kinase (PIK3CA) occurs at a frequency of 30%40% and is the
most frequent genetic abnormality in ER+ breast cancer.33,34
A majority of the mutations, including the three hot-spot
mutations E542K, E545K, and H1047R, are missense acti-
vating mutations that cluster in the evolutionarily conserved
accessary domain and the kinase domain.35 In preclinical
models, ER+ breast cancer carrying PIK3CA mutations was
highly dependent on p110 alpha for cell survival.31,36
Rapalogs are among the first agents introduced in the
clinic that indirectly inhibit the activity of mTOR complex 1
(mTOC1) through its interaction with FKBP12.37 Everolimus
The incidence of ESR1 mutations increases dramatically after treatment with long- is now approved for AI-resistant metastatic breast cancer.
term endocrine therapy for recurrent or metastatic ER+ disease. The hot-spot ligand-
binding domain mutations induce a constitutive agonist conformation of ER, leading
However, inhibition of mTORC1 has the potential to upre-
to estrogen independence. gulate Akt activity due to the negative feedback loop be-
Abbreviations: AF1, activation function 1; DBD, DNA-binding domain; ER, estrogen
receptor; LBD, ligand-binding domain. tween the downstream S6K and the upstream PI3K.38,39
Direct kinase inhibitors against both mTORC1 and mTORC2,
as well as inhibitors against Akt and PI3K, are in clinical trials
advanced solid tumors (NCT01953926), was recently re- for more effective pathway inhibition. Promising activity has
ported in an abstract form.25 Among the 19 evaluable pa- been observed in some studies.40-43 However, it has become
tients, objective response was observed in six (overall evident that the efficacy of pan-PI3K inhibitors is limited by
response rate 32%). As a majority of breast cancers with dose-limiting toxicities that include rash, diarrhea, and el-
HER2 mutation are ER+, the combination of fulvestrant and evated transaminases.43,44 Alpha-specific inhibitors are
neratinib is being studied among this patient population likely advantageous in improving the therapeutic window,
(NCT01670877). but resistance mechanisms through acquiring mutations in
PTEN, leading to growth dependence on PI3K-beta, have
Fibroblast Growth Factor Receptors and Ligands been reported in clinical trials of alpelisib, an alpha-specific
Amplification inhibitor.45 Preclinical modeling also indicated that effective
The fibroblast growth factor (FGF) signaling is composed inhibition of mTOR remains important for upstream in-
of 18 ligands that exert their function through four highly hibitors,46 but combined PI3K and mTOR inhibition may not
conserved transmembrane tyrosine kinase receptors be feasible due to overlapping toxicities. There has been
(FGFR1, FGFR2, FGFR3, and FGFR4) to control a wide range significant interest in developing biomarkers of treatment
of biologic functions and regulating cellular proliferation, efficacy, in particular PIK3CA mutation status. However, no
survival, migration, and differentiation.26 FGFR1 ampli- clear association has been identified even with the direct
fication has been identified in 16%27% of luminal B ER+ PI3K inhibitors.40-43,47
breast cancers and associated with increased Ki67, early
relapse, and poor survival.27 Less frequently, the pathway
could be activated by amplification of FGFR2 or different Cyclin D/CDK4/6/Rb Pathway
ligands including FGF3 and FGF4.26 In preclinical studies, The G1 to S phase transition is controlled by CDK4/6, which
FGFR1 amplification enhanced PI3K and MAPK pathway are activated upon binding to D-type cyclins,48-51 leading to
signaling and rendered cancer cells resistance to endocrine phosphorylation of retinoblastoma susceptibility (RB1) gene
therapy, which was reversed by RNAi silencing of FGFR1.27 product (Rb) and the release of the E2F transcription fac-
Dovitinib (TKI258), a first-generation oral tyrosine kinase in- tors.51 There is a strong link between the action of estrogen
hibitor of FGFR1-3, VEGFR, and PDGFR, inhibited proliferation and CDK4/6 activity.52-56 Persistent cyclin D1 expression and
of FGFR1/2-amplifiedbut not FGFRnormalbreast cancer Rb phosphorylation has been associated with resistance to
cell lines, and demonstrated promising antitumor activity for endocrine therapy in ER+ breast cancer.57 The poorer prog-
patients with FGFR1/2/3-amplified breast cancers in a phase II nosis, luminal B ER+ diseases are preferentially enriched with
trial.28 Several FGFR inhibitors are currently being in- gains of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal
vestigated in advanced HR+ breast cancer to overcome A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of
endocrine resistance. CDKN2A (p16) and CDKN2C (p18), which are negative regu-
lators of CDK4/6.34
In preclinical studies, the CDK4/6 inhibitor palbociclib was
PI3K/Akt/mTOR Pathway preferentially effective in inhibiting the cell proliferation of
The PI3K/Akt/mTOR pathway is a cardinal nodal point in the ER+ cancer cells, including those resistant to anti-estro-
transduction of extracellular and intracellular growth and gens.58 Synergism was observed when combining palbociclib

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RUGO, VIDULA, AND MA

with various anti-estrogens,58,59 and efficacy was demon- complicated because of its functional redundancy with the
strated in patient-derived xenograft models of ER+ breast insulin receptor.75 In addition to mediating endocrine therapy
cancer carrying ESR1 mutations.59 Cells lacking Rb (and resistance, data also support the importance of IGF1R in
hence not dependent on cyclin D1/CDK4/6 for proliferation) mediating treatment resistance to inhibitors against mTOR or
were resistant to palbociclib. Therefore lack of Rb may serve Akt in endocrine-resistant ER+ breast cancer because of the
as a biomarker of resistance to this class of agents. Palbo- negative feedback loop between the downstream target S6K
ciclib in combination with letrozole is now approved as first- and the upstream IGF1R/IRSs/PI3K signaling.38,76 Preclinical
line treatment of postmenopausal women with metastatic data support the clinical investigation for the combined in-
ER+ HER2 breast cancer. Several other CDK4/6 inhibitors hibition of IGF1R/IR and Akt, along with ER targeting.76
are in various stages of clinical development.
Vascular Endothelial Growth Factor
Combining PI3K and CDK4/6 Inhibitors in PIK3CA- In addition to contributing to neoangiogenesis, VEGF has
Mutant Breast Cancer been shown to induce breast cancer cell proliferation and
A drug screen of 42 agents identified the CDK4/6 inhibitor resistance to endocrine therapy via an autocrine mecha-
ribociclib as a strong sensitizer to PI3K inhibition in three ER+ nism.77,78 VEGF and the VEGF receptor have shown to be
breast cancer cell lines with acquired resistance to PI3K overexpressed in breast cancers, and high levels of VEGF
inhibitors.60 In this study, acquired resistance to PI3K in- have been linked to early recurrence and resistance to
hibition was associated with maintained phosphorylation of hormonal therapy.79,80 These provided the preclinical ra-
S6 and Rb. Addition of ribociclib reduced Rb phosphorylation tional for investigating the addition of VEGF inhibitors to
and induced synergist antitumor effect of the PI3K inhibitor, hormonal therapy for the treatment of ER+ breast cancer.
particularly in those with PIK3CA mutation and intact Rb. The The challenge so far has been the difficulty in identifying a
synergism was also observed in the parental cell lines and those target patient population who would derive the most benefit
with de novo resistance to PI3K inhibitors. The impressive an- from these agents.
titumor activity and the nonoverlapping toxicities of these two
classes of agents has led to clinical evaluation of triplet regimens
composed of letrozole, ribociclib, and alpelisib. Microenvironment and Immune Checkpoint Pathway
The immune checkpoint pathway, PD-1, and the PD-L1 path-
Epigenetic Pathways way has been implicated in tumor immune invasion.81 In-
Preclinical studies indicated that epigenetic silencing of hibitors against PD-1 and PD-L1, which disrupt the interaction
ER and deregulation of growth factor receptorpathway between PD-1 on T cells and its ligands PD-L1, have shown
components play an important role in the development of antitumor activity in a variety of tumor types. Approximately
endocrine resistance.61-64 In addition, an array of mutations 4%20% of ER+ breast cancers, perhaps more frequently in the
have been identified in genes that regulate histone and DNA more proliferative luminal B versus luminal A subtypes, have
modification.34 An example is the MLL3 (myeloid/lymphoid been reported to overexpress PD-L1 in cancer and stroma
or mixed-lineage leukemia gene) mutation, which occurred cells.82-84 PD-1 and PD-L1 antibodies are being tested in HR+
in 8% of luminal A and 6% of luminal B breast cancers.34 breast cancer, with preliminary results available.

Insulin-Like Growth Factor/Type 1 Insulin-Like REVERSING HORMONE RESISTANCE IN THE


Growth Factor Signaling CLINIC
The insulin-like growth factor (IGF)/type 1 insulin-like With a greater understanding of the mechanisms of re-
growth factor receptor (IGF1R) signaling has a critical role sistance to hormone therapy, new therapies have emerged
in cell growth, survival, and migration and is required for that hold the potential to overcome hormone resistance and
mammary gland development.65 The IGF ligands, IGF1 and improve response, duration of response, and, hopefully,
IGF2, stimulate cell growth and survival signaling primar- survival. Targeted therapies that are being actively in-
ily via binding to IGF1R and the subsequent activation of vestigated in the clinic include mTOR inhibitors (ever-
the PI3K/Akt and RAS/MAPK pathways.65,66 Extensive bi- olimus), PI3K inhibitors (buparlisib, alpelisib, and taselisib),
directional regulation exists between ER and the IGF1R CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib),
pathway.67 ER-alpha is a major regulator of IGF signaling as HDAC inhibitors (entinostat), FGFR inhibitors (dovitinib and
IGF1R and other IGF signaling components are its direct lucitinib), and IGFR inhibitors. Altering the host immune re-
transcription target,68-70 while IGF1R upregulates the tran- sponse with checkpoint inhibition is also being investigated in
scription level of ER-alpha and increases ER phosphorylation via advanced disease. Table 1 summarizes the major ongoing
activation of mTOR/S6K signaling.71 Hyperactivation of IGF1R phase II and III trials with the most-promising novel targeted
and downstream signaling has been associated with the de- agents. Table 2 provides a summary of these agents, their
velopment of endocrine resistance in ER+ breast cancer mechanisms of action, developmental status, and toxicity
preclinical models and patient specimens.65,72-74 However profile. This section provides a more detailed review of these
targeting IGF1R in the endocrine-resistant setting has been emerging therapies, focusing on non-HER2 amplified disease.

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Of note, two randomized trials have demonstrated im- 0.45; 95% CI, 0.380.54). Median OS was not significantly
proved progression-free survival (PFS) with the addition of improved at 31 months with everolimus compared with
HER2-targeted agents to AIs in the treatment of metastatic, 26.6 months with placebo (HR 0.89; 95% CI, 0.731.10;
HR, and HER2+ disease.22,85 However, given the demonstrated p = .14).90 A subset analysis of BOLERO-2 demonstrated
improvement in overall survival (OS) with chemotherapy, efficacy of combination therapy among patients with visceral
trastuzumab, and pertuzumab in the first-line metastatic set- metastases and those with nonvisceral disease.91 Based on
ting, this is generally the preferred treatment approach, with the PFS data, everolimus is now being used clinically in
hormone therapy reserved for maintenance in combination combination with exemestane in the metastatic setting.
with HER2-targeted therapy following response. Toxicity is a substantial issue with everolimus, but data
from subsequent trials suggest that physician and patient
education and expectant management reduces common
Inhibition of mTOR toxicity and increases tolerability.
Several randomized trials have demonstrated that inhibition The most common toxicity in BOLERO-2 was stomatitis
of the mTOR pathway can improve duration of response to (56% all grade, aphthous-type ulcers), although the in-
hormone therapy, despite an initial rocky start. The first cidence of grade 3 stomatitis was low (8%), and no grade 4
randomized trial evaluated the efficacy of temsirolimus in events were oberved.92 Stomatitis occurs early, with 80% of
combination with the AI letrozole as first-line therapy for cases occurring in the first 6 weeks of therapy.93 A meta-
metastatic HR+ breast cancer.86 There was no difference in PFS analysis of seven phase III studies of everolimus in different
between the two arms. It may be that the dose and schedule of cancer types evaluated whether the incidence of stomatitis
temsirolimus were not optimal, as stomatitis (a marker of drug correlated with clinical efficacy.94 There was commonality of
exposure) was seen at a lower rate than expected. everolimus-induced stomatitis across solid tumors (66.9% all
Greater success leading to the first approval of a targeted grades of all patients), with 8.6% grade 3/4 stomatitis, and
therapy in combination with hormone therapy in HER2 the incidence of stomatitis correlated with at least as good if
disease was seen with everolimus. A phase II neoadjuvant not better PFS compared with the control population. This
trial was conducted to evaluate efficacy and biomarkers, suggests that stomatitis may be a marker of drug exposure
with the primary endpoint of clinical response.87 Two for everolimus and that dose reductions and delays for this
hundred-seventy postmenopausal women with HR+ early- toxicity do not impact efficacy. A phase II trial evaluated a
stage breast cancer were randomly selected to receive commercially available steroid-based mouthwash among
letrozole plus everolimus or placebo for 4 months prior to patients taking prophylactic exemestane and everolimus to
surgery. Clinical response was higher in the combination arm determine if the incidence and severity of stomatitis might
compared with placebo (68.1% vs. 59.1%; p = .062). More be reduced with this approach.95 Data will be presented at
importantly, a significant decrease in cell proliferation on the 2016 American Society of Clinical Oncology (ASCO)
repeat biopsy performed 2 weeks after treatment was noted Annual Meeting.
in the combination therapy arm compared with placebo Other commonly noted side effects with everolimus in-
(57% vs. 30% decrease; p , .01). These data encouraged clude fatigue, diarrhea, rash, hyperglycemia, pneumonitis,
further investigation of everolimus in combination with weight loss, anemia, and thrombocytopenia. The risk of
hormone therapy. pneumonitis persists over the course of therapy at a low
Two subsequent trials tested everolimus in the metastatic rate, with a 3% rate of grade 3 pneumonitis observed in
setting. The TAMRAD trial was a phase II open-label trial that BOLERO-2. Additional clinical trials with everolimus are on-
randomly selected 111 postmenopausal women whose going, summarized in Table 1. These include studies in the
disease had progressed on an AI to receive tamoxifen and neoadjuvant, adjuvant, and metastatic settings. Results from
everolimus or tamoxifen alone.88 The primary endpoint, BOLERO-6, comparing everolimus plus exemestane with
clinical benefit rate at 6 months, was improved with com- capecitabine, are expected this year.
bination therapy compared with tamoxifen alone (61% vs.
42%; p = .045). Progression-free survival in the combination
therapy arm was significantly longer at 8.6 months versus Inhibition of PI3K
4.5 months (p = .002). Two classes of PI3K inhibitors are being studied in HR+ breast
Finally, regulatory approval of everolimus in combination cancer, the pan-class I inhibitors (buparlisib [BKM120] and
with exemestane for the treatment of metastatic breast pictilisib [GDC0941]) and the alpha-specific inhibitors
cancer progressing on nonsteroidal AIs was based on data (alpelisib [BYL719] and taselisib [GDC0032]).
from the BOLERO-2 trial, a double-blind phase III trial that Results with the pan-PI3K inhibitors have been compli-
randomly selected 724 postmenopausal women in a 2:1 ratio cated by toxicity and disappointing efficacy. The FERGI trial
to receive exemestane with everolimus at 10 mg a day or was a phase II trial that randomly selected 168 women with
placebo.89 At a median follow-up of 18 months, investigator- HR+ postmenopausal metastatic breast cancer previously
assessed PFS (the primary endpoint) was more than doubled treated with an AI to receive fulvestrant with pictilisib or
with the addition of everolimus (7.8 months for everolimus placebo.44 Toxicity was increased in the pictilisib arm; 17% of
compared with 3.2 months for placebo; hazard ratio [HR] patients had at least grade 3 rash and 7% had at least grade 3

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TABLE 1. Phase II/III Trials of the Novel Targeted Agents Under Development for Hormone ReceptorPositive
Breast Cancer

No.
Trial Novel Agent Primary Endpoint Patients Trial Status
Everolimus: mTOR Inhibitor
Baselga et al87 Everolimus Clinical examination response 270 Completed; response rate of 68.1% in
everolimus/letrozole arm compared with
59.1% in placebo/letrozole arm (p = .062)
GINECO88 Everolimus Clinical benefit rate at 6 months 111 Completed; clinical benefit rate of 61% in
everolimus/tamoxifen arm compared with
42% in tamoxifen arm (p = .045)
BOLERO-289 Everolimus PFS 724 Completed; median PFS of 7.8 months in
everolimus/exemestane arm compared
with 3.2 months in exemestane/placebo
(HR 0.45; 95% CI, 0.380.54)
UNIRAD127 Everolimus Disease-free survival 1,984 Ongoing
SWOG 1207128 Everolimus Invasive disease-free survival using 1,900 Ongoing, recruiting patients
a stratified log-rank test, assessed
up to 10 years
NCT02088684130 Everolimus PFS 46 Ongoing, recruiting patients
BOLERO-4143 Everolimus Percentage of patients progression- 202 Ongoing
free after completion of first-line
treatment
BOLERO-6144 Everolimus PFS 297 Ongoing, recruitment completed
BRE-43145 Everolimus Time to progression 33 Completed
LEO146 Everolimus PFS 137 Ongoing, active recruitment
147
FEVEX Everolimus PFS 745 Not yet open
PrE0102148 Everolimus PFS 130 Ongoing
NCT02236572113 Everolimus Achievement of a PEPI score of 0 66 Ongoing, recruiting patients
following neoadjuvant treatment
with everolimus and an aromatase
inhibitor at 26 weeks
NCT02123823149 BI 836845 (monoclonal antibody PFS 174 Ongoing, recruiting patients
to insulin like growth factor)
and everolimus
Taselisib (GDC0032): Alpha-Specific PI3K Inhibitor
LORELEI150 Taselisib Objective response rate and 330 Ongoing, recruiting patients
pathologic complete response
rate at 16 weeks of treatment
SANDPIPER98 Taselisib PFS 600 Ongoing, recruiting patients
Buparlisib (BKM120) Pan-Class I PI3K Inhibitor
BELLE-296 Buparlisib PFS 1147 Completed; PFS was slightly improved with
buparlisib vs. placebo (6.9 vs. 5 months; HR
0.78; 95% CI, 0.670.89)
BELLE-3151 Buparlisib PFS 420 Ongoing, recruiting patients
Pictlisib (GDC0941): Pan-Class I PI3K Inhibitor
FERGI44 Pictlisib PFS 168 PFS of 6.6 months for pictilisib/fulvestrant
arm compared with 5.1 months in
fulvestrant/placebo arm (HR 0.7; 95% CI,
0.521.06)
Palbociclib: CDK4/6 Inhibitor
PALOMA-1/TRIO- Palbociclib PFS 165 Completed; PFS for palbociclib/letrozole was
1899 20.2 months compared with 10.2 months
in letrozole arm (HR 0.49; 95% CI,
0.3190.748)
PALOMA-2100 Palbociclib PFS 650 Ongoing, closed to accrual
Continued

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TABLE 1. Phase II/III Trials of the Novel Targeted Agents Under Development for Hormone ReceptorPositive
Breast Cancer (Contd)
No.
Trial Novel Agent Primary Endpoint Patients Trial Status
PALOMA-3101 Palbociclib PFS 417 Completed; PFS of 9.2 months in palbociclib/
fulvestrant arm vs. 3.8 months in fulves-
trant/placebo arm (HR 0.42; 95% CI,
0.320.56)
PEARL104 Palbociclib PFS 348 Ongoing, recruiting patients
PENELOPEB103 Palbociclib Invasive disease-free survival 800 Ongoing, recruiting patients
PALOMA-4152 Palbociclib PFS 330 Ongoing, recruiting patients
PALOMA-2139 Palbociclib Treatment discontinuation rate 160 Ongoing, not recruiting patients
PALLET153 Palbociclib Change in proliferation rate (Ki67) 306 Ongoing, recruiting patients
at 2 weeks
FLIPPER154 Palbociclib PFS 190 Ongoing, recruiting participants
PARSIFAL155 Palbociclib PFS 304 Ongoing, currently recruiting patients
NCT02384239156 Palbociclib Tumor Progression as measured by 70 Ongoing, currently recruiting patients
RECIST 1.1
NCT02592746157 Palbociclib PFS 122 Ongoing, not yet recruiting patients
Abemaciclib: CDK4/6 Inhibitor
neoMONARCH134 Abemaciclib Change in proliferation rate (Ki67) 220 Ongoing, recruiting patients
at 2 weeks
monarcHER158 Abemaciclib PFS 225 Ongoing, not yet recruiting patients
MONARCH-1110 Abemaciclib Objective response rate 128 Closed to accrual
MONARCH-2112 Abemaciclib PFS 550 Ongoing
MONARCH-3113 Abemaciclib PFS 450 Ongoing
NCT02308020114 Abemaciclib Percentage of participants achieving 247 Recruiting
complete response or partial
response: objective intracranial
response rate
Ribociclib: CDK4/6 Inhibitor
MONALEESA-2141 Ribociclib PFS 667 Ongoing
159
MONALEESA-3 Ribociclib PFS 660 Ongoing, recruiting participants
Entinostat: HDAC Inhibitor
Yardley et al117 Entinostat PFS 130 Completed; PFS was 4.3 months in
exemestane/entinostat arm compared
with PFS of 2.3 months with exemestane
alone arm (p = .055); overall survival was
28.1 months in exemestane/entinostat
arm compared with 19.8 months in
exemestane alone arm (HR 0.59; 95% CI,
0.360.97)
E2112118 Entinostat PFS 600 Ongoing
Azacitidine: DNA Methylation Inhibitor
NCT01349959120 Azacitidine and entinostat Confirmed response rate 40 Ongoing
NCT02374099119 Azacitidine Time period of PFS 92 Ongoing, recruiting patients
Abbreviations: HR, hazard ratio; PFS, progression-free survival.

diarrhea, and 18% of patients discontinued due to adverse randomly selected to fulvestrant with either buparlisib or
events. Progression-free survival was similar between the placebo, with a primary endpoint of PFS in the full pop-
two treatment arms at 6.6 months for pictilisib and ulation and in those with PI3K pathwayactivated tumors. In
5.1 months for placebo (HR 0.7; 95% CI, 0.521.06; p = .096), the 1,147 women who received study therapy, PFS was
and among patients with PI3KCA-mutant tumors. In an slightly improved with buparlisib compared with placebo
exploratory analysis, there was a suggestion of benefit for (6.9 vs. 5 months; HR 0.78; 95% CI, 0.670.89; p , .001).
patients with PR+ disease. Progression-free survival was not significantly improved for
The pan-PI3K inhibitor buparlisib was evaluated in the patients with PI3K activation (6.8 vs. 4 months). In an ex-
phase III BELLE-2 trial.96 Patients with prior AI therapy were ploratory analysis of PIK3CA mutations in circulating tumor

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TABLE 2. Summary of the Most-Promising Targeted Agents Under Development in the Treatment of Hormone
ReceptorPositive Breast Cancer

Agent Mechanism of Action Developmental Status Toxicity Profile


Everolimus mTOR inhibition FDA approval for everolimus plus exemestane as at Main toxicities include stomatitis, hyperglycemia,
least second-line therapy for HR+ advanced fatigue, pneumonitis
breast cancer
Palbociclib, Ribociclib, CDK4/6 inhibition FDA approval for palbociclib plus letrozole as first- Main toxicities include neutropenia without
Abemaciclib line therapy, and palbociclib plus fulvestrant as an increase in febrile neutropenia, QTc
at least second-line therapy for advanced breast prolongation, and fatigue; diarrhea most
cancer; ongoing trials with all 3 agents in the common with abemaciclib
metastatic, adjuvant, and neoadjuvant settings
Alpha-Specific
Alpelisib, Taselisib PI3K inhibition Ongoing trials Main toxicities include hyperglycemia, rash, and
liver dysfunction
Pan-PI3K
Buparlisib, Pictilisib PI3K inhibition Ongoing trials Main toxicities include hyperglycemia, rash, and
liver dysfunction
Entinostat HDAC inhibition FDA breakthrough status; ongoing phase III trial Main toxicities include fatigue, myelosuppression,
with exemestane diarrhea, nausea, and vomiting
Dovitinib, Lucitinib FGFR inhibition Pre-clinical and preliminary clinical efficacy with Main toxicities include diarrhea, nausea, and
FGFR/VEGF inhibition dovitinib and lucitinib hypertension, proteinuria, and liver dysfunction
(lucitinib)
Abbreviation: FDA, U.S. Food and Drug Administration.

DNA (ctDNA; 87 patients for buparlisib and 113 for placebo), cancer. Palbociclib and ribociclib are given on a 3-week-on,
PFS was improved for those with PIK3CA mutations receiving 1-week-off schedule, and abemaciclib is given continuously.
buparlisib compared with placebo (7.0 vs. 3.2 months; HR A number of studies are evaluating CDK4/6 inhibitors in the
0.56), with no difference in the wild-type population. neoadjuvant, adjuvant, and metastatic settings, as sum-
Toxicity was increased in the buparlisib arm, with grade marized in Table 1. The results of pivotal trials and key
3/4 transaminitis (. 20%; approximately 0% grade 4), hy- planned trials are summarized here.
perglycemia (15.4%), rash (7.9%), anxiety (5.4%), and de- PALOMA-1 was a phase II trial that randomly selected 165
pression (4.4%); 13% of patients discontinued treatment due postmenopausal women with untreated HR metastatic
to adverse events. breast cancer to receive letrozole with or without palbociclib.99
The data from BELLE-2, although disappointing in the Progression-free survival with combination therapy was
overall population, provide the first data suggesting that 20.2 months vs. 10.2 months in the control arm (HR 0.49;
ctDNA could be a potential marker to select patients who 95% CI 0.3190.748; p = .0004). The trial was not powered
might benefit from specific targeted therapies. Ongoing to evaluate OS, which was similar between the two arms.
trials are evaluating the use of PIK3CA mutations in ctDNA as
The primary toxicity was at least grade 3 neutropenia,
predictive markers for response to alpha-specific PI3K in-
occurring in 54% of patients, with no cases of febrile
hibitors, such as alpelisib and taselisib.
neutropenia; 13% of patients in the study arm dis-
The alpha-specific PI3K inhibitors alpelisib and taselisib
continued therapy due to adverse events.
have demonstrated encouraging efficacy in early-phase
Based on this data, in 2015, the U.S. Food and Drug Ad-
trials, with modest toxicity. Two ongoing placebo-controlled
ministration (FDA) granted accelerated approval for pal-
phase III trials are evaluating the potential improvement in
bociclib and letrozole for the first-line treatment of
PFS with the addition of alpelisib (SOLAR-197) or taselisib
(SANDPIPER98) to fulvestrant among patients with HR+ postmenopausal patients with HR+ metastatic breast can-
metastatic breast cancer, and neoadjuvant trials in combi- cer. PALOMA-2 is a phase III trial designed to validate these
nation with AIs are also ongoing (the buparlisib arm of the findings; data are expected to be presented at the 2016
NeoORB study was recently closed based on results from ASCO Annual Meeting.100
BELLE-2). More details regarding ongoing studies are pro- PALOMA-3, a phase III trial, randomly selected 521 women
vided in Table 1. Results are eagerly awaited. with advanced pretreated breast cancer 2:1 to treatment
with palbociclib and fulvestrant versus fulvestrant and
placebo.101 Progression-free survival was significantly im-
Inhibition of CDK4/6 proved in the combination arm versus placebo (9.2 months vs.
Three CDK4/6 inhibitors (palbociclib, ribociclib, and abe- 3.8 months; HR 0.42; 95% CI, 0.320.56; p , .001). Pre-
maciclib) are in advanced clinical testing, and palbociclib has menopausal women with ovarian suppression and pa-
regulatory approval for treatment of metastatic breast tients with one line of prior chemotherapy appeared to

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have similar benefit. Toxicity was similar to PALOMA-1, al- toxicities; 11% of patients discontinued due to adverse
though only 2.6% of patients discontinued treatment due to events. A phase III trial, E2112, with a similar design is
adverse events. Fulvestrant and palbociclib were approved ongoing (Table 1).118
by the FDA in early 2016. Azacitidine, a DNA methylation inhibitor, is also being
An international adjuvant trial of 4,600 patients is compar- investigated in breast cancer with hormonal therapy119 and
ing 2 years of treatment with palbociclib versus placebo entinostat.120
(PALLAS),102 and PENELOPE-B103 is studying 1 year of palbo-
ciclib as postneoadjuvant therapy for high-risk patients. Nu- Inhibition of IGFR
merous other trials are evaluating palbociclib as neoadjuvant A number of IGFR inhibitors have been studied in the clinic, with
therapy compared with capecitabine in metastatic disease generally disappointing results to date. A randomized phase II
(PEARL)104 and following chemotherapy, among others. trial evaluated the benefit of adding ganitumab to either ful-
Ribociclib is a similar CDK4/6 inhibitor that is being studied vestrant or exemestane as second-line therapy for 156 patients
in the metastatic and neoadjuvant settings in the ongoing with metastatic HR+ breast cancer.121 There was no difference
MONALEESA trials.105,106 In addition, ongoing studies are in PFS (3.9 months for the ganitumab arm vs. 5.7 months for
evaluating ribociclib combined with exemestane and ever- placebo). New agents that do not cause hyperglycemia may
olimus,107 and letrozole and the PI3K inhibitor alpelisib.108 offer advantages; the monoclonal antibody BI 836845 is being
Abemaciclib is a potent inhibitor of CDK4, more than CDK6, studied in combination with everolimus and exemestane in a
and is the only agent in this class that can be given con- randomized phase II trial based on promising phase I results.107
tinuously. A phase IB trial including 47 patients demon-
strated single-agent activity with a clinical benefit rate of
61.1%,109 leading to the single agent MONARCH-1 trial of Inhibition of Angiogenesis
patients with heavily pretreated HR+ metastatic breast Although not currently in the clinical arena, a discussion of
cancer; data are expected to be presented at the 2016 ASCO this approach is important. Two randomized phase III trials
Annual Meeting.110 An expansion cohort of the phase IB trial evaluated the potential efficacy from adding bevacizumab,
evaluated abemaciclib plus fulvestrant; the clinical benefit the VEGF antibody, to first-line hormone therapy with
rate was 72.2%.111 The most common toxicity from abe- letrozole or fulvestrant.122,123 Both trials demonstrated im-
maciclib is diarrhea, with a lower incidence of neutropenia. provement in PFS comparing letrozole or fulvestrant plus
Additional ongoing MONARCH trials are evaluating abe- bevacizumab with hormone therapy alone, although only the
maciclib in the neoadjuvant setting,105 in metastatic disease CALGB trial found this difference to be statistically significant
in combination with fulvestrant,112 or nonsteroidal AIs113 in (LEA trial: 19.3 vs. 14.4 months; HR 0.83; 95% CI, 0.651.06;
brain metastases114 and in HER2+ disease.112 p = .126; CALGB 40503: 20 vs. 16 months; HR 0.75; 95% CI,
0.590.96; p = .016); no difference was seen in OS. Adverse
events included at least grade 3 hypertension and proteinuria.
Inhibition of FGFR Further combined biomarkers analysis is ongoing.
Dovitinib, an oral tyrosine kinase inhibitor of FGFR, has been
shown to have both preclinical and clinical efficacy.28 In a
Immune Checkpoint Inhibition
study of 81 patients, five patients with tumor FGFR ampli-
Based on the expression of PD-L1 in HR+ breast cancer, there
fication experienced clinical benefit at 6 months. These
has been interest in evaluating the efficacy of this approach
results prompted further trials with dovitinib and hormonal
in the advanced disease setting. Pembrolizumab, a PD-1
therapy combinations, although toxicity is a limiting fac-
antibody, was tested in a number of solid malignancies in the
tor.115 Lucitanib is a FGFR/VEGFR tyrosine kinase inhibitor
phase IB KEYNOTE-28 trial.124 Out of 248 patients who had
with encouraging phase IB response data under evaluation
tissue available for screening, 48 (19.4%) had at least 1%
in a phase II single-agent trial.116 Toxicity is again limiting,
staining for PD-L1. The overall response rate among 25
including hypertension, proteinuria, and transaminitis.
treated patients was 12%, with a clinical benefit rate of 20%.
The median time to response was 8 weeks, and the median
Inhibition of HDAC duration of response had not yet been reached.
A randomized phase II trial evaluated the addition of enti- The phase IB Javelin trial evaluated the efficacy of the anti-
nostat or placebo to exemestane for 130 women with ad- PD-L1 antibody avelumab for patients with metastatic solid
vanced breast cancer.117 Progression-free survival was tumors, including breast cancer.125 Out of the 72 patients
slightly improved in those receiving entinostat compared with HR+ disease, an objective response was seen in only
with placebo (4.3 vs. 2.3 months; p = .055), but the ex- 2.8%, but 54% were found to have PD-L1 expression. This
ploratory endpoint of OS was significantly improved (28.1 vs. brings into question the antibodies used for PD-L1 testing as
19.8 months; HR 0.59; 95% CI, 0.360.97; p = .036), leading well as potential differences in efficacy between different
to breakthrough drug status by the FDA. Interestingly, checkpoint inhibitors.
protein lysine hyperacetylation in the entinostat biomarker Overall, therapy was well tolerated in both trials, with
subset was associated with prolonged PFS. Fatigue and the primary toxicity reversible and immune related (e.g.,
neutropenia were the most common grade 3 or worse thyroid disorders, hepatitis). Further studies will evaluate

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combination therapy with agents that could increase The development of ESR1 mutation following endocrine
expression of neo-antigens (such as HDAC inhibitors), and therapy provides further evidence that ER remains relevant
therefore enhance immunogenicity. in resistant tumors. Combination strategies that target both
ER and resistant pathways are therefore rational approaches
CONCLUSION to overcome endocrine resistance. Toxicity and cost are
Progress in the understanding of endocrine resistance increased with the addition of targeted agents. Awareness of
mechanisms has led to the development of a number of both expected toxicity and appropriate management is
agentssome approved and many in clinical trialsto important. There is a critical need to develop predictive
target growth factor receptor signaling, PI3K/Akt/mTOR, biomarkers; recent data using ctDNA are encouraging.
CDK4/6, HDAC, and immune checkpoints, among others. Further studies are ongoing.

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113. NCT02236572. Neoadj ph 2 AI plus everolimus in postmenopausal ceiving at least 1 year of adjuvant hormone therapy. http://www.icr.
women w/ ER pos/HER2 neg, low risk score. https://clinicaltrials.gov/ ac.uk/our-research/our-research-centres/clinical-trials-and-
ct2/show/NCT02236572. Accessed March 26, 2016. statistics-unit/clinical-trials/unirad. Accessed January 30, 2016.
114. NCT02308020. A study of abemaciclib (LY2835219) in participants with 128. NCT01674140. SWOG 1207. Phase III randomized, placebo-controlled
breast cancer, non-small cell lung cancer, or melanoma that has spread to clinical trial evaluating the use of adjuvant endocrine therapy +/2 one
the brain. https://clinicaltrials.gov/ct2/show/NCT02308020?term= year of everolimus in patients with high-risk, hormone receptor-
abemaciclib+brain&rank=1. Accessed March 3, 2016. positive and HER2/neu negative breast cancer. e3 breast cancer
115. NCT01484041. Dovitinib plus an aromatase inhibitor for metastatic study- evaluating everolimus with endocrine therapy. http://swog.org/
breast cancer. https://clinicaltrials.gov/show/NCT01484041. Accessed Visitors/ViewProtocolDetails.asp?ProtocolID=2248. Accessed January 30,
January 31, 2016. 2016.

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RUGO, VIDULA, AND MA

129. NCT02308020. A study of abemaciclib (LY2835219) in participants breast cancer. (BOLERO-6). https://clinicaltrials.gov/ct2/show/
with breast cancer that has spread to the brain. https://clinicaltrials. NCT01783444. Accessed March 26, 2016.
gov/ct2/show/record/NCT02308020?term=abemaciclib&rank=6. 145. NCT00570921. Study of combined fulvestrant and everolimus in
Accessed January 30, 2016. advanced/metastatic breast cancer after aromatase inhibitor failure
130. NCT02088684. Study of LEE011 with fulvestrant and BYL719 or (BRE-43). https://clinicaltrials.gov/ct2/show/NCT00570921. Accessed
BKM120 in advanced breast cancer. http://www.cancer.gov/ March 26, 2016.
clinicaltrials/search/view?cdrid=759365&version=HealthProfessional& 146. NCT02344550. Study of GnRH plus leterozole +/2 everolimus for
protocolsearchid=12773476. Accessed May 27, 2014. premenopausal women with metastatic breast cancer (LEO). https://
131. NCT01872260. Study of LEE011. BYL719 and letrozole in advanced ER+ clinicaltrials.gov/ct2/show/NCT02344550. Accessed March 26, 2016.
breast cancer. http://www.cancer.gov/clinicaltrials/search/view?cdrid= 147. NCT02404051. Fulvestrant and EVerolimus Plus EXemestane in
750319&version=HealthProfessional&protocolsearchid= metastatic breast cancer (FEVEX). https://clinicaltrials.gov/ct2/show/
12773476. Accessed May 27, 2014. NCT02404051. Accessed March 26, 2016.
132. NCT02057133. A study of LY2835219 in combination with therapies 148. NCT01797120. Study of fulvestrant +/2 everolimus in post-menopausal,
for breast cancer that has spread. https://clinicaltrials.gov/ct2/show/ hormone-receptor 1 metastatic breast ca resistant to AI (PrE0102). https://
record/NCT02057133. Accessed May 27, 2014. clinicaltrials.gov/ct2/show/NCT01797120. Accessed March 26, 2016.
133. NCT02117648. A study of LY2835219 in participants with cancer. 149. NCT02123823. A phase Ib/II randomized study of BI 836845 in com-
https://clinicaltrials.gov/ct2/show/NCT02117648. Accessed March bination with exemestane and everolimus versus exemestane and
26, 2016. everolimus alone in women with locally advanced or metastatic breast
134. NCT02441946. A neoadjuvant study of abemaciclib (LY2835219) in cancer. https://clinicaltrials.gov/ct2/show/record/NCT02123823?term5
postmenopausal women with hormone receptor positive, HER2 BI1836845&rank53. Accessed March 26, 2016.
negative breast cancer (neoMONARCH). https://clinicaltrials.gov/ct2/ 150. NCT02273973. A study of neoadjuvant letrozole 1 GDC-0032 versus
show/NCT02441946?term=abemaciclib&rank=3. Accessed May 15, letrozole 1 placebo in post-menopausal women with breast cancer
2015. (LORELEI). https://clinicaltrials.gov/ct2/show/NCT02273973. Accessed
135. Caldon CE, Sergio CM, Kang J, et al. Cyclin E2 overexpression is as- March 26, 2016.
sociated with endocrine resistance but not insensitivity to CDK2 in- 151. NCT01633060. A phase III study of BKM120 with fulvestrant in
hibition in human breast cancer cells. Mol Cancer Ther. 2012;11: patients with HR1, HER2-, AI treated, locally advanced or meta-
1488-1499. static breast cancer who progressed on or after mTORi (BELLE-3).
136. Casimiro MC, Velasco-Velazquez M, Aguirre-Alvarado C, et al. Over- https://clinicaltrials.gov/ct2/show/NCT01633060. Accessed March
view of cyclins D1 function in cancer and the CDK inhibitor landscape: 26, 2016.
past and present. Expert Opin Investig Drugs. 2014;23:295-304. 152. NCT02297438. A study of palbociclib (PD-0332991) 1 letrozole vs.
137. Finn RS, Crown JP, Lang I, et al. Final results of a randomized phase II placebo1 letrozole for 1st line treatment of Asian postmeno-
study of PD 0332991, a cyclin-dependent kinase (CDK-4/6 inhibitor), in pausal women with ER1/HER2- advanced breast cancer [PALOMA-4].
combination with letrozole vs letrozole alone for first-line treatment https://clinicaltrials.gov/ct2/show/NCT02297438. Accessed March
of ER+/HER2- advanced breast cancer (PALOMA-1; TRIO-18). Cancer 26, 2016.
Res. 2014;74 (suppl; abstr CT101). 153. NCT02296801. A phase II randomized study evaluating the biological
138. NCT01320592. PD0332991 and paclitaxel in treating patients with and clinical effects of the combination of palbociclib with letrozole
metastatic breast cancer. http://www.cancer.gov/clinicaltrials/ as neoadjuvant therapy in post-menopausal women with estrogen-
search/view?cdrid=697909&version=HealthProfessional&protocolsearchid= receptor positive primary breast cancer (PALLET). https://clinicaltrials.
12773356. Accessed May 27, 2014. gov/ct2/show/NCT02296801. Accessed March 26, 2016.
139. NCT02040857. Palbociclib and endocrine therapy in treating patients 154. NCT02690480. Comparison of efficacy and tolerability of fulvestrant1
with hormone receptor-positive stage II-III breast cancer. http:// placebo vs fulvestrant1palbociclib as first line therapy for post-
www.cancer.gov/clinicaltrials/search/view?cdrid=757030&version= menopausal women with HR1 metastatic BC treated with 5 years of
HealthProfessional&protocolsearchid=12773356. Accessed May 27, hormonal therapy remaining disease free more than 12 months after
2014. completion or have de novo metastatic disease (FLIPPER). https://
140. Byrd JC, Peterson BL, Gabrilove J, et al; Cancer and Leukemia Group B. clinicaltrials.gov/ct2/show/NCT02690480. Accessed March 26, 2016.
Treatment of relapsed chronic lymphocytic leukemia by 72-hour 155. NCT02491983. Study to evaluate the efficacy and safety of palbociclib
continuous infusion or 1-hour bolus infusion of flavopiridol: results in combination with fulvestrant or letrozole in patients with ER1,
from Cancer and Leukemia Group B study 19805. Clin Cancer Res. HER2- locally advanced or metastatic breast cancer (PARSIFAL). https://
2005;11:4176-4181. clinicaltrials.gov/ct2/show/NCT02491983. Accessed March 26, 2016.
141. NCT01709370. Letrozole and CDK 4/6 inhibitor for ER positive, HER2 156. NCT02384239. A study of palbociclib in combination with fulvestrant
negative breast cancer in postmenopausal women. https://clinicaltrials. or tamoxifen as treatment for metastatic breast cancer. https://
gov/ct2/show/NCT01709370. Accessed March 26, 2016. clinicaltrials.gov/ct2/show/NCT02384239. Accessed March 26, 2016.
142. NCT02102490. A study of abemaciclib (LY2835219) in participants 157. NCT02592746. A study of palbociclib with exemestane plus goserelin
with previously treated breast cancer that has spread (MONARCH 1). versus capecitabine in premenopausal women with HR1 MBC. https://
https://clinicaltrials.gov/ct2/show/NCT02102490. Accessed March clinicaltrials.gov/ct2/show/NCT02592746. Accessed March 26, 2016.
26, 2016. 158. NCT02675231. A study of abemaciclib (LY2835219) in women with
143. NCT01698918. Open-label, phase II, study of everolimus plus letrozole HR1, HER21 locally advanced or metastatic breast cancer (monarcHER).
in postmenopausal women with ER1, HER2- metastatic or locally https://clinicaltrials.gov/ct2/show/NCT02675231. Accessed March
advanced breast cancer (Bolero-4). https://clinicaltrials.gov/ct2/ 26, 2016.
show/NCT01698918. Accessed March 26, 2016. 159. NCT02422615. Study of efficacy and safety of LEE011 in postmenopausal
144. NCT01783444. A phase II study of everolimus in combination with women with advanced breast cancer (MONALEESA-3). https://clinicaltrials.
exemestane versus everolimus alone versus capecitabine in advance gov/ct2/show/NCT02422615. Accessed March 26, 2016.

e54 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


BREAST CANCER

Treatment of Premenopausal
Women With Endocrine-Sensitive
Breast Cancer

CHAIR
Nancy E. Davidson, MD
University of Pittsburgh Cancer Institute
Pittsburgh, PA

SPEAKERS
Hatem A. Azim Jr., MD, PhD
Institut Jules Bordet
Brussels, Belgium

Kathryn J. Ruddy, MD, MPH


Mayo Clinic
Rochester, MN
TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER

Challenges in Treating Premenopausal Women with


Endocrine-Sensitive Breast Cancer
Hatem A. Azim Jr., MD, PhD, Nancy E. Davidson, MD, and Kathryn J. Ruddy, MD, MPH

OVERVIEW

For the hundreds of thousands of premenopausal women who are diagnosed annually with endocrine-sensitive breast
cancer, treatment strategies are complex. For many, chemotherapy may not be necessary, and endocrine therapy decision
making is paramount. Options for adjuvant endocrine regimens include tamoxifen for 5 years, tamoxifen for 10 years,
ovarian function suppression (OFS) plus tamoxifen for 5 years, and OFS plus an aromatase inhibitor for 5 years. There are
modest differences in efficacy between these regimens, with a benefit from OFS most obvious among patients with higher-risk
disease; therefore, choosing which should be used for a given patient requires consideration of expected toxicities and
patient preferences. An aromatase inhibitor cannot be safely prescribed without OFS in this setting. Additional research is
needed to determine whether genomic tests such as Prosigna and Endopredict can help with decision making about
optimal duration of endocrine therapy for premenopausal patients. Endocrine therapy side effects can include hot flashes,
sexual dysfunction, osteoporosis, and infertility, all of which may impair quality of life and can encourage nonadherence
with treatment. Ovarian function suppression worsens menopausal side effects. Hot flashes tend to be worse with
tamoxifen/OFS, whereas sexual dysfunction and osteoporosis tend to be worse with aromatase inhibitors/OFS. Preg-
nancy is safe after endocrine therapy, and some survivors can conceive naturally. Still, embryo or oocyte cryopreservation
should be considered at the time of diagnosis for patients with endocrine-sensitive disease who desire future childbearing,
particularly if they will undergo chemotherapy.

I n the United States, approximately 20% of patients with


breast cancer are diagnosed before age 50.1 This translates
into almost 50,000 new patients per year, which well ex-
have unique challenges, most notably fertility-related issues,
poorer perceived quality of life, and difficulties adhering
to prescribed endocrine therapy. Therefore, treating pre-
ceeds the total number of women diagnosed with acute menopausal women with early breast cancer, particularly
leukemia and brain and stomach cancers in all ages com- those with endocrine-sensitive disease, is rather complex.
bined.1 A higher proportion of patients with breast cancer
are diagnosed at a younger age in other parts of the world,
such as Africa and the Middle East, where the average age of HOW TO CHOOSE ENDOCRINE THERAPY FOR
developing breast cancer hardly exceeds 50.2 PREMENOPAUSAL PATIENTS?
Over the past decade, several studies have indicated In recent years, several trials have evaluated different
that diagnosis at a younger age is associated with poorer strategies of adjuvant endocrine therapy for premenopausal
prognosis,3-5 especially for women with endocrine-sensitive patients. These include tamoxifen for 5 years, tamoxifen for
disease.3,5 Compared with patients with breast cancer who 10 years, OFS plus tamoxifen for 5 years, and OFS plus an
are postmenopausal, younger patients are more commonly aromatase inhibitor for 5 years. As reviewed below, modest
diagnosed with highly proliferative estrogen receptor differences between these options in terms of long-term
positive tumors (i.e., luminal-B breast cancer).6 Further- outcome have been reported. These approaches have different
more, these tumors are enriched for molecular aberrations toxicity profiles. Deciding which approach should be used for
that could render them more aggressive, including high a given patient requires consideration of risk of recurrence,
expression of stem cell markers and high prevalence of fertility considerations, and patient preferences regarding
GATA3 mutations,3,7 the latter of which has been implicated expected toxicities.8 Unfortunately, premenopausal patients
in endocrine resistance. In addition, younger patients often with breast cancer have been found to have poor persistence

From the Department of Medicine, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium; University of Pittsburgh Cancer Institute and UPMC Cancer Center, Pittsburgh,
PA; Department of Oncology, Mayo Clinic, Rochester, MN.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Hatem A. Azim Jr., MD, PhD, Institut Jules Bordet, Boulevard de Waterloo, 121, 1000 Brussels, Belgium; email: hatemazim@icloud.com.

2016 by American Society of Clinical Oncology.

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 23


AZIM, DAVIDSON, AND RUDDY

with endocrine therapy.9,10 Some studies have shown that only study did not accrue as planned, and it closed early with only
50% of women complete the 5 years of scheduled tamoxifen.9 345 patients. Notably, 85% of patients had T1 disease and,
Therefore, it is very important for clinicians to engage young per protocol, none were treated with adjuvant chemo-
patients in therapeutic decision making and to discuss toxicities therapy. This underpowered study showed no difference in
and expectations. Salient points pertaining to the use of the 10-year disease-free survival (DFS; 85.9% vs. 87.1%; p = .62)
different endocrine therapy options are discussed in this article. or overall survival (OS; 92.5% vs. 92.4%; p = .67) between
Figure 1 summarizes a schema to help optimize treatment both arms. The Suppression of Ovarian Function Trial (SOFT)
decisions in daily practice. was a larger, properly powered trial that included 2,033
patients who were randomly assigned to either tamoxifen
with OFS or tamoxifen alone.14 In this trial, the main analysis
Value of Ovarian Function Syndrome indicated no significant difference in 5-year DFS between the
Induction of amenorrhea for premenopausal patients with OFS plus tamoxifen and tamoxifen alone arms (84.7% vs.
endocrine-sensitive breast cancer has consistently been 86.6%; p = .10). Subgroup analyses suggested a benefit with
shown to reduce risk of recurrence.11,12 This is true for OFS the addition of OFS in women who had received chemo-
by luteinizing hormone-releasing hormones (LHRH) agonists therapy (who were more likely to have node-positive dis-
or surgical or radiation ablation. However, because adjuvant ease) and those younger than age 35 at diagnosis. Of those
tamoxifen was not routinely administered to patients who diagnosed with breast cancer younger than age 35 (94% of
were premenopausal until the early 2000s, uncertainty whom received chemotherapy), the proportion who were
remained regarding the benefit of amenorrhea induction in free of breast cancer for at least 5 years was 67.7% with
the presence of tamoxifen. Within the last several years, two tamoxifen alone and 78.9% with tamoxifen with OFS, sug-
studies have provided important insights on this issue. The gesting that OFS cut the risk of recurrence by approximately
first is the E-3193, INT-0142 trial, which randomly assigned one-third in this group.
node-negative, estrogen receptorpositive patients to ta- These results underscore several important points. First,
moxifen or OFS plus tamoxifen, both given for 5 years.13 This endocrine therapy alone, without chemotherapy, is a very
effective option for selected premenopausal women with
early-stage breast cancer. Second, in older premenopausal
women with low-risk early-stage breast cancer, OFS adds
KEY POINTS little if any benefit to 5 years of tamoxifen. Finally, induction
of amenorrhea is therapeutic for younger premenopausal
Several adjuvant endocrine therapy options are
currently available for premenopausal patients with
patients with higher-risk disease.
endocrine-responsive early-stage breast cancer, and it
can be challenging to decide which is best for a given
patient. Tamoxifen Versus Aromatase Inhibitors
Recent evidence from randomized trials indicates that a In the postmenopausal setting, aromatase inhibitors have
substantial proportion of premenopausal women with largely replaced tamoxifen as the standard endocrine adju-
early-stage breast cancer can achieve excellent vant therapy.15 Among premenopausal patients, the final
outcomes with endocrine therapy only, in the absence results of the ABCSG-12 trial did not show a difference in DFS
of chemotherapy, challenging the notion that adjuvant between tamoxifen and anastrozole when administered for
chemotherapy should be considered in all young 3 years in combination with LHRH agonists, but OS was inferior
patients with breast cancer.
in the aromatase inhibitor arm.16 This raised concerns about
Careful attention must be paid to the toxicities of
endocrine therapies including hot flushes, sexual
the use of aromatase inhibitors with OFS among pre-
dysfunction, osteoporosis, and infertility, which could all menopausal patients. Recently, the results of a joint analysis
reduce adherence to endocrine therapy and of the long-awaited SOFT and TEXT trials were published.17 In
detrimentally impact patients quality of life. total, 4,690 women were randomly assigned to receive either
Pregnancy following endocrine-responsive breast tamoxifen or exemestane in addition to OFS for 5 years.
cancer is safe, although challenges exist in the era of Approximately 40% of patients had node-positive disease and
extended adjuvant therapy. A prospective trial currently nearly 50% received adjuvant chemotherapy. The results
is addressing the feasibility of temporary interruption of demonstrated a 28% reduction in DFS hazard ratio (HR) at
endocrine treatment to allow pregnancy. 5 years with exemestane compared to tamoxifen (91.1% vs.
Embryo or oocyte cryopreservation prior to 87.3%, p , .001), with no difference in OS.
chemotherapy is the best option to preserve fertility for
Although in line with the hypothesis and results observed
premenopausal patients with breast cancer, even those
who have endocrine-sensitive disease. Evolving data
in the postmenopausal setting, the results of this pooled
suggest that LHRH agonists could reduce risk of analysis contrasted with those observed in the ABCSG-12
chemotherapy-induced amenorrhea and, thus, may trial. However, it is important to note that the ABCSG-12 trial
serve as a valid alternative to embryo or oocyte was smaller in size and administered therapy for only
cryopreservation if these are not feasible. 3 years, which does not reflect todays standard practice. An
unplanned analysis of ABCSG-12 suggested that the worse

24 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER

FIGURE 1. Schema to Guide Decision Making of Primary Systemic Therapy of Premenopausal Women With
Endocrine ReceptorPositive (HER-Negative) Breast Cancer

Abbreviations: AI, aromatase inhibitor; ER, estrogen receptor; LHRH, luteinizing hormone-releasing hormone; OFS, ovarian function suppression; PR, progesterone receptor; y, years.
*No evidence on extended adjuvant therapy in women treated with adjuvant OFS/AI during first 5 years.
**Clinical utility of genomic tests to guide extended endocrine therapy is yet to be proven.

outcome observed in the aromatase inhibitor arm was re- Thus, although the combination of OFS and exemestane
stricted to patients who were overweight or obese18; these may be the most effective 5-year endocrine therapy regi-
patients constituted nearly one-third of the study population. men, adequate suppression of estradiol levels appears to be
This was hypothesized to reflect incomplete estrogen level more challenging for patients who are overweight or obese,
suppression by aromatase inhibitor for these women, which in whom ABCSG-12 suggests that OFS with tamoxifen may
has been seen among postmenopausal patients who were produce equal if not better outcomes. Yet it is unclear
obese,19 or incomplete ovarian suppression by LHRH agonists whether measurement of estradiol levels during LHRH ag-
in larger patients. Research is limited regarding the impact of onists therapy will be clinically useful in guiding the choice of
body weight on the efficacy of OFS, but it is possible that adjuvant endocrine therapy in daily practice.24
surgical or radiation ablation would be more effective than One final point that should be underscored is the very
LHRH agonists in women who are overweight and obese.20 favorable outcome of the 50% of women in the joint analysis
Alternatively, cross talk between estrogen signaling and in- who did not receive adjuvant chemotherapy. Although these
sulin growth factor signaling may play a role in the impact of patients were mostly low risk by virtue of stage, their 5-year
weight on the efficacy of OFS and AI.21 A randomized pro- DFS was greater than 93%. Because the benefit of adjuvant
spective study from Japan in the neoadjuvant setting showed chemotherapy is largely a reduction in risk of recurrence
superiority of aromatase inhibitor plus OFS over tamoxifen during the first few years after diagnosis, it is likely that
plus OFS with a near doubling of clinical response rate on chemotherapy would not have been beneficial in the ma-
MRI.22 However, in this study, only 17% of patients were jority of these patients. These results strongly challenge the
overweight or obese. Correlation between body mass index notion that young premenopausal women should be offered
(BMI) and outcome in the joint analysis of SOFT and TEXT is yet more chemotherapy, and they indicate that endocrine
to be published, but high BMI was shown to be associated therapy alone remains a very effective option for a large
with high on-treatment estradiol levels in SOFT patients fraction of young patients with endocrine-sensitive breast
randomly assigned to exemestane and OFS.23 Although most cancer.
SOFT patients maintained a low estradiol level on treatment,
34% of patients on OFS and aromatase inhibitor had high
estradiol levels at some point during the 12 months after 10-Year Versus 5-Year Schedule
study initiation. No correlation with long-term outcome was Unlike estrogen receptornegative tumors, endocrine-
seen, perhaps because of the small number of patients in this sensitive cancers have a propensity for late relapse. 25
analysis (86 patients on LHRH agonist plus exemestane). Therefore, extending treatment beyond 5 years seems

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 25


AZIM, DAVIDSON, AND RUDDY

logical to improve the outcomes of these patients. In the report, and thus validation of the role of genomic tests to
ATLAS and aTTom trials,26,27 taking tamoxifen for 10 years inform on the benefit of this approach is warranted. Until then,
was shown to be superior to the standard 5-year schedule, no solid statements could be made regarding their role in
and benefit was observed independent of menopausal guiding the use of extended endocrine therapy.
status. Given the established role of aromatase inhibitors in
treating postmenopausal women during the first 5 years,
these results appear to be most relevant for the treatment
TOXICITIES OF ENDOCRINE THERAPY FOR
of premenopausal women for whom tamoxifen is still
PREMENOPAUSAL WOMEN
Premenopausal women with breast cancer who require
considered a mainstay treatment. Another study, MA17,
endocrine therapy are vulnerable to a variety of treatment
which previously showed the added benefit of extended
toxicities. Although excess tamoxifen-associated uterine
therapy with letrozole after 5 years of tamoxifen, demon-
cancer diagnoses and thromboembolic events have not been
strated that this benefit is mostly observed in women who
observed among patients younger than age 50, some side
were premenopausal at the time they initiated tamoxifen
effects of endocrine therapy are more severe for young
but became postmenopausal during its administration.28
patients, particularly if OFS is used. These side effects are
These results in aggregate underscore the value of con-
discussed below.
sidering extending endocrine therapy to 10 years for pre-
menopausal women. However, the question remains as to
whether all women need this approach. This question is Hot Flashes
relevant as prolonged treatment increases toxicity and could Hot flashes are problematic for the majority of young re-
impair quality of life. Acknowledging the adherence issues cipients of adjuvant endocrine therapy,33 especially with the
highlighted earlier, it is important to define tools that can addition of OFS,34 and perhaps more substantially with
identify the subsets of patients who will benefit the most tamoxifen than aromatase inhibitors. These hot flashes
from this approach and spare others the burden of long-term often are accompanied by night sweats, which can interrupt
treatment. sleep and impair quality of life. In 345 young women enrolled
Recently, several genomic tests, particularly Prosigna and in the E-3193, INT-0142 phase III trial, grade 3 hot flashes
Endopredict, have been evaluated for their ability to predict occurred in 4.7% of those receiving tamoxifen monotherapy
long-term recurrence in women who were treated with compared with 16.1% of those receiving tamoxifen with
5 years of adjuvant endocrine therapy in the context of OFS.13 In SOFT, grade 3 or 4 hot flashes occurred in 7.6% of
randomized phase III trials.29-31 Notably, these trials were patients assigned to receive tamoxifen, compared with
conducted among postmenopausal women and genomic 13.2% of those assigned to OFS and tamoxifen.14 However,
testing was not part of the initial study plan. In the ABCSG-8 the use of an aromatase inhibitor instead of tamoxifen with
trial, which randomly assigned postmenopausal patients to OFS was associated with less sweating (reported by 54.5%
receive either tamoxifen or anastrozole, approximately vs. 59%, respectively).17
1,300 patients were free of relapse at completion of 5 years
of endocrine therapy and were analyzed by Prosigna test-
Sexual Dysfunction
ing.29 None of these patients received adjuvant chemo-
In contrast, sexual dysfunction is most severe for patients
therapy and 30% were node-positive. Thirty-seven percent
who received an aromatase inhibitor with OFS.17 In the TEXT
of patients were classified as low risk by the genomic test, of
trial, 52.4% of 2,318 women who received exemestane with
whom only 2.4% developed distant recurrence. In contrast,
OFS and 47.4% of 2,325 women who received tamoxifen
17.5% of the 30% of patients classified as high risk developed
with OFS had vaginal dryness. Forty-five percent of the
distant recurrence between years 5 and 15. Similar results
exemestane/OFS group and 40.9% of the tamoxifen/OFS
were observed in a combined analysis of the ABCSG-8 and
group had decreased libido, although dyspareunia was re-
ATAC datasets.30 Endopredict showed comparable findings
ported in 30.5% and 25.8%, respectively. Of note, ovarian
when tested on the ABCSG-6 and ABCSG-8 trial. In 1,702
dysfunction secondary to chemotherapy can cause similar
patients free of relapse after 5 years of endocrine therapy,
vaginal symptoms and sexual dysfunction.35 Tamoxifen
Endopredict identified 64% as low risk, with an absolute risk
alone is less problematic,13 and it may even improve vaginal
of recurrence of 1.8% at 10 years.31
dryness in some survivors by causing vaginal discharge.34
Thus, it appears that extending endocrine therapy beyond
Sexual dysfunction in survivors of breast cancer can be
5 years for women in the low-risk group category is very
compounded by body image issues associated with local
unlikely to add any benefit because their risk of recurrence is
therapies and the weight gain that many experience during
negligible. On the other hand, extended therapy could be more
systemic chemotherapy.
useful for patients classified as high risk. Of note, none of these
studies included premenopausal patients, yet data with other
genomic tests such as Oncotype Dx32 and an in silico analysis3 Depression and Cognitive Dysfunction
indicated that the prognostic performance of genomic tests SOFT results showed a nonstatistically significant trend
is largely comparable irrespective of age. Currently, several toward more mood impairment in those who received ta-
studies investigating extended endocrine therapy have yet to moxifen with OFS than in those who received tamoxifen

26 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER

monotherapy, with depressive symptoms identified in received OFS with tamoxifen compared with those who
51.9% and 46.6%, respectively.14 An aromatase inhibitor received tamoxifen monotherapy,14 identified in 23.3%
does not appear to cause more depression than tamoxifen.17 versus 17.2% of patients, respectively. But among TEXT
Treatment of depression can be complex for patients re- and SOFT participants who received OFS, hypertension
ceiving tamoxifen because of concerns that certain anti- was equally likely with tamoxifen versus exemestane.17
depressants (e.g., fluoxetine, paroxetine, and sertraline) Thrombosis or embolism occurred in 2.2% (95% CI, 1.62.8)
may reduce the efficacy of tamoxifen by inhibiting of patients who received OFS plus tamoxifen and 1.0% (95%
CYP2D6.36,37 One study found that survivors of breast cancer CI, 0.71.5) of those who received OFS plus aromatase
who took paroxetine with tamoxifen had increased breast inhibitors.17
cancer mortality, although another study identified no im-
pact of CYP2D6 inhibitor use on recurrence risk for patients
taking tamoxifen. Possibly, the CYP2D6 genotype is partic- PREGNANCY AFTER ESTROGEN
ularly relevant for tamoxifen efficacy for premenopausal RECEPTORPOSITIVE BREAST CANCER: SAFETY
patients,38 but definitive studies of this issue are needed. AND FEASIBILITY IN THE ERA OF EXTENDED
Cognitive dysfunction related to endocrine therapy is ADJUVANT THERAPY
understudied among premenopausal patients. However, in Infertility remains a main concern for young patients with
the ZIPP trial, patient self-evaluation of memory and con- breast cancer. A recent prospective study including more
centration was similar for patients with breast cancer who than 600 patients demonstrated that up to 50% of young
received chemotherapy with or without goserelin, goserelin patients with breast cancer are concerned about infertility,
plus tamoxifen, or tamoxifen alone.34 In addition, pre- and, in a substantial fraction, this has an impact on treat-
liminary results at 1 year from 86 of a planned 321 par- ment decisions.44
ticipants in the cognitive function substudy of SOFT The safety of subsequent pregnancy in women with a
demonstrated no worse objective cognitive function in history of estrogen receptorpositive breast cancer con-
those who received tamoxifen plus OFS compared with tinues to be an area of concern. In a recent survey, ap-
tamoxifen monotherapy.39 proximately 40% of oncologists believed that hormonal
changes secondary to pregnancy could increase risk of re-
currence particularly during the first 2 years after cancer
Bone Health
diagnosis.45 Although this question has been addressed in
Tamoxifen is known to improve bone mineral density for
several studies over the past 3 to 4 decades,46-48 definitive
postmenopausal women, but it can thin bones in pre-
answers were complicated by lack of information on es-
menopausal women.40 This is likely because of its mixed
trogen receptor status in many of these studies and
agonist/antagonist effect on estrogen receptor. Therefore,
methodological concerns about patient selection. In 2013, a
bone loss is a concern in most young patients with breast
large multicenter study was published in which the long-
cancer, not just in those who experience chemotherapy-
term outcome of 333 women who became pregnant after
related premature menopause or receive OFS. A recent
breast cancer diagnosis was compared with 874 survivors of
study of survivors of breast cancer who were premenopausal
breast cancer who did not become pregnant.49 Both groups
at the time of breast cancer diagnoses and had no known
were matched according to relevant tumor characteristics
history of osteoporosis revealed a 12% fracture risk during a
and use of adjuvant systemic therapy. The primary endpoint
median 3.1-year follow-up after the completion of 56 years
was 5-year DFS of the estrogen receptorpositive cohort. In
of endocrine therapy. This was similar to the 15% fracture
this cohort, which comprised 194 pregnant and 492 non-
risk this study identified in survivors of postmenopausal
pregnant patients, no difference in 5-year DFS was observed
breast cancer.41 However, the fractures in survivors of
by pregnancy status (HR 0.91; 95% CI, 0.671.24; p = .55).
premenopausal breast cancer were more commonly toe/
Secondary endpoints, which included DFS in estrogen
finger fractures, although those in postmenopausal women
receptornegative patients and OS, also did not differ be-
were more commonly hip fractures. The median time to
tween the pregnant and nonpregnant groups. These results
first fracture was shorter in premenopausal than in post-
underscore the safety of pregnancy following breast cancer
menopausal women (1.4 vs. 2.4 years; p = .01). Zoledronic
irrespective of the estrogen receptor status of the primary
acid has been proven an effective preventative agent against
tumor. Similar to other studies,47 approximately 30% of
bone loss in this population.42,43 The lifetime fracture risk of
patients underwent abortion in this study. A preplanned
young recipients of endocrine therapy deserves additional
subgroup analysis showed that abortion did not have any
study in the new era of increased use of OFS and prolonged
impact on patient prognosis, indicating that abortion should
duration of treatment.
not be recommended for therapeutic purposes.
However, with the increasing use of long-term endocrine
Cardiovascular Toxicity therapy up to 10 years, the feasibility of becoming pregnant
Although it occurs at low frequency in young patients, after completion of 510 years of endocrine therapy is a
cardiovascular toxicity also must be considered. Hyperten- major challenge. This raises the question of whether tem-
sion developed more frequently in SOFT participants who porary interruption of endocrine therapy to allow pregnancy

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 27


AZIM, DAVIDSON, AND RUDDY

is safe. This approach is sometimes considered in selected Potential Detrimental Impact on Breast Cancer
cases, particularly for patients with low risk of recurrence or Outcome Particularly in Patients With Estrogen
advanced age at the time of diagnosis. Presently, it is not ReceptorPositive Disease
known whether this approach is detrimental because it was This is perhaps the greatest concern when considering assisted
not investigated in any of the reported studies. As such, the reproduction in young patients with breast cancer, as this
first international prospective trial (POSITIVE) was recently procedure is associated with significant rise in serum estradiol
launched to address the safety of temporary interruption of levels. Despite the fact that estradiol peaks only last for a few
endocrine therapy to allow pregnancy in young women days, defining protocols that would reduce estradiol peaks
with estrogen receptorpositive breast cancer who wish to without majorly compromising oocyte yield is desirable. Oktay
become pregnant.50 This trial allows patients to receive et al have performed a series of studies investigating the
1830 months of endocrine therapy. Patients with adequate addition of letrozole to standard ovarian stimulation protocols
ovarian function can temporarily interrupt endocrine therapy to reduce estradiol peaks.60,61 They showed that this strategy
for up to 2 years to allow pregnancy with or without breast- was associated with a comparable oocyte yield and significantly
feeding. Afterward, they are encouraged to resume endocrine lower estradiol peaks. In one study, the mean estradiol level at
therapy for a total course of 510 years according to local human chorionic gonadotropin (known as hCG) triggering was
practice. POSITIVE is sponsored by the International Breast 483.4 pg/mL with letrozole compared with 1,464 pg/mL for
Cancer Study Group and is performed in collaboration with the standard protocol (p , .001), with similar numbers of
ALLIANCE in the United States. This study is expected to recruit mature oocytes (8.7 vs. 9.7; p = .43) and fertilization rates
approximately 500 patients, which would provide solid evi- (74.1% vs. 73.2%; p = .71). In addition, there was no difference
dence for the safety and feasibility of endocrine therapy in- in days needed for stimulation, which was approximately
terruption to allow pregnancy. 12 days.61 Other studies have confirmed these results.62,63 In
terms of fertility and pregnancy outcome, recent results from
ASSISTED REPRODUCTION TO BECOME 131 patients with breast cancer who underwent ovarian
PREGNANT AFTER BREAST CANCER: TIMING stimulation with letrozole before initiating adjuvant chemo-
AND IMPACT ON OUTCOME therapy showed that 40 patients attempted to transfer
Given the progressive decline in ovarian function with age51 embryos back at an average time of 5.2 years following initial
and the detrimental impact of chemotherapy on ovarian embryo cryopreservation. The overall live birth rate was 45%,
function,52 fertility preservation must be considered and which is comparable to figures observed in the general pop-
offered soon after breast cancer diagnosis to improve the ulation of women of the same age. Importantly, no congenital
chances of future conception. Ovarian stimulation for oocyte malformations were observed in 25 children after a mean
or embryo cryopreservation is a standard procedure. It is follow-up of 40 months.64
currently endorsed by several guidelines for patients who To provide more robust evidence regarding the safety of
are newly diagnosed with breast cancer and are also con- this approach, a prospective study was initiated to eval-
sidering future pregnancy.53-55 However, several concerns uate the association between using ovarian stimulation
hinder the wide application of this approach. with letrozole and long-term breast cancer outcome.62 In
this study, 337 young patients with breast cancer (median
Potential Delay of Adjuvant Systemic Therapy age 35) were included, of whom 120 underwent ovarian
Optimally, ovarian stimulation should be performed before stimulation with letrozole. At a median follow-up of
the initiation of adjuvant therapy to precede the de- 5 years, there was no difference in DFS between patients
struction of oocytes by cytotoxic agents. Standard stimu- who underwent stimulation and those who did not.65 No-
lation protocols are classicaly applied during the first days tably, in this study, patients who underwent stimulation
of the menstrual cycle, which can result in a delay in ini- initiated adjuvant chemotherapy later compared with the
tiation of chemotherapy as some woman can have to wait control group (45 days vs. 33 days; p , .01). This is not
up to 3 weeks for stimulation. Such a delay could be po- unexpected because this study did not offer random stimu-
tentially detrimental to patient outcome because the in- lation protocols. A subsequent analysis investigating patient
terval between surgery and initiation of chemotherapy is outcome according to the number of ovarian stimulation
crucial, particularly in treating young patients with breast cycles (one vs. two cycles) showed no difference in patient
cancer.56 Over the past 5 years, several studies were prognosis with better fertility preservation cycle outcome in
published on random stimulation protocols, in which ovarian those undergoing two cycles in terms of number of mature
stimulation is performed at any time during the menstrual oocytes (10.3 vs. 6.2; p = .004), fertilized oocytes (7.4 vs. 4.4;
cycle.57-59 The number of days required for ovarian stimu- p = .04) and embryos (6.4 vs. 3.7; p =.019).66
lation is slightly longer using the random protocol, on av- Although more data on larger series of patients with
erage 1 to 2 days more, yet the oocyte yield is almost breast cancer are still needed to establish the safety and
identical. This approach increases the feasibility of per- effectiveness of using ovarian stimulation with letrozole
forming ovarian stimulation prior to starting systemic in newly diagnosed patients, this approach is currently
therapy without substantial delay. preferred.

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TREATING PREMENOPAUSAL ENDOCRINE-SENSITIVE BREAST CANCER

Feasibility and Safety of Ovarian Stimulation for p = .04), although absolute numbers remain low (33 vs. 19
Patients Already Treated With Chemotherapy pregnancies) in the combined results from five different
The postchemotherapy setting is suboptimal for ovarian trials.72
stimulation because of the detrimental effects of adjuvant Although these data suggest that giving LHRH agonists
systemic therapy on ovarian function.52 Nevertheless, often before and during chemotherapy could improve chances of
we are confronted by situations in which a patient did not future fertility for young patients with breast cancer,
freeze embryos or oocytes before chemotherapy initiation several important considerations should be taken into
and wants to become pregnant but requires assisted re- account. First, these trials evaluated chemotherapy-
production to conceive. In the one study reported in this induced amenorrhea, which is an imperfect surrogate for
setting, 25 women underwent ovarian stimulation some adequate ovarian function. Previous studies have shown
years after primary chemotherapy to conceive. Their that even women who resume menses after chemo-
outcome was compared with more than 170 women therapy have reduced ovarian reserve73 and will most
who had spontaneous pregnancy after breast cancer likely develop early menopause.74 Chemotherapy has
diagnosis.67 Approximately 50% of patients had endocrine- been shown to induce structural changes in the ovary
sensitive disease. At a median follow-up of 4.5 years after including hyalinization of cortical vessels, collagen de-
conception, no difference in breast cancer outcome was position, and cortical fibrosis, even in women who
observed between the two groups. This small study sug- resume menses after chemotherapy.75 Whether the co-
gests that this approach may be considered in selected administration of LHRH agonists avoids any of these phe-
patients who did not have fertility preservation at di- nomena remains unclear. Second, long-term data are scant.
agnosis, completed their adjuvant therapy, and cannot The PROMISE trial did report that the 5-year cumulative
conceive spontaneously. incidence estimate of resumption of menses was 72.6% in
the LHRH agonist group versus 64% in the control group
USE OF CONCOMITANT ADMINISTRATION OF (age-adjusted HR 1.48; 95% CI, 1.121.95; p = .006).76
LHRH AGONISTS WITH CHEMOTHERAPY TO Unfortunately, none of the published studies has ade-
PRESERVE FERTILITY quate evaluation of ovarian function parameters over
Several randomized studies have addressed the role of LHRH time.
agonists as a mean of preserving fertility with conflicting An individual-patient meta-analysis including all ran-
results.68-71 Table 1 summarizes results from the main trials, domized trials of LHRH agonist in this setting currently is
the largest of which, PROMISE and POEMS, showed reduced underway. This will allow subgroup analyses according to
rates of chemotherapy-induced amenorrhea with the con- age and estrogen receptor status. Yet based on current data,
current administration of LHRH agonists.70,71 A recent meta- LHRH agonists can be considered during chemotherapy to
analysis of published data showed higher odds of achieving potentially preserve the fertility of women in whom ovarian
pregnancy as well (odds ratio 1.83; 95% CI, 1.023.28; stimulation was not possible.

TABLE 1. Main Randomized Trials That Investigated the Role of LHRH Agonist to Reduce Chemotherapy-Induced
Amenorrhea

PROMISE71,76 GBG 37 ZORO68 NCT0009084469 POEMS70


Country Italy Germany United States International
Number of Patients 281 61 49 135
Median Age 39 36 39 38
Chemotherapy Any chemotherapy AC-T AC-T or FEC Any chemotherapy
LHRH Agonists/28d Triptorelin Goserelin Triptorelin Goserelin
ER Status Any Negative Any Negative
Median Follow-up 7.3 years NR 1.5 years 4.1 years
Primary Endpoint (POF defined as) Amenorrhea + postmenopausal Amenorrhea at 6 Amenorrhea at Amenorrhea + postmenopausal
FSH and E2 at 12 months months 12 months FSH at 24 months
Absence of POF (%) LHRH: 91% LHRH: 56% LHRH: 88% LHRH: 92%
No LHRH: 74% No LHRH: 70% No LHRH: 90% No LHRH: 78%
Positive Negative Negative Positive
Pregnancies Achieved (number) LHRH: 8 LHRH: 1 LHRH: 0 LHRH: 22
No LHRH: 3 No LHRH: 1 No LHRH: 2 No LHRH: 12
Abbreviations: AC, doxorubicin, cyclophosphamide; E2, estradiol; ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; FSH, follicle-stimulating hormone; LHRH,
luteinizing hormone-releasing hormone; POF, premature ovarian failure; T, taxane.

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AZIM, DAVIDSON, AND RUDDY

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to preserve ovarian function and fertility of breast cancer patients: 75. Meirow D, Dor J, Kaufman B, et al. Cortical fibrosis and blood-vessels
a meta-analysis of randomized studies. Ann Oncol. 2015;26:2408-2419. damage in human ovaries exposed to chemotherapy. Potential
73. Partridge AH, Ruddy KJ, Gelber S, et al. Ovarian reserve in women who mechanisms of ovarian injury. Hum Reprod. 2007;22:1626-1633.
remain premenopausal after chemotherapy for early stage breast 76. Lambertini M, Boni L, Michelotti A, et al; GIM Study Group. Ovarian
cancer. Fertil Steril. 2010;94:638-644. suppression with triptorelin during adjuvant breast cancer chemo-
74. Partridge A, Gelber S, Gelber RD, et al. Age of menopause among therapy and long-term ovarian function, pregnancies, and disease-free
women who remain premenopausal following treatment for early survival: a randomized clinical trial. JAMA. 2015;314:2632-2640.

32 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


BREAST CANCER

Triple-Negative Breast Cancer: Is


Change on the Horizon?

CHAIR
Carey K. Anders, MD
The University of North Carolina at Chapel Hill
Chapel Hill, NC

SPEAKERS
Rebecca Dent, MD
National Cancer Center Singapore
Singapore

Vandana Abramson, MD
Vanderbilt University Medical Center
Nashville, TN
ANDERS ET AL

The Evolution of Triple-Negative Breast Cancer: From Biology


to Novel Therapeutics
Carey K. Anders, MD, Vandana Abramson, MD, Tira Tan, MBBS, and Rebecca Dent, MD

OVERVIEW

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor
(ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes
compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of
TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as immune-activated,
consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic
of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian
cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic
approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are
routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies
in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic
complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has
shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in
the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to
optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

T riple-negative breast cancer is a unique subset of breast


cancer that accounts for approximately 15%20% of all
breast cancer diagnoses.1 Clinically defined as lacking ex-
commonly targeted biomarkers in the treatment of breast
cancer: ER, PR, and HER2. The definition of TNBC has varied
throughout the decades, namely around the definition of
pression of ER/PR and HER2, TNBC is characterized by an ER and/or PR positivity (i.e., 1%10% vs. $ 1% by immu-
aggressive natural history and worse disease-specific out- nohistochemistry [IHC]). More recently, ER/PR positivity
comes compared with other breast cancer subtypes.2 Despite has been more strictly defined as greater than or equal to 1% by
initial responses to chemotherapy, early and higher rates of the American Society of Clinical Oncology guidelines.7 Endo-
distant, typically visceral, recurrences are observed for TNBC.3 crine therapy is generally recommended for breast cancers
Anthracycline and taxane-based chemotherapy traditionally exhibiting greater than or equal to 1% ER and/or PR positivity
has been the mainstay of therapy for TNBC, but with the across all stages of breast cancer. HER2-postivity also has been
advent of NGS, molecular dissection of TNBC is revealing novel
strictly defined as protein expression of 3+, and/or HER2/neu
targets currently under investigation.4-6 Herein, we will review
gene amplification greater than or equal to 2.0 by fluorescence
the natural history of TNBC, our current understanding of the
in situ hybridization (FISH).8 Thus, the pathologic definition of
molecular characteristics of this unique subset of breast
TNBC is currently defined as ER and/or PR IHC expression of
cancer, and emerging clinical strategies in the modern era,
with a highlight on immunotherapy and DNA damaging agents. 0 and HER2 negativity defined as either IHC expression of 01+
or lack of gene amplification (FISH , 2.0). This universal
definition is being incorporated into the design of TNBC clinical
DEFINITION OF TRIPLE-NEGATIVE BREAST trials. Such an approach will help interpret results of individual
CANCER clinical trials in the context of others because the biology of
The term triple-negative breast cancer is a pathologic breast cancers expressing hormone receptors at 1%10% is
definition based on the protein expression of the three most likely distinct from those without any expression.

From the Department of Medicine, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Nashville, TN; Department of Medicine, National Cancer Center Singapore, Singapore;
Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC; UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Carey K. Anders, MD, Division of Hematology Oncology, University of North Carolina at Chapel Hill, 710 Oxfordshire Ln., Chapel Hill, NC 27517; email:
carey_anders@medunc.edu.

2016 by American Society of Clinical Oncology.

34 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


TRIPLE-NEGATIVE BREAST CANCER: EVOLUTION OF BIOLOGY AND NOVEL THERAPEUTICS

NATURAL HISTORY AND CLINICAL BEHAVIOR OF to a pCR with novel chemotherapy combinations (platinums)
TRIPLE-NEGATIVE BREAST CANCER and novel targeted therapies (inhibitors of PARP inhibitors)
In addition to its distinct pathologic definition, TNBC is have shown superior pCR rates on a trial-level basis.13-15 It is
characterized by a unique clinical history as compared with unclear, however, if incremental increases in pCR rates ul-
other subsets of breast cancer. Smid and colleagues reported timately will translate into improvement in recurrence-free
among 344 primary lymph nodenegative breast cancers survival.16
that the site of distant recurrence differed by breast cancer Triple-negative breast cancer is characterized by recurrence
subtype.9 In this analysis, visceral relapses, including lung patterns and natural history that are distinct from other
(p = .01) and brain metastases (p = .0035), more commonly were subtypes of breast cancer. Dent et al compared the natural
observed among patients with basal-like tumors. In contrast, history and clinical behavior of TNBC to non-TNBC subtypes
bone relapse was more commonly seen among the luminal among 1,601 patients diagnosed with early-stage breast
subtype (p = .0031), and those with HER2-enriched breast cancer in Toronto between 1987 and 1997.2 At a median
cancer more commonly recurred in the liver (p = .17; Fig. 1). follow-up of 8 years, this analysis illustrated that women with
Moreover, Harrell et al evaluated tumor gene expression TNBC were more likely to experience a distant recurrence
using a dataset of approximately 1,000 human breast tumors (hazard ratio [HR] 2.6; p , .0001); survival for patients with
and confirmed that HER2-enriched tumors more commonly TNBC was inferior compared with others (HR 3.2; p , .001)
spread to the liver, whereas basal-like and claudin-low breast within 5 years of diagnosis. Interestingly, and compared with
tumors, both commonly triple-negative, spread to the brain patients with non-TNBC breast cancer, the risk of recurrence
and lung.10 Among patients with advanced TNBC, brain re- peaked at the 3-year mark and declined thereafter. This
lapse has been observed in approximately 50% of patients.11 observation is in contrast to non-TNBC, in which the risk of
Response to chemotherapy also differs by breast cancer recurrence is lower during the initial 3-year follow-up period,
subtype, with the high-grade TNBC subset typically more but it remains constant over time. These important dis-
responsive to preoperative chemotherapy (i.e., higher rates tinctions between the clinical behaviors of TNBC versus
of pCR) but with higher overall rates of relapse.3,12 This non-TNBC must be considered when designing clinical
phenomenon has been coined the triple-negative para- interventions to prevent recurrence for this subset of
dox.3 The higher rate of distant recurrence for patients with aggressive breast cancer.
TNBC following neoadjuvant chemotherapy is likely attrib-
uted to residual disease (i.e., inability to achieve pCR).
Multiple studies have shown superior survival for patients TRIPLE-NEGATIVE BREAST CANCER SUBTYPES
who experience pCR compared with those who do not Breast cancer is a heterogeneous disease characterized by
experience pCR in this setting. Efforts to convert patients distinct intrinsic subtypes, traditionally defined as luminal A
with residual disease following neoadjuvant chemotherapy and B, normal-like, HER2-enriched, and basal-like, each with
corresponding unique clinical behavior.1,17,18 Over the past
decade, TNBC also has been recognized as a similarly het-
erogeneous disease. Several groups have sought to dissect
KEY POINTS the biology of TNBC using IHC, gene expression, and se-
quencing tools. Perhaps the most well-known classification
Triple-negative breast cancer (TNBC) is a pathologic of TNBC by gene expression, when compared with all breast
classification defined as lack of estrogen and cancers, is the basal-like subtype. The basal-like subtype,
progesterone receptors (0% by IHC) expression and
which represents 15%20% of all breast cancers, originally
HER2 negativity (01+ by IHC or lack of HER2/neu gene
amplification).
was classified by a basal epithelial cell gene expression
Although TNBC comprises only 15% to 20% of all breast cluster including keratin 5, keratin 17, integrin-b4, and
cancer diagnoses, it is over-represented among laminin.1 Basal-like breast cancer is approximately 80%
advanced disease as recurrences are early and typically concordant with the IHC classification of TNBC.19 A more
visceral (e.g., lung and brain). rare subtype of breast cancer, termed the claudin-low
Next-generation sequencing has provided a powerful subtype, is also commonly triple-negative.20 The claudin-
platform to dissect the biology of TNBC to provide novel low subtype is characterized by low to absent expression of
therapeutic targets under clinical investigation. luminal differentiation markers, high enrichment for
Checkpoint inhibitors, including PD-1 and PD-L1, are epithelial-to-mesenchymal transition (EMT) markers, im-
showing responses in TNBC in initial clinical trials, and mune response genes, and cancer stem celllike features.
several studies are underway to confirm activity and
This breast cancer subtype, with high frequency of meta-
understand biomarkers of response.
Platinum-based chemotherapy, with a DNA-damaging
plastic and medullary differentiation, illustrates a response
mechanism of action, is active in TNBC and is routinely to therapy that is intermediate between the basal-like and
incorporated into the neoadjuvant and metastatic luminal breast cancer subtypes.
settings. Investigation of platinums in the adjuvant A different, yet complementary, approach has been taken
setting is ongoing. by other investigators in which only TNBCs have been
subtyped using gene expression and sequencing tools to

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 35


ANDERS ET AL

FIGURE 1. Subtype-Specific Patterns of Distant Recurrence From 344 Primary Breast Cancers

Copyright pending as of February 1, 2016.

reveal distinct biologic subtypes with unique therapeutic MOLECULAR DISSECTION OF TRIPLE-NEGATIVE
implications.5,6 Lehmann and colleagues analyzed gene BREAST CANCER
expression from over 500 TNBC tumors and identified six As with other breast cancer subtypes, the biology of triple-
unique subtypes: basal-like (two subtypes, BL1 and BL2), negative, specifically basal-like, breast cancer was a focus of
immunomodulatory (IM), mesenchymal (M), mesenchymal The Cancer Genome Atlas (TCGA) project.4 In this large-scale
stemlike (MSL), and luminal androgen receptor (LAR).5 Cell- analysis of primary human breast cancers, genomic DNA
line models representative of each subtype were identified copy number arrays, DNA methylation, exome sequencing,
and therapeutically targeted. Results indicated that cell lines messenger RNA arrays, microRNA sequencing, and reverse-
of the BL1 and BL2 subtypes, with higher expression of cell phase protein arrays were evaluated. Among the 81 basal-
cycle and DNA damage response genes, were sensitive to like breast cancers, of which 65 were both triple-negative
cisplatin. Mesenchymal and MSL subtype cell lines, which
and basal-like, several hallmark findings were reported: (1) a
were enriched for EMT and growth factor pathways, illus-
high frequency of TP53 mutations (80%); (2) loss of RB1 and
trated sensitivity to dual PI3K/mTOR inhibition and Src in-
BRCA1; (3) high activation of the PI3K pathway (either
hibition. Finally, LAR subtype cell lines were sensitive to an
through PIK3CA gene mutation of approximately 9% or loss of
androgen receptor (AR) antagonist, a strategy that has shown
early success in the clinical arena.21 In parallel, Burnstein et al the negative regulators INPP4B and/or PTEN); (4) an enhanced
performed DNA and RNA sequencing on approximately 200 proliferation signature with hyperactivated FOXM1 as a tran-
TNBC tumors with confirmation in independent datasets and scriptional driver of this signature; and (5) genetic similarity
identified four subtypes: LAR, mesenchymal (MES), basal-like between basal-like breast cancer and serous ovarian cancers.
immunosuppressed (BLIS), and basal-like immune-activated These similarities included high frequencies of ATM and TP53
(BLIA).6 The BLIS subtype conferred the worst prognosis and mutations, high expression of AKT3 and MYC, inactivation of
BLIA the best prognosis, for both disease-free and disease- BRCA1 and BRCA2, RB1 loss, and cyclin E1 amplification. From a
specific survival. In this analysis, subtype-specific targets were therapeutic targeting perspective, approximately 20% of basal-
identified (such as AR in the LAR and STAT signal transduction like tumors harbored a germline or somatic BRCA mutation,
molecules and cytokines in the BLIA) that are worthy of which may confer sensitivity to platinum and/or PARP in-
continued exploration. hibitors that will be discussed below. Finally, copy number

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TRIPLE-NEGATIVE BREAST CANCER: EVOLUTION OF BIOLOGY AND NOVEL THERAPEUTICS

analysis revealed several amplifications or deletions that may prone. BRCA1 and BRCA2 are well-described tumor sup-
be targetable in the clinical arena. Amplifications included pressor genes that participate directly in homologous
PIK3CA (49%), KRAS (32%), BRAF (30%), and EGFR (23%). Other recombinationmediated repair of double-stranded breaks.27
less common amplifications were seen in FGFR1, FGFR2, IGFR1, In humans, mutation in one copy of either of these genes in the
KIT, MET, and PDGFRA. As cited above, deletions were seen in germline results in hereditary breast and ovarian cancer syn-
PTEN and INPP4B, which confer activation of the PI3K pathway. drome; tumors that subsequently develop are defective in
Results of this valuable analysis are summarized in Sidebar 1 homologous recombinationmediated DNA repair.27 Recent
and provide a wealth of knowledge pertaining to our un- reports have expanded the range of genes implicated in familial
derstanding of the biology of TNBC and ways to target this breast cancers, many of which are involved in the homologous
disease more effectively. recombination pathway.23,28-30 In addition, defective homol-
ogous recombination also can be found in sporadic breast
cancers as shown by comparative genome hybridization
TRIPLE-NEGATIVE BREAST CANCER: IS CHANGE studies.31 Finally, impairment of homologous recombination
ON THE HORIZON? deficiency can occur through epigenetic mechanisms, such as
In addition to our evolving understanding of the biology of methylation of BRCA1/2, which is also part of the BRCAness
TNBC over the decades, therapeutic strategies to treat TNBC spectrum.22
across different stages are maturing. Although many mo-
lecularly targeted strategies under investigation exist, for
the purposes of this review, we will focus on the use of Incorporation of Platinums in the Neoadjuvant
platinums and the incorporation of immunotherapy into the Treatment of Triple-Negative Breast Cancer
treatment of TNBC. Over the past few decades, there has been considerable
interest in the use of platinum salts in the treatment of TNBC
Optimal Use of Platinum in Triple-Negative on the basis that dysfunction of homologous recombination
Breast Cancer DNA repair sensitizes tumor cells to these agents and in-
A subset of TNBC has been postulated to be phenotypically duces cell death. As a proof of concept, a small neoadjuvant
and molecularly similar to familial BRCA1-associated breast study reported a strikingly high pCR of 90% to four cycles of
cancers, so called BRCAness.22 It is estimated that more neoadjuvant cisplatin in a group of 10 patients from Poland
than 75% of tumors arising in BRCA1 mutation carriers are with BRCA1 mutation, the majority of whom were the TNBC
triple-negative and/or have a basal-like phenotype.23 These phenotype.32 Larger phase II studies involving patients with
tumors are characterized by their heightened sensitivity to predominantly sporadic TNBC have described conflicting
damage by DNA cross-linking.24-26 Double-stranded DNA results. Alba and colleagues reported a randomized phase II
breaks caused by agents such as platinum salts are con- study of standard neoadjuvant epirubicin plus cyclophos-
sidered the most incisive form of DNA damage, and they are phamide chemotherapy followed by docetaxel with or
repaired by homologous recombination, an error-free without carboplatin AUC 6 given every 21 days.33 The
process, and nonhomologous end-joining, which is error prespecified primary endpoint of improvement in pCR rates
(defined as pCR in breast) was not met, with pCR rates in
breast and axilla of 30% of patients in both treatment
arms.33 In contrast, the German Breast Cancer Group ad-
SIDEBAR 1. The Cancer Genome Atlas Molecular ministered neoadjuvant paclitaxel, liposomal doxorubicin,
Characteristics of Basal-like Breast Cancer and bevacizumab with or without weekly carboplatin AUC 1.5-2
Characteristics in the GeparSixto trial. Of the 315 patients with TNBC, 53.2%
High concordance with TNBC (approximately 80%) of those treated with the addition of weekly carboplatin, as
High rates of TP53 pathway alterations (TP53 mutations in compared with 36.9% treated without the addition of carbo-
84%; gain of MDM2 14%) platin, achieved a pCR (p = .005).14 Similarly, CALGB 40603, a
High rates of PI3K pathway alterations (PIK3CA mutation
two-by-two factorial randomized phase II trial evaluating
7%; PTEN mutation or loss 35%; INPP4B loss 30%) weekly paclitaxel with or without carboplatin (AUC 6) and/or
High rates of RB pathway alterations (RB1 mutation or loss
bevacizumab followed by dose dense doxorubicin plus cyclo-
20%; cyclin E1 amplification 9%; high expression of
phosphamide showed an increase in pCR rate (defined as
CDKN2A; low expression of RB1)
High genomic instability
ypT0/is) from 46% to 60% (odds ratio 1.76; p = .0018).15
Hypomethylation compared with other breast cancer
Furthermore, an important clinical question revolves
subtypes around these data: does the purported improvement in pCR
Similarities with serous ovarian carcinomas, including rates translate to improved survival outcomes? Early survival
approximately 20% rate of germline or somatic BRCA analysis of GeparSixto and CALGB 40603 simultaneously
mutations were reported at the San Antonio Breast Cancer Symposium
in December 2015. In the GeparSixto study, the improved
Abbreviation: TNBC, triple-negative breast cancer. pCR rate translated into a significant increase in 3-year
disease-free survival (DFS) from 76.1% to 85.8% (HR 0.56;

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 37


ANDERS ET AL

95% CI, 0.330.96; p = .035).34 This contrasts with the CALGB outcome. The addition of carboplatin enhances acute tox-
40603 study, which reported a numerical improvement, but icities associated with chemotherapy with higher discon-
no statistical difference in 3-year event-free survival nor tinuation rates, more dose reductions, and higher grade 3/4
overall survival (OS), with the caveat that this trial was adverse events, which could potentially compromise the
underpowered to determine a survival benefit.13 Of note, current standard of care in an already high-risk population
GeparSixto used a nonstandard, more intensive regimen of of patients. It may be reasonable to consider off-trial use of
concurrent anthracycline-taxane chemotherapy with the carboplatin in locally advanced TNBC for rapid control of
incorporation of bevacizumab in all arms. Pharmacologic locoregional disease and in young, fit patients with a high
synergy, as well as potentially the weekly schedule of risk of relapse as we await definitive results from ongoing
carboplatin, may have contributed to the better overall phase III trials powered for survival outcomesPEARLY
prognosis in the GeparSixto trial. (NCT02441933), Gerpar-Octo (NCT021253144), NRG-
BR003 (NCT02488967), and TPPC (NCT02455141).
Incorporation of Platinums in the Metastatic
Treatment of Triple-Negative Breast Cancer
In the metastatic setting, retrospective studies have been
BIOMARKER DISCOVERY IN TRIPLE-NEGATIVE
conflicting and largely focused on comparing TNBC with
BREAST CANCER
Triple-negative breast cancer is a heterogeneous disease.
other subtypes.35-38 In the largest randomized phase III trial,
Given the trade-off of greater toxicities in the early setting
the Triple Negative Breast Cancer Trial (TNT), 376 patients in
and mixed results in the metastatic setting, it would be ideal
U.K. centers were randomly assigned to receive either
to be better able to identify patients most likely to benefit
carboplatin or docetaxel monotherapy as first-line treat-
from this treatment strategy. TBCRC009, a phase II bio-
ment with cross-over on progression.39 In the unselected
marker discovery trial, has reported an improved response
TNBC population, there was no difference in the primary
rate in patients who harbored deleterious germline BRCA
outcome of objective response rates in both treatment arms
mutation(s) without durability of response nor improve-
when treated up front (31.4% vs. 35.6%; p = .44) or following
ment in PFS or OS.42 The TNT trial lends support to BRCA
cross-over (22.8% vs. 25.6%; p = .73).39 Similarly, the sec-
genotyping and gene expression profiling to improved
ondary endpoint of progression-free survival (PFS) did not
therapy selection in metastatic TNBC.39 Patients with BRCA1
significantly differ in both arms.39 To add to the burgeoning
or BRCA2 mutations treated with carboplatin fared better
evidence in favor of a role for platinum-based chemother-
with a greater response rate (68% vs. 33.3%; p = .03) and PFS
apy, two studies from China have been reported: (1) a
(6.8 vs. 3.1 months; p = .03) as compared with docetaxel,
randomized phase II trial comparing docetaxel and cisplatin
whereas nonbasal-like tumors did better with docetaxel
versus docetaxel and capecitabine and (2) a multicenter
(73.7% vs. 16.7%; p # .01).39 Lastly, DNA-based assays have
randomized phase III trial of gemcitabine and cisplatin versus
been developed based on whole genome tumor loss of
gemcitabine and paclitaxel.40,41 In the phase II study, 53
heterozygosity score (LOH),43 telomeric allelic imbalance
patients with metastatic TNBC were randomly selected to
score (TAI),44 and large-scale state transitions score (LST).45
receive docetaxel with cisplatin or capecitabine in the first-
These assays measure patterns of genomic instability derived
line setting. Both overall response rates (63.0% vs. 15.4%;
through comparison of BRCA1/2 mutated and nonmutated
p = .001) and PFS (10.9 vs. 4.8 months; p # .001) were
tumors. The unweighted sum of LOH, TAI, and LST together
significantly better in the cisplatin group.40 CBCSG006 was a
form the homologous recombination deficiency score. This
phase III study in which 240 patients were randomly assigned
has been evaluated in the translational component of the
to receive a maximum of eight cycles of gemcitabine and
TBCRC009 and TNT trials. Again, results are conflicting. In
either cisplatin or paclitaxel dosed every 21 days.41 The trial
TBCRC009, tumors from patients with platinum-responsive
used a hybrid design and was powered for noninferiority by
disease exhibited higher values for LST and LOH assays.42 This
allowing for a prespecified superiority hypothesis to be
was not so in TNT, in which the homologous recombination
tested. Gemcitabine plus cisplatin was both noninferior to and
deficiency score did not select for sensitivity to carboplatin
superior to gemcitabine plus paclitaxel (PFS: HR 0.692; 95% CI,
over docetaxel.39 Therefore, further development of an assay
0.5230.915; p , .0001 [noninferiority] and p , .009
to identify homologous recombination defect in non-BRCA1/2
[superiority]).41 Therefore, in both studies, the cisplatin-
tumors is needed. Finally, the group from Memorial Sloan
containing regimen outperformed the comparator.
Kettering Cancer Center reported a comparison of homologous
recombination deficiency scoring methodologies and con-
Challenges in Incorporating Platinums Into Standard cluded that homologous recombination DNA repair gene
Practice: Toxicities and Dosing Strategies sequencing demonstrated good sensitivity and specificity,
Given this encouraging clinical data on the role of platinum providing a potential biomarker for clinical trials of homologous
agents in TNBC, important clinical questions still remain on recombination deficiencytargeted therapies.46
how best to choose the dose and/or schedule of the plat- In summary, for the practicing oncologist, what would be
inum agent. No trials to date have been powered adequately the current standard of care with respect to the use of
to demonstrate an improvement in long-term survival platinum salts? In the neoadjuvant setting, platinum is a

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TRIPLE-NEGATIVE BREAST CANCER: EVOLUTION OF BIOLOGY AND NOVEL THERAPEUTICS

reasonable choice for selected patients, especially if those substantial infiltration with TILs.55-58 Higher levels of TILs
who are BRCA positive. There are no data to support platinum generally are associated with poor-prognostic clinicopath-
salts in the adjuvant setting; clinical trials are ongoing. In the ologic features, including ER negativity, higher grade, higher
metastatic setting, where the goal of therapy is palliative, proliferative rate, and lymph node positivity.55,59-62 How-
platinum is one of the standard chemotherapies oncologists ever, despite worse clinical features, higher levels of TILs are
include in their armamentarium of chemotherapies, although associated with improved DFS and OS, independent of
with the caveat that the most convincing data are in the front- systemic therapy.59,63,64 This apparent paradox highlights
line setting for BRCA-germline mutation carriers. the role that the immune system may play in a subset of
TNBCs and suggests that TILs may be a surrogate for an
adaptive immune response in these cancers.
IMMUNOTHERAPY AND IMMUNOCONJUGATES
FOR TRIPLE-NEGATIVE BREAST CANCER:
PROMISE AND POTENTIAL ASSOCIATION OF TUMOR INFILITRATIVE
Modern immunotherapy, in the form of monoclonal anti- LYMPHOCYTES AND RESPONSE OF TRIPLE-
bodies that act as checkpoint inhibitors, has revolutionized NEGATIVE BREAST CANCER TO CHEMOTHERAPY
the landscape of the treatment of metastatic melanoma in a Generally, TILs are divided into intratumoral TILs that have
relatively short period of time. Antibodies to cytotoxic direct contact with tumor cells, and stromal TILs, which are
T-lymphocyte antigen 4 (CTLA-4), PD-1, and PD-L1, all of which found between tumor cells within the tumor stroma, but
increase the immune response against the tumor by blocking they do not have direct contact with tumor cells. A study of
immune regulating proteins that downregulate the immune patients with breast cancer receiving neoadjuvant chemo-
system, have increased response rates and OS.47-49 Perhaps therapy with an anthracycline/taxane combination showed
more interestingly, other solid tumor malignancies, such as lung an independent association between percentage of intra-
cancer, which traditionally are not considered immunogenic, tumoral TILs and pCR.64 Those with lymphocyte-predominant
have shown clinical benefit to checkpoint inhibitors.50 The role breast cancer, defined as more than 60% of stromal or
of immunotherapy in breast cancer has yet to be defined, but tumoral infiltration, had a particularly high rate of pCR (41.7%)
increasing evidence points to TNBCs as possibly having unique compared with only a 2% pCR rate in those tumors without any
characteristics that may make them more responsive to tumoral lymphocyte infiltration. In the GeparSixto study that
checkpoint inhibition. Given the lack of targeted treatment evaluated the addition of carboplatin to chemotherapy in TNBC
options for TNBC, immunotherapy poses an exciting opportu- or HER2-positive cancers, the presence of stromal TILs was
nity for the treatment of this aggressive disease. predictive of response to the addition of carboplatin, although
this correlation reached statistical significance only in HER2-
positive tumors.65 Regardless, this association between re-
OVERVIEW OF TUMOR IMMUNE SURVEILLANCE sponse to chemotherapy based on the presence of TILs suggests
IN THE SETTING OF BREAST CANCER that TILs not only are predictive markers of response in TNBC,
In a process called tumor immune surveillance, tumor immune
but that cell death induced by platinum agents may prime or
cells, including CD8+ T cells, recognize tumor-associated an-
generate neoantigens to stimulate nearby lymphocytes.
tigens presented by tumor cells and attack the tumor cells. The
PD-1 receptor pathway plays an important role in modulating
immune responses and provides an escape mechanism to PROGNOSTIC IMPLICATIONS OF IMMUNE GENE
tumor immune surveillance. PD-1 is an inhibitory immune SIGNATURES IN TRIPLE-NEGATIVE BREAST
checkpoint receptor expressed on activated T cells, B cells, CANCER
natural killer cells, and other lymphocytes that can remain Several other studies promote the exploration of the PD-1
active in inflammatory states such as cancer.51,52 PD-L1 is a pathway and immunotherapy in TNBC. Data from TCGA4
ligand of PD-1 and acts to suppress antitumor immunity by have confirmed higher PD-L1 mRNA expression in TNBC
binding PD-1. Ligation of PD-L1 with PD-1 inhibits T-cell pro- versus non-TNBC samples.66 This and other studies have
liferation, cytokine production, and cytolytic activity, which shown that PD-L1 is not detected in normal breast tissue but
leads to the functional inactivation or exhaustion of T cells.53 is expressed in about half of all breast cancers, including
Through upregulation of PD-L1 and other adaptive immune approximately 20% to 30% of TNBCs.67,68 PD-L1 expression
resistance mechanisms, tumors are able to use this pathway to is associated with TILs,69 correlates with higher histologic
evade the antitumor immune response. grade, greater tumor size, and higher expression of the
The balance of cells in the tumor microenvironment, which proliferation marker Ki-67.70
includes tumor cells, stromal cells (i.e., fibroblasts and mi- Further supporting the link between immunotherapy and
crovasculature), and immune cells (i.e., lymphocytes), ap- TNBC are gene expression profiling studies that demonstrate
pears to influence breast cancer outcome.54 An association an association between expression of IM genes and better
between greater tumor infiltrative lymphocytes (TILs) and clinical outcomes in TNBC.71 Desmedt et al were among the
better prognosis in breast cancer has been recognized for first to create gene modules and correlate them with out-
some time, but newer studies have shown the specific come in different subtypes of breast cancer. Of the seven
relevance in TNBC, which has been shown to have gene expression modules they described (tumor invasion,

asco.org/edbook | 2016 ASCO EDUCATIONAL BOOK 39


ANDERS ET AL

immune response, angiogenesis, apoptosis, proliferation, FUTURE DIRECTIONS FOR IMMUNOTHERAPY IN


and ER and HER2 signaling), only the immune response TRIPLE-NEGATIVE BREAST CANCER
module correlated with prognosis in the ER-/HER2- sub- A decade ago, very little was known about the make-up of
group. Since that time, several groups have described the TNBC, and the only promising treatments on the horizon
prognostic value of immune gene signatures and TNBC.72-74 involved cytotoxic chemotherapy. Now, with a better
More recently, analysis of gene expression profiles of 587 understanding of the heterogeneity of TNBC and the
TNBC samples identified six distinct subtypes, including an understanding that immune targets are relevant in this
IM subtype characterized by high expression of immune- disease, we are in a new era in which we are exploring
related genes.5 This subtype is composed of immune- checkpoint inhibitors, vaccines, and immune antagonists.
activated and associated signaling components contributed Two large phase III randomized studies of atezolizumab
from both the tumor and the infiltrating lymphocytes, and and pembrolizumab are now ongoing in metastatic TNBC;
it has been associated with improved relapse-free survival the first is nab-paclitaxel with or without atezolizumab
compared with other subtypes.5 RNA sequencing showed and the other is pembrolizumab versus single agent
this subtype to have substantially higher expression of PD-L1, chemotherapy. Studies with both agents are also planned
PD-1, and CTLA-4. These and other data provide evidence that in the neoadjuvant setting. Finally, two studies evaluating
there may be a subset of TNBC in which checkpoint inhibitors carboplatin with atezolizumab are to begin accrual
may have particular efficacy. through the TBCRC in upcoming months to capitalize on
data with platinums in TNBC. Tissue samples from these
CLINICAL EXPERIENCE AND OUTCOMES WITH studies will further clarify the relationship of response and
IMMUNOTHERAPY IN TRIPLE-NEGATIVE BREAST resistance to PD-1 and PD-L1 expression, and to the
CANCER presence of TILs. The reported studies to date that show
The first reported study of an immune checkpoint inhibitor in responses in heavily pretreated patients with TNBC are
TNBC was a single-arm phase IB study of single-agent notable, but more impressive is the duration of response
pembrolizumab, a PD-1 antibody (KEYNOTE-012).75 This study seen in a disease that usually has a PFS of 2 to 3 months
showed that pembrolizumab 10 mg/kg given every 2 weeks was after the first or second line of treatment of metastatic
not only well-tolerated; it also showed activity in heavily pre- disease. Immunotherapy rapidly has become a great
treated patients with metastatic PD-L1positive TNBC. In- contender in the treatment of TNBC. Our next challenges
terestingly, of all patients with TNBC who were screened, 58% will be to identify how to use it best, whether it is with
tested positive for PD-L1 in greater than 1% of tumor stroma or chemotherapy or in combination with other immune
tumor cells. Over 45% of patients had received more than three modulators, and to identify biomarkers of response.
prior treatments in the metastatic setting, and 21.9% had
received five or more treatments. Of the 27 participants
with centrally confirmed measurable disease (32 patients CONCLUSION
total enrolled), one participant (3.7%) had a complete Triple-negative breast cancer is an established subset of
response (CR), four participants (14.8%) had a confirmed breast cancer with characteristic clinical behavior and
partial response (PR), 25.9% had stable disease, and 44.4% natural history. Until recently, the mainstay of therapy
had progressive disease by central review. The median against TNBC has been cytotoxic chemotherapy. The
time to response was 18 weeks (range, 732 weeks), and advent of NGS has opened our eyes to the possibility of
the median duration of response had not been reached targeted therapy in a subset of breast cancer that lacks the
(range, 15more than 40 weeks). classic biomarkers (ER, PR, and HER2) in breast cancer.
The PD-L1 antagonist atezolizumab (MPDL3280A) also is Despite this challenge, investigators spanning the re-
being evaluated in TNBC. An ongoing phase I study of atezo- search spectrum from bench-to-bedside are tackling TNBC
lizumab has an expansion cohort in heavily pretreated patients head on. We are seeing an explosion of activity in basic,
with PD-L1positive and negative TNBC.76 Initial data show translational, and clinical research that includes plati-
the overall response rate for evaluable patients with metastatic nums, immunotherapy, and others. Coordinated research
TNBC is 19%, including 9.5% CR and 9.5% PR, with 75% of efforts such as this are the way forward to improve the
responses ongoing (range, 18 to more than 56 weeks). outcome for our thousands of patients with TNBC.

References
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41. Hu XC, Zhang J, Xu BH, et al. Cisplatin plus gemcitabine versus paclitaxel 60. Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al. Prospective validation of
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42. Isakoff SJ, Mayer EL, He L, et al. TBCRC009: a multicenter phase II clinical 61. Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to
trial of platinum monotherapy with biomarker assessment in metastatic neoadjuvant chemotherapy of breast carcinoma is associated with the
triple-negative breast cancer. J Clin Oncol. 2015;33:1902-1909. disappearance of tumor-infiltrating Foxp3+ regulatory T cells. Clin
43. Abkevich V, Timms KM, Hennessy BT, et al. Patterns of genomic loss of Cancer Res. 2008;14:2413-2420.
heterozygosity predict homologous recombination repair defects in 62. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are
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44. Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates zumab benefit in early breast cancer: results from the FinHER trial. Ann
defective DNA repair and sensitivity to DNA-damaging agents. Cancer Oncol. 2014;25:1544-1550.
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BRCA1/2 inactivation. Cancer Res. 2012;72:5454-5462. 64. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an
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that HR-defective sporadic breast cancers are enriched for genetic 65. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lympho-
alterations in DNA repair genes. 2015, San Antonio, TX: 2015 San cytes and response to neoadjuvant chemotherapy with or without
Antonio Breast Cancer Symposium. carboplatin in human epidermal growth factor receptor 2-positive
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48. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated 66. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in
melanoma without BRAF mutation. N Engl J Med. 2015;372:320-330. triple-negative breast cancer. Cancer Immunol Res. 2014;2:361-370.
49. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with 67. Ghebeh H, Mohammed S, Al-Omair A, et al. The B7-H1 (PD-L1)
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50. Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators. Pem- tients with infiltrating ductal carcinoma: correlation with important
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infiltrating lymphocytes in a phase III randomized adjuvant breast 72. Nagalla S, Chou JW, Willingham MC, et al. Interactions between im-
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Breast Cancer Res. 2012;14:R48. 74. Rody A, Holtrich U, Pusztai L, et al. T-cell metagene predicts a favorable
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negative breast cancer. Breast Cancer Res Treat. 2012;132:793-805. for Cancer Research 106th Annual Meeting.

42 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


BREAST CANCER

Updates and Controversies in


HER2-Positive Breast Cancer

CHAIR
Sunil Verma, MD, MSEd, FRCPC
Cumming School of Medicine, University of Calgary
Calgary, AB, Canada

SPEAKERS
Kimberly L. Blackwell, MD
Duke University Medical Center
Durham, NC

Speaker
Miguel Martin, MD, PhD
~
Hospital General Universitario Gregorio Maranon
Madrid, Spain
NIXON AND VERMA

A Value-Based Approach to Treatment of HER2-Positive


Breast Cancer: Examining the Evidence
Nancy Nixon, MD, FRCPC, and Sunil Verma, MD, MSEd, FRCPC

OVERVIEW

Over the past decade, treatment of HER2-positive breast cancer has been revolutionized with the introduction of targeted
therapies. Survival in both early and advanced HER2-positive breast cancer has improved significantly. With evidence for
major clinical benefit, it is imperative that health systems evaluate new treatments to maximize the value of health
expenditures. Physicians, funding agencies, and policy makers are tasked with analyzing available evidence to ensure that
each individual patient receives the optimal treatment in a resource-challenged environment.

A pproximately 15% to 20% of breast cancer patients


overexpress HER2 protein. 1 Over the past decade,
treatment of HER2-positive breast cancer has been revo-
the EGFR family. The rationale for the addition of pertu-
zumab to trastuzumab is to overcome resistance to tras-
tuzumab caused specifically by formation of HER2:HER3
lutionized. Although previously a poor prognostic marker, heterodimers. It was evaluated for metastatic disease in the
HER2-positive breast cancer now gives patients an equiva- CLEOPATRA trial,6 which studied patients with HER2-positive
lent, if not superior, survival to those patients that are HER2- disease with no prior treatment of metastatic disease and
negative.2 In metastatic disease, the median overall survival randomly assigned them 1:1 to trastuzumab and docetaxel,
(OS) has dramatically increased over the course of 15 years, plus either pertuzumab or placebo. Ninety percent of the
from 20 months, 50 months, and beyond.3 For metastatic patients in this trial had not been on prior trastuzumab
patients, American Society of Clinical Oncology (ASCO) therapy in the adjuvant setting, meaning the majority of the
guidelines4 now recommend HER2-targeted therapies in all patients were naive to anti-HER2 therapies. The results of
lines of treatment of metastatic disease. this trial established a new first-line standard of metastatic
HER2-positive breast cancer, with an increase in progression-
TREATMENT OF METASTATIC HER2-POSITIVE free survival (PFS) of 6 months (18.6 vs. 12.4 months; p , .001)
BREAST CANCER and OS (56.5 vs. 40.8 months; p = .002; Table 1).7
First Line
Trastuzumab, a human monoclonal IgG antibody that se- Second Line
lectively targets HER2, was the first targeted drug to be For patients progressing on an anti-HER2 therapy combined
approved. It has since has been shown to be effective in with a cytotoxic or endocrine agent, additional anti-HER2
combination with multiple chemotherapy drugs including therapy should be offered based on evidence showing it is
docetaxel, paclitaxel, vinorelbine, and capecitabine. In the beneficial to continue suppression of the HER2 pathway.8-12
landmark trial by Slamon et al,5 patients were randomly Laptinib is an oral tyrosine kinase inhibitor that functions
assigned 1:1 to standard chemotherapy alone versus downstream of HER2, inhibiting both EGFR and HER2 re-
standard chemotherapy plus trastuzumab. In this study, ceptors. It was shown to be an effective option for second-
there was a substantial improvement in time to pro- line treatment in 2006 by Geyer et al13 for patients who
gression (TTP, 7.4 vs. 4.6 months; p , .001). Median OS had locally advanced or metastatic HER2-positive breast
increased from 20.3 to 25.1 months (p = .046), establishing cancer previously treated with regimens that included an
trastuzumab as a standard of care in combination with anthracycline, a taxane, and trastuzumab. The addition of
taxanes (Table 1). lapatinib resulted in a significant improvement in median
Pertuzumab, a recombinant humanized monoclonal an- TTP of 8.4 versus 4.4 months at interim analysis, meeting
tibody, binds to a separate domain on the HER2 receptor, specified criteria for early reporting (hazard ratio [HR] 0.49;
preventing the dimerization of HER2 with other members of p , .001). There was no noticeable improvement in OS

From the University of Calgary, Calgary, Alberta, Canada.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Sunil Verma, MD, MSEd, FRCPC, University of Calgary, 1331 29 St. NW, Calgary, Alberta, Canada; email: drsunil.verma@albertahealthservices.ca.

2016 by American Society of Clinical Oncology.

e56 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


HER2-POSITIVE BREAST CANCER: A VALUE-ORIENTED APPROACH TO TREATMENT

TABLE 1. Clinical Benefit of Targeted Therapies for Early HER2-Positive Breast Cancer
Indication Regimen Overall Survival Disease-Free Survival
NSABP-B31 and Adjuvant early breast AC T vs. AC TH HR 0.63; 75.2% vs. 84.0% at HR 0.60; p , .001; 62.3% vs.
NCCTG N983120 cancer 8.4 years follow-up 73.7% at 8.4 years follow-up
10-Year Follow-up Adjuvant early breast AC T vs. AC TH vs. TCH HR 0.63 (AC-TH p , .0001; 85.9% HR 0.72 (AC-TH p , .001; 74.6%
BCIRG 00621 cancer vs. 78.7%) vs. 67.9%)
HR 0.76 (TCH p = .0075; 83.8% vs. HR 0.77 (TCH p = .0011; 73.0%
78.7%) vs. 67.9%)
10-Year Follow-up Adjuvant early breast Standard chemotherapy vs. standard HR 0.74; p , .001; 79.4% vs. HR 0.75; p , .001; 69.3% vs.
HERA cancer chemotherapy + 1-y trastuzumab 72.9% at 10 years follow-up 62.5% at 10 years follow-up
Abbreviations: T, taxane; H, trastuzumab, C, cyclophosphamide, c, carboplatin; AC, doxorubicin and cyclophosphamide; HR, hazard ratio.

observed in this trial, likely in part because of early crossover Beyond Second Line
(Table 1). After progression on trasuzumab, pertuzumab, and treat-
In 2012, the EMILIA study14 was published, establishing a ment with T-DM1, there remain multiple options of treat-
new standard of care for second-line treatment. This trial ment, still including anti-HER2targeted treatments. These
looked at T-DM1, an antibody-drug conjugate of trastuzumab include capecitabine plus lapatinib, trastuzumab plus
and the cytotoxic agent emtansine (DM1). The antibody lapatinib,15-17 or trastuzumab in combination with another
trastuzumab binds to the HER2 on tumor cell surfaces and cytotoxic agent. There is insufficient evidence to recommend
upon internalization the emtansine moiety is released, one regimen over another. Alternatively, patients may be
binding to tubules and disrupting microtubule dynamics. considered for enrollment on clinical trial.
EMILIA compared T-DM1 versus lapatinib plus capectiabine In 2015, the THERESA trial was presented at the San
in patients with locally advanced or metastatic HER2-positive Antonio Breast Cancer Symposium. Showing OS benefit for
breast cancer who had previously received zero to more than T-DM1 for patients who have had prior therapy with taxane,
three prior regimens. All the patients on this trial had prior trastuzumab, and lapatinib. This confirms the efficacy for
exposure to trastuzumab and a taxane. T-DM1 showed a T-DM1 in later lines of therapy for patients who may not
significant improvement in median PFS (9.6 vs. 6.4 months, HR have had received T-DM1 in the second-line setting.
0.65; p , .001) and median OS (30.9 vs. 25.1 months; HR 0.68;
p , .001; Table 1). In addition, rates of grade 3 or higher TREATMENT OF EARLY HER2-POSITIVE BREAST
adverse events were higher in the lapatinib plus capecitabine CANCER
group. This established T-DM1 as the new standard for second- Adjuvant
line treatment. With the success of anti-HER2 therapy in the metastatic
setting, trastuzumab was evaluated in the adjuvant setting
in a series of pivotal trials, first reported in 2005. In the HERA
trial,18 patients were randomly assigned 1:1:1 to observa-
tion, versus 1 or 2 years of trastuzumab given every 3 weeks.
When compared with observation, trastuzumab given after
KEY POINTS primary therapy reduced the rate of recurrence, in particular
Treatment of HER2-positive breast cancer, and its
distant recurrence, by approximately 50% after interim ef-
prognosis, has been revolutionized since the ficacy analysis with median follow-up of 12 months. This
introduction of targeted treatment. benefit was confirmed in a 2012 meta-analysis of eight trials
Significant improvements in overall survival have been of chemotherapy plus trastuzumab versus trastuzumab
observed in both metastatic and adjuvant settings over alone.19 The HR for recurrence was 0.60, also with an im-
the past decade. provement in OS and HR for death of 0.66. The benefit in OS
Despite significant clinical benefit with introduction of was most strongly associated with concurrent administra-
targeted treatments, there is a risk that cost on a tion of trastuzumab with chemotherapy, as opposed to with
population level may become prohibitive for sequential treatment. In 2014, Perez et al published the
widespread use. results of a planned joint analysis on survival from NSABP-31
Physicians, funding agencies, and policy makers are
and NCCTG N9831, where patients were randomly assigned
tasked with finding a means to ensure that treatments
are cost-effective in an environment of limited
to doxorubicin plus cyclophosphamide followed by pacli-
resources. taxel plus trastuzumab for 1 year versus paclitaxel alone.20
Careful evaluation of the evidence and consideration of Adding trastuzumab led to 37% relative improvement in OS
clinical benefit alongside the cost-effectiveness of novel (HR 0.63; p , .001). An improvement in disease-free survival
therapies will help to guide clinical practice. (DFS) of 40% was observed (HR 0.60; p , .001) with increase
in 10-year DFS rate from 62.2% to 73.7% (Table 2).

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TABLE 2. Clinical Benefit of Targeted Therapies for Early and Advanced HER2-Positive Breast Cancer
Indication Regimen Overall Survival Progression-Free Survival
Slamon et al, First-line advanced breast Standard chemotherapy vs. standard che- 25.1 vs. 20.3 months (p = .046) 7.4 vs. 4.6 months
20015 cancer motherapy + H (p , .001)
CLEOPATRA6 First-line advanced breast TH + placebo vs. THP 56.5 months vs. 40.8 months 7.7 vs. 6. 3 months
cancer (HR 0.68; p , .001) (HR 0.68; p , .001)
EMILIA14 Second-line advanced T-DM1 vs. capecitbine + lapatinib 20.9 vs. 25.1 months (HR 0.68; 9.6 vs. 6.4 months
breast cancer p , .001) (HR 0.65; p , .001)
Geyer et al, Second-line advanced Lapatinib + capecitabine vs. capecitabine TTP 8.4 vs. 4.4 months
200613 breast cancer (HR 0.49; p , .001)
Abbreviations: T, taxane; H, trastuzumab; P, pertuzumab; DM1, emtansine; HR, hazard ratio; TTP, time to progression.

The benefit of adjuvant trastuzumab has been maintained Several studies have been done to look at lapatinib in
with longer follow-up. An updated analysis of the HERA trial neoadjuvant treatment, both in combination with or in place
showed continued significant DFS and OS benefit of tras- of trastuzumab. Lapatinib has been consistently inferior to
tuzumab despite substantial crossover (Table 2). Ten-year trastuzumab when compared head to head.25-27 The com-
follow-up from the BCIRG 006 trial, which randomly assigned bination was looked at in the NeoALLTO study, which en-
patients to three arms (doxorubicin plus cyclophosphamide rolled women with HER2-positive, early breast cancer and
followed by taxane plus or minus trastuzumab, vs. docetaxel randomly assigned them 1:1:1 to lapatinib, trastuzumab, or
plus carboplatin plus trastuzumab) was presented in 2015 trastuzumab plus laptinib for 6 weeks followed by the anti-
at the San Antonio Breast Cancer Symposium (Table 2). HER2 treatment combined with paclitaxel for 12 weeks.
With 10.3 years of follow-up, there was significant benefit After surgery, women received three cycles of FEC followed
in OS for both trastuzumab-containing arms compared by 34 weeks of the assigned anti-HER2 neoadjuvant therapy.
with chemotherapy alone (p , .001 for doxorubicin plus Although patients in the combination group had improve-
cyclophosphamide followed by docetaxel plus trastuzu- ment in pCR, this did not translate to improved DFS or OS in
mab, and p = .0018 for docetaxel plus carboplatin plus the confirmatory phase III adjuvant ALTTO study.
trastuzumab).
Near Future Directions
There continues to be new data that will add to our
Neoadjuvant
knowledge of how to optimize treatment of early disease.
There is greater interest in evaluating HER2 therapies in the
The APHINITY trial evaluating adjuvant pertuzumab plus
neoadjuvant setting, given the correlation between path-
trastuzumab versus trastuzumab after surgery is yet to be
ologic complete response (pCR) and long-term outcomes
reported but may provide evidence for adjuvant utilization
including event-free survival (EFS).22 The U.S. Food and Drug
of pertuzumab. Similarly, the KATHERINE trial, which recently
Administration granted approval to the addition of neo-
completed accrual, is evaluating the addition of T-DM1 as ad-
adjuvant pertuzumb to trastuzumab based on two random-
juvant treatment of patients treated with neoadjuvant che-
ized phase II studies, in which higher pCR rates were seen
motherapy and trastuzumab who do not achieve pCR. T-DM1 is
compared with trastuzumab arms. NeoSphere compared four
also being evaluated in direct comparison to paclitaxel and
regimens preoperatively (docetaxel plus trastuzumab vs.
trastuzumab in the adjuvant setting for patients with low-risk
docetaxel plus trastuzumab plus pertuzumab vs. trastuzumab
HER2-positive disease (ATEMPT trial).
plus pertuzumab. vs. docetaxel plus pertuzumab).23 After
surgery, patients in the docetaxel arms received three cycles
of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) VALUE-BASED APPROACH
and completed a year of trastuzumab, whereas patients Over the past decade, there has been rapid growth in the
who had received only antibody treatment received both cost of cancer care as a whole. In the United States, it is
docetaxel and FEC followed by trastuzumab for a full year. expected to increase from $125 billion in 2010 to $158 billion
pCR rates were 29%, 46%, 17%, and 24% in each group, in 2020.28 Although drug treatment costs account for as
respectively. In the TRYPHA-ENA study, women were ran- much as 20% of total cost, it is imperative that health
domly assigned to trastuzumab plus pertuzumab and con- systems evaluate new treatments strategically to maximize
current FEC followed by concurrent docetaxel, FEC alone value of health expenditures. In HER2 breast cancer, the
followed by concurrent docetaxel, or concurrent docetaxel benefits gained by new treatments have been undeniably
and carboplatin.24 After surgery, patients completed 1 year important clinically. Physicians, policy makers, and funding
of trastuzumab. The pCR rate was equivalent across arms. In agencies are tasked with identifying economic trade-offs and
both studies, patients with ER-negative disease were more ensuring patients have access to treatments with mean-
likely to achieve pCR. ingful health benefits in a resource-limited environment.

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Clinical Benefit Value Assessment


The definition of clinical benefit is variable. Ideally, it would Economists use a variety of methods to assess value.
include all patient-important outcomes. In practice, the evi- Commonly used in evaluations of medical intervention are
dence used to create treatment guidelines is the highest quality quality-adjusted life-years (QALYs) and incremental cost
available, such as the randomized controlled trials described. In effectiveness ratios (ICERs; Table 3). QALY incorporates both
ASCOs 2015 value framework, clinical endpoints used to assess quality and quantity of life achieved with treatment. A
benefit (OS, PFS, DFS) were selected based on their repre- treatment with a low cost per QALY is more cost effective
sentation of data collected in clinical trials.29 Based on this than one with high cost per QALY. An ICER is simply the ratio
framework, Table 1 summarizes the clinical benefit observed in between the difference in cost and the difference in benefit
landmark trials in early breast cancer. Table 2 summarizes of two interventions. In cost-effectiveness analyses, ICER are
clinical benefit in advanced disease. commonly expressed as incremental cost per QALY. Defining

TABLE 3. Summary of Key North American Cost-Effectiveness Analyses on Targeted HER2 Therapies in Various
Lines of Treatment
Study Country HER2 Test and Treatment ICER/QALY
33
Neoadjuvant Pertuzumab Attard et al Canada HER2 test: not included in analysis Neosphere: $25,388 per QALY
NeoSphere: neoadjuvant TRYPHAENA: $46,196 per
docetaxel + trastuzumab 6 QALY
pertuzumab surgery
fluorouracil + epirubicin +
cyclophosphamide (FEC)
TRYPHAENA: docetaxel + carbo-
platin + trastuzumab +
pertuzumab
Adjuvant Trastuzumab Kurian et al32 United States HER2 test: not included in analysis Anthracycline based: $39,98
per QALY
Treatment: anthracycline-based Nonanthracycline is more ex-
regimens in NSABP B-31 and pensive and less effective,
NCCTGN9831 trials; nonan- therefore both with and
thracycline regimen from without trastuzumab ex-
BCIRG 006 + trastuzumab for 52 ceed $100,000 per QALY
weeks vs. chemotherapy only compared with anthracy-
cline regimens
Garrison et al46 United States HER2 test: not included in analysis $26,417 per QALY over
a lifetime
Treatment: anyhtacycline-based
regimens from NSABP B-31 and
NCCTG N9831 trials plus
trastuzumab (at actual dose/
duration received in trial) vs.
chemotherapy alone
Metastatic trastuzumab Elkin et al34 United States HER2 test: IHC +3; IHC with FISH Initial IHC with FISH confir-
for IHC 2+ and 3+; IHC with FISH mation: $125,0000 per
for IHC 2+; FISH only QALY
Treatment: trastuzumab + Initial FISH: $145,000 per
paclitaxel vs. paclitaxel only QALY
Other strategies for HER2
testing less cost effective
First-line pertuzumab Durkee et al36 United States HER2 testing: not included in $713,219 per QALY
analysis
Treatment: docetaxel + trastuzu-
mab + pertuzumab vs. doce-
taxel and trastuzumab alone
Metastatic T-DM1 PCODR Canada HER2 testing: not included in $162,839 per QALY
analysis
Treatment: T-DM1 vs. lapatinib
capecitabine
Metastatic capecitabine + lapatinib Le et al35 United States HER2 testing: not included in $166,113 per QALY
analysis
Treatment: capecitabine + lapati-
nib vs. capecitabine alone
Abbreviations: ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life-years; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; DM1, emtansine.

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the threshold for cost effectiveness is a focus for funding focus on treatment according to best evidence, while finding
sources worldwide and is variable depending on the funding ways to minimize costs and avoid overtreatment.
party and the basic structure of the health care system. In
most analysis from the United States using USD, a threshold Should dual anti-HER2 maintenance be continued after
level of $100,000 per QALY is considered cost-effective maximal response? There is limited evidence to answer
(range 50,000 to three times the United States per capita whether maintenance with dual anti-HER2 blockade should
gross domestic product, or $160,000 per QALY).30 This be continued once maximal response is achieved. There is,
method of assessment is fraught with variability that is however, evidence of continued efficacy of trastuzumab
highly subjective to the approach used to estimate OS in the after progression on a trastuzumab-based regimen. A trial
control group when crossover is allowed in the trial, in- by Von Minckwitz et al looked at the combination of
clusion of treatment past progression, and the cost of HER2 capecitabine plus trastuzumab versus trastuzumab alone
testing as demonstrated in a systemic review by Parkinson as a second-line treatment.10 This showed a significant im-
et al.31 provement in TTP (8.2 vs. 5.6 months; p = .03) and a non-
In the adjuvant setting, trastuzumab was shown to be cost- significant trend in OS (25.5 vs. 20.4 months; p = .257). In a
effective by Kurian et al, who estimated an ICER of $39,982 separate study, the combination of trastuzumab plus laptinib
USD per QALY.32 Cost-effectiveness of pertuzumab in the versus lapatinib alone after progression on a trastuzumab-
neoadjuvant setting was investigated by Attard et al based based regimen was investigated.16 This showed a significant
on pCR data from both NeoSphere and TRYPHAENA.33 improvement for PFS in the combination arm (12 weeks vs.
Published EFS and OS data for patients achieving and not 8.1 weeks; p = .008) and OS (14 vs. 9.5 months).
achieving pCR were used in combination with percentage Currently, no trials have been done to address con-
achieving pCR in trials to estimate survival. The incremental tinuation of targeted therapy after maximal response is
cost per QALY ranged from $25,388 CAD (NeoSphere) to achieved. In most trials, HER2-targeted therapy was ad-
$46,196 CAD (TRYPHAENA analysis), making the addition of ministered until disease progression or until significant
pertuzumab cost-effective with a threshold of $100,000. toxicity leading to discontinuation of therapy. Current
For treatment of advanced disease, the cost of even a recommendations on duration from ASCO and the cost-
single targeted agent increases significantly per QALY. For effectiveness analysis mentioned before are based on the
HER2 testing and treatment with trastuzumab in the met- approach used in relevant clinical trials. Potential gains in
astatic setting, Elkin et al determined an ICER of $125,000 both quality of life and cost-effectiveness may be achieved
USD per QALY.34 A similar method was used to determine if we consider treatment breaks in patients who have
the ICER for lapatinib pus capecitabine to be $166,113 USD sustained a response with no evidence of progression. This
per QALY, not including testing for HER2 positivity.35 The approach needs to evaluated and studied in the metastatic
pan-Canadian Oncology Drug Review (pCODR) calculated a setting and could be guided by utilization of functional
cost of $162,839 CAD for T-DM1 based on EMILIA trial re- imaging/circulating tumor cells.
sults. The addition of pertuzumab to docetaxel and tras-
tuzumab according to the CLEOPATRA trial, was found to be, Do all patients need dual anti-HER2 blockade up front? If
again, incrementally higher in a recent publication, with an we are able to identify a certain subgroup within the HER2
estimated ICER of $713,219 USD per QALY gained.36 Despite population that derives the greatest benefit from dual-
the high cost, most funding agencies have adopted these antibody treatment, it allows us to be selective in who re-
therapies into clinical practice. This brings to question what ceives the treatment, sparing others both toxicities and cost.
practical considerations can be made to maximize access to Baselga et al looked to answer this question by assessing a
highly effective, costly treatments in an environment of protocol-prespecified panel of biomarkers in tumor and
limited resources. serum samples from patients on the CLEOPATRA trial.17
Biomarkers were identified based on previous under-
PRACTICAL CONSIDERATIONS standing of HER2-signaling pathways, or HER2-targeted
Metastatic Disease therapy resistance. Pertuzumab was found to have a con-
There are several limitations to QALY as a means of eval- sistent benefit for PFS, independent of biomarker sub-
uation for treatment of advanced breast cancer patients. In groups. This indicates that to our current knowledge, HER2 is
the metastatic setting, successful treatments are victims of the only marker that should be used for patient selection for
their own success, because longer PFS extrapolates to more the combination of trastuzumab plus pertuzumab. There is a
time accruing costs for expensive therapies. Additionally, need for further studies that may help to elucidate tumor, or
QALY does not capture an individual patients priorities. For patient-related factors that may ultimately help us de-
patients with metastatic disease, the balance between termine which patients are best candidates for dual anti-
quality versus quantity of life is a much more personal bodies up front.
determination than for early breast cancer, where the goal One of the key questions that must be asked when ap-
is to cure. It also does not take into account the benefit of plying evidence to practice is whether the patient population
time-off treatment or symptom improvement. Based on in the study matches the patient being treated in the real-
these limitations, we pose questions for discussion that still world setting. In the CLEOPATRA trial, 90% of patients were

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HER2-POSITIVE BREAST CANCER: A VALUE-ORIENTED APPROACH TO TREATMENT

nave to any HER2-targeted therapy. In practice, many of the patients, 47% had been given adjuvant chemotherapy and
patients we treat in the first line for metastatic disease are trastuzumab. Disease-free survival at 40 months was 93% for
being treated for recurrence, and have already received patients who had not received chemotherapy versus 99% for
antibody treatment in the adjuvant setting. Swain et al those who had. In multivariate analysis, tumor size was not
recently published the results that suggest incremental associated with clinical outcomes, leading the authors to
improvement for patients who relapsed postadjuvant state adjuvant treatment should be discussed with all HER2-
trastuzumab; however, although the HR was similar, the positive T1a-b tumors. Based on the available data, one has
prognosis and overall results for this population were in- to weigh the potential benefit:risk of toxicity and cost im-
ferior compared with de novo patients.37 Forty-one patients plications specifically for patients with T1a/T1b tumors.
in the control group and 47 patients in the treatment arm
were enrolled after 1 year of adjuvant trastuzumab. The OS Does everyone need neoadjuvant pertuzumab? In the
was 46.6 months and 53.8 months, respectively (HR 0.8; adjuvant setting similarly to advanced disease, there is
95% CI, 0.441.47), with a large confidence interval owing question of whether patients who are positive for both HER2
to relatively small numbers. The study authors point out, and hormone receptors should be treated the same. In the
however, that since the introduction of trastuzumab in the NeoSphere study, patients were stratified according to
adjuvant setting the proportion of patients who had re- hormone receptor status at the time of randomization. They
current disease had significantly decreased, as shown in the subsequently compared pCR results across these groups.
SystHERs trial.38 This means that the results of the CLEO- Patients that were estrogen receptor (ER) and progesterone
PATRA trial may reflect what is seen in practice today, with receptor (PgR)negative showed a pCR rate of 63% when
increased proportion of patients being treated with HER2- pertuzumab was added to docetaxel and trastuzumab, com-
positive de novo presentation. pared with 36.8% with trastuzumab and docetaxel alone. In
patients who were also ER-positive, PgR-positive, or both, the
three-drug regimen had a pCR of 26%, compared with 20% with
Early Breast Cancer docetraxel and trastuzumab. The updated EFS data show a
Treatment of early breast cancer is distinct from advanced nonsignificant trend for improvement in EFS. One requires
breast cancer because the treatment goals are more clearly confirmatory adjuvant data to truly assess the benefit of adding
defined and uniform across patients. Treatment with the pertuzumab to standard trastuzumab-based therapy.42
goal of cure makes decreasing treatment intensity an un-
common target. However, because outcomes of HER2- Do patients need 1 year of trastuzumab? Duration of
positive breast cancer exceed survival rates of 95%, it is trastuzumab has been looked at in multiple studies. In the
important to consider whether a subset of patients exists in original HERA study, trastuzumab for 1 year plus chemo-
whom we can de-escalate therapy. therapy was compared with chemotherapy alone, and in a
third arm trastuzumab for 2 years was given. At a median
Is there a population who do not need HER2-targeted follow-up of 8 years, there was no difference between 1 and
treatment? For patients who are HER2-negative, chemo- 2 years with respect to DFS (HR 0.99; p = .86) or OS (HR 1.05;
therapy is generally not recommended unless they are p = .63). The other pivotal trials discussed before used the
lymph nodepositive, or high-risk lymph nodenegative. In duration of 1 year somewhat empirically. Shorter duration of
the HER2+ population, however, the threshold for treatment adjuvant trastuzumab was studied in the FinHER trial.43 This
is lower based on our knowledge that even earlier stage study tested nine cycles of weekly trastuzumab with adju-
tumors are more likely to recur. OSullivan et al performed a vant docetaxel or vinorelbine followed by FEC in a subset of
meta-analysis of five trastuzumab randomized controlled early breast cancer patients with HER2-positive, high-risk
trials in early breast cancer and tumors 2 cm or smaller.39 disease (node-positive or node-negative with tumors at least
They concluded that patients with HER2-positive and tumors 2 cm). The primary endpoint of recurrence-free survival
2 cm or smaller had major DFS and OS benefits from tras- favored the trastuzumab arm (HR 0.41; p = .01), as did OS (HR
tuzumab as part of the treatment regimen. 0.41; p = .07). Documented clinical improvement was similar
For patients with T1a or T1b tumors that are node- to standard of 1-year therapy seen in previous trials.
negative, prognosis is less well-defined, even in the set- In a larger phase III study, PHARE randomly assigned 1,693
ting of HER2 positivity. Ferenbacher et al did a retrospective patients with HER2-positive high-risk (node-positive) disease
analysis of 234 patients with HER2-positive, lymph node to chemotherapy plus 6 months versus 1 year of trastuzu-
negative, and T1a or T1b tumors.40 Distant invasive re- mab.44 This study failed to achieve its primary outcome of
currence was the primary endpoint. Five-year distant noninferiority at a median follow-up of 3.5 years. Addi-
relapse-free survival was 98.2% for T1a, 89.4% for T1b, and tionally, more patients in the 6 months group had a distant
84.5% for 1-cm tumors. A majority (74%) of these patients recurrence as the first DFS event.
had no adjuvant treatment, raising the possibility of not There are a number of ongoing studies to evaluate
requiring therapy for certain T1a patients. In contrast, a shorter treatments of adjuvant trastuzumab comparing 6 to
study by Rodriguez et al41 looked at 276 patients with 12 months (e.g., the Hellenic group trial, the Persephone
node-negative, T1a-b HER2-positive breast cancer. Of these study) and 3 to 12 months (e.g., SOLD study, Short-HER

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study). These studies will provide insight into possibly reducing There are important questions raised that must be con-
the duration of adjuvant treatment and, subsequently, costs. sidered despite the attraction of reduced cost. These include
While awaiting these results, 1 year continues to be the questions on what patient population was included to es-
standard of care. tablish comparable clinical efficacy. To date, studies have
been in metastatic patients, which is a varied population
Biosimilars compared with patients with early breast cancer. Primary
The most intuitive way to receive the benefit of targeted endpoints have also been questioned, with the overall re-
treatments without the cost is to find a cheaper, equally sponse rate being most commonly chosen. Another concern
effective alternative. For this purpose, there has been great is that, up to now, biosimilar trials have looked at trastu-
interest in the production of biosimilar agents. Biosimilars zumab as a single agent, but the new standard of care in first-
are distinct from generic formulations in that they are not line advanced disease is a combination treatment with
biochemically identical to the original. Biologic agents are pertuzumab. Ongoing efforts are underway to evaluate
complex, with larger size and more intricate structure, such biosimilars in a neoadjuvant setting and with more clinically
that exact replication is impossible.45 Biosimilars, therefore, relevant endpoints to guide us about its use in early-stage
must be tested to ensure noninferior biologic activity, safety, and advanced breast cancer.
and efficacy.46 At least 10 trastuzumab biosimilar mono- Overall, we have made major strides in the management
clonal antibodies are in active development. The furthest of HER2-positive early-stage and advanced breast cancer.
along in testing is CT-P6, produced by Celltrion. CT-P6 has These impressive gains are based on inclusion of newer
been through phase III testing and has demonstrated an HER2-targeted therapies and the related financial impact of
equivalent overall response rate (primary endpoint) to integrating these drugs. The future in HER2-positive breast
trastuzumab in patients with metastatic disease. Based on cancer clinical research needs to focus on how best to
this trial, CT-P6 has already been approved as a biosimilar in optimize therapy that provides us with a more individualized
South Korea. As this becomes available, the cost of tras- approach based on inclusion of biomarkers, imaging, and
tuzumab may drop by as much as 40%. patient factors.

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1659-1672. 33. Attard CL, Pepper AN, Brown ST, et al. Cost-effectiveness analysis of
19. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regi- neoadjuvant pertuzumab and trastuzumab therapy for locally ad-
mens for early breast cancer. Cochrane Database Syst Rev. 2012;4: vanced, inflammatory, or early HER2-positive breast cancer in Canada.
CD006243. J Med Econ. 2015;18:173-188.
20. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant 34. Elkin EB, Weinstein MC, Winer EP, et al. HER-2 testing and trastuzumab
chemotherapy for human epidermal growth factor receptor 2-positive therapy for metastatic breast cancer: a cost-effectiveness analysis. J Clin
breast cancer: planned joint analysis of overall survival from NSABP B-31 Oncol. 2004;22:854-863.
and NCCTG N9831. J Clin Oncol. 2014;32:3744-3752. 35. Le QA, Hay JW. Cost-effectiveness analysis of lapatinib in HER-2-positive
21. Slamon DJ, Eiermann W, Robert NJ, et al. Ten year follow up of the advanced breast cancer. Cancer. 2009;115:489-498.
BCIRG-006 Trial comparing doxorubicin plus cyclophosphamide 36. Durkee BY, Qian Y, Pollom EL, et al. Cost-effectiveness of pertuzumab in
followed by docetaxel (ACT) with doxorubicin plus cyclosphosphamide human epidermal growth factor receptor 2-positive metastatic breast
followed by docetaxel and trastuzumab (ACTH) with docetaxel, carbo- cancer. J Clin Oncol. 2015;63:1-12.
platin, and trastuzumab (TCH) in HER2+ early breast cancer. Presented at: 37. Swain S, Baselga, J. Treatment of HER2-positive metastatic breast
San Antonio Breast Cancer Symposium; December 2015; San Antonio, cancer. N Engl J Med. Correspondence. 2015;372:1964-1965.
TX. Abstract S5-S04. 38. Tripathy D, Brufsky A, Cobleigh M, et al. Increasing proportion of de
22. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and novo compared with recurrent HER2-positive metastatic breast cancer:
long-term clinical benefit in breast cancer: the CTNeoBC pooled early results from the systemic therapies for HER2-positive metastatic
analysis. Lancet. 2014;384:164-172. breast cancer registry study. Presented at the 37th Annual San Antonio
23. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant Breast Cancer Symposium; December 2014; San Antonio, TX.
pertuzumab and trastuzumab in women with locally advanced, in- 39. OSullivan CC, Bradbury I, Campbell C, et al. Efficacy of adjuvant
flammatory, or early HER2-positive breast cancer (NeoSphere): trastuzumab for patients with human epidermal growth factor receptor
a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012; 2-positive early breast cancer and tumors #2cm: A meta-analysis of the
13:25-32. randomized trastuzumab trials. J Clin Oncol. 2015;33:2600-2608.
24. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in 40. Fehrenbacher L, Capra AM, Quesenberry CP Jr, et al. Distant invasive
combination with standard neoadjuvant anthracycline-containing and breast cancer recurrence risk in human epidermal growth factor re-
anthracycline-free chemotherapy regimens in patients with HER2- ceptor 2-positive T1a and T1b node-negative localized breast cancer
positive early breast cancer: a randomized phase II cardiac safety diagnosed from 2000 to 2006: a cohort from an integrated health care
study (TRYPHAENA). Ann Oncol. 2013;24:2278-2284. delivery system. J Clin Oncol. 2006;32:2151-2158.
25. Baselga J, Bradbury I, Eidtmann H, et al; NeoALTTO Study Team. 41. Rodrigues JM, Wassermann J, Albiges L, et al. Trastuzumab treatment
Lapatinib with trastuzumab for HER2-positive early breast cancer in T1ab, node-negative human epidermal growth factor receptor
(NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. 2-overexpressing breast carcinomas. J Clin Oncol. 2010;28:e541-e542.
Lancet. 2012;379:633-640. 42. Gianni L, Pienkowski T, Im Y, et al. Five-year analysis of the phase II
26. Guarneri V, Frassoldati A, Bottini A, et al. Preoperative chemo- NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D)
therapy plus trastuzumab, lapatinib, or both in human epidermal and/or trastuzumab (T) and/or pertuzumab (P). J Clin Oncol. 2015;33:
growth factor receptor 2-positive operable breast cancer: results of 15s (suppl; abstr 505).
the randomized phase II CHER-LOB study. J Clin Oncol. 2012;30: 43. Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cy-
1989-1995. clophosphamide with either docetaxel or vinorelbine, with or without
27. Robidoux A, Tang G, Rastogi P, et al. Lapatinib as a component of trastuzumab, as adjuvant treatments of breast cancer: final results of
neoadjuvant therapy for HER2-positive operable breast cancer (NSABP the FINHER trial. J Clin Oncol. 2009;27:5684-5692.
protocol B-41): an open-label, randomised phase 3 trial. Lancet Oncol. 44. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of
2013;14:1183-1192. adjuvant trastuzumab for patients with HER2-positive early breast cancer
28. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer PHARE: a randomized phase 3 trial. Lancet Oncol. 2013;14:741-748.
care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103: 45. Thill M. New frontiers in oncology: biosimilar monoclonal antibodies for
117-128. the treatment of breast cancer. Expert Rev Anticancer Ther. 2015;15:
29. Schnipper LE, Davidson NE, Wollins DS, et al; American Society of 331-338.
Clinical Oncology. American Society of Clinical Oncology Statement: A 46. Garrison LP Jr, Lubeck D, Lalla D, et al. Cost-effectiveness analysis of
Conceptual Framework to Assess the Value of Cancer Treatment Op- trastuzumab in the adjuvant setting for treatment of HER2-positive
tions. J Clin Oncol. 2015;33:2563-2577. breast cancer. Cancer. 2007;110:489-498.

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MARTIN AND LOPEZ-TARRUELLA

Emerging Therapeutic Options for HER2-Positive Breast


Cancer
Miguel Martin, MD, PhD, and Sara Lopez-Tarruella,
MD, PhD

OVERVIEW

The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2
directed therapy (trastuzumab). Trastuzumab has significantly increased survival of patients with HER2-positive metastatic
breast cancer and, after the standardization of the use of this drug in the adjuvant setting in 2005, has also avoided many
disease recurrences and, consequently, saved many lives. Later on, the introduction of lapatinib offered new choices for
patients with advanced HER2-positive breast cancer, although the drug has failed to show a clear efficacy in the adjuvant
setting. New promising drugs have been approved to broaden the horizon of HER2-positive breast cancer such as per-
tuzumab or T-DM1, but we need new options to further improve the management of these diseases. In this review, we cover
new strategies that are currently under evaluation for the treatment of patients with HER2-positive breast cancer, including
new tyrosine kinase inhibitors (neratinib, ONT-380), new antibody-drug conjugates targeting HER2 (MM-302), and new
indications of already approved drugs (T-DM1), as well as the potential dual combinations of anti-HER2 therapy with
phosphoinositide 3-kinase/mTOR or cell cycle inhibitors (palbociclib, abemaciclib). Last but not least, we briefly review a new
paradigm of emerging approaches that involve the host immune response, HER2 breast cancer vaccines, and other immune
strategies, including immune checkpoint inhibition.

A dvances in the treatment of patients with HER2-positive


breast cancer have been made over the past few de-
cades, both in the metastatic setting and in the neo/adjuvant
ORAL, SMALL-MOLECULE INHIBITORS
Neratinib
Neratinib is an oral, small-molecule, anti-HER receptor ty-
treatment of earlier stages. In the neo/adjuvant setting, the rosine kinase inhibitor with a complex history. It was designed
combination of chemotherapy, trastuzumab, and perhaps in the early 1990s at Lederle Laboratories (Pearl River, NY) and
pertuzumab (for high-risk patients) has significantly im- was later was developed by Wyeth-Ayerst (Quebec, Canada),
proved patient outcomes. In the metastatic setting, the Pfizer (Quebec, Canada), and, finally, Puma Biotechnology
outcome of patients with HER2-positive tumors has also (Los Angeles, CA), the current owner of the drug.3,4 Neratinib
significantly improved, owing to the introduction of effective is a covalent drug that, differently from lapatinib, binds ir-
anti-HER therapies, including trastuzumab, pertuzumab, reversibly to the ATP active site of the tyrosine kinase domain
lapatinib, and T-DM1. The reported median survival time of HER2. A phase I study of neratinib among patients with
using these modern combination therapies is now approx- solid tumors showed that the maximum tolerated dose and
imately 5 years compared with approximately 1.5 years in the recommended dose for phase II trials was 320 mg and
the pretrastuzumab era.1,2 240 mg once daily, respectively. Grade 3 diarrhea was the
Despite this, 15%20% of patients with HER2-positive local- dose-limiting toxicity.5 The drug has good oral bioavailability
regional breast cancer still relapse after receiving the currently and, in the presence of food, the half-life elimination on day
available neo/adjuvant therapies. In addition, metastatic HER2- 1 after a single 240-mg administration is 14 hours, supporting
positive breast cancer essentially remains an incurable disease, a once-daily dosing regimen.
despite the improvement in survival seen after the introduction Neratinib was initially tested in a phase II trial of patients
of the new anti-HER2 therapies. Newer therapies and newer with breast cancer with HER2-positive metastatic tumors (66
approaches are therefore necessary to further improve the patients with and 70 without prior trastuzumab therapy,
current results. Here, we review the most promising emerging respectively) at a dose of 240 mg once daily. The study
therapeutic options currently in development for the treat- showed that single-agent neratinib has relevant antitumor
ment of HER2-positive breast cancer (Table 1). activity among patients with HER2-positive breast cancer

From the Instituto de Investigacion ~on,


Sanitaria Gregorio Maran Universidad Complutense, Madrid, Spain.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Miguel Martin, MD, PhD, Servicio de Oncologa Medica,


Instituto de Investigacion ~on,
Sanitaria Gregorio Maran Universidad Complutense, Dr. Esquerdo 46,
28007 Madrid, Spain; email: mmartin@geicam.org.

2016 by American Society of Clinical Oncology.

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EMERGING THERAPEUTIC OPTIONS FOR HER2 BREAST CANCER

who were pretreated. Objective response rates (ORRs) were TABLE 1. Emerging Therapies for HER2-Positive Breast
24% for patients who received prior trastuzumab treatment Cancer
and 56% for trastuzumab-naive patients. Responses were of
long duration (9 months for patients pretreated with tras- Class Drug Mechanism of Action
tuzumab and 12 months for trastuzumab-naive patients). Oral, Anti-HER2, Neratinib Tyrosine kinase inhibitor (HER2
Median progression-free survival (PFS) was approximately Small and HER1)
Molecules
5 months for patients pretreated with trastuzumab and ONT-380 Tyrosine kinase inhibitor (HER2)
approximately 9 months for trastuzumab-naive patients. Anti-HER2 Anti- T-DM1 Trastuzumab-like effect
The downside of the treatment was the high incidence of Body-Drug
Intracellular release of emtan-
Conjugates
adverse events, particularly diarrhea and, to a much lesser sine-cytotoxic toxicity in HER2-
overexpressing cells
extent, nausea, vomiting, and fatigue. Diarrhea was reported
MM-302 Intracellular release of pegylated
for 85% of patients pretreated with trastuzumab (grade 3 to liposomal doxorubicin in
4 for 30% of patients). The incidence of diarrhea was greater HER2-overexpressing cells
in the first week of therapy (85%) but significantly declined mTOR/PI3K/Akt Everolimus mTOR inhibition
with loperamide therapy from that time onward (60% at Inhibitors
Buparlisib Pan-class I PI3K inhibitor
weeks 2 to 4, less than 40% at month 2, and approximately
Pictilisib Pan-class I PI3K inhibitor
15% at month 3).6
Taselisib Alpha-specific PI3K inhibitor
Based on these appealing phase II data, single-agent
Alpelisib Alpha-specific PI3K inhibitor
neratinib was compared with the combination of lapatinib
and capecitabine in a phase II noninferiority study. The CDK4/6 Palbociclib CDK4/6 inhibition, cell cycle arrest
Inhibitors
comparator was the standard therapy for trastuzumab- Abemaciclib CDK4/6 inhibition, cell cycle arrest
pretreated HER2-positive metastatic breast cancer at the Vaccines E75 Peptide-based vaccine
time the study was designed (capecitabine plus lapatinib). Of GP2 Peptide-based vaccine
the study patients, 117 were allocated to receive 240 mg Immune Pembrolizumab AntiPD-1
of neratinib daily and 116 patients received 1,250 mg of Checkpoint
lapatinib daily plus 2,000 mg/m2 of capecitabine daily on Inhibitors
days 1 to 14 of each 21-day cycle. The study failed to show Abbreviation: PI3K, phosphoinositide 3-kinase.

noninferiority of neratinib compared with lapatinib plus


capecitabine. However, neratib showed indisputable single-agent
activity in the trial, with a response rate of 29% versus 41%
with the combination of lapatinib and capecitabine (p = .067).
KEY POINTS Median PFS and overall survival (OS) times were 4.5 and
19.7 months (neratinib) versus 6.8 and 23.6 months for the
The currently available anti-HER2 therapies have combination, respectively. Eighty-five percent of patients taking
changed the natural history of HER2-positive breast neratinib experienced diarrhea (grade 3 or greater for 28% of
cancer, but new therapeutic options are necessary patients). Diarrhea was more frequent in the first cycle of therapy
because the disease is essentially incurable in the and was properly managed with loperamide or dose modifica-
metastatic setting and a relevant proportion of patients tions for most patients.7
with early-stage disease still relapse in spite of the use of In view of the lack of demonstration of noninferiority of
currently available therapies.
neratinib versus the standard lapatinib plus capecitabine and to
Neratinib is one of the most promising new drugs for
HER2-positive breast cancer, although the management
prepare the registration trial of neratinib for trastuzumab-
of its main side effect, diarrhea, should be addressed pretreated HER2-positive metastatic breast cancer, a phase
and resolved to allow safe use of the drug. I/II study combining neratinib and capecitabine was con-
Other drugs, such as ONT-380 (an oral, small-molecule, ducted.8 The study was carried out in two parts. The first part
HER2-selective inhibitor) and MM-302 (an anti-HER2 was a dose-escalation trial among 33 patients with advanced
antibody-drug conjugate carrying pegylated liposomal solid tumors; they received oral neratinib once a day contin-
doxorubicin) have shown initial promising activity and uously plus capecitabine twice a day (days 1 to 14 every
good tolerance among patients with HER2-positive 3 weeks) at predefined dose levels, to define the recom-
breast cancer. mended dose/schedule for phase II/III trials. In part two, 72
Interest in the inhibition of downstream signaling of the patients with trastuzumab-pretreated HER2-positive meta-
HER2 pathway with mTOR/phosphoinositide 3-kinase/
static breast cancer received the combination at the recom-
Akt and CDK4/6 inhibitors is currently under clinical
evaluation.
mended dose for phase II trials (240 mg of neratinib per day
Some immunologic approaches (vaccines, alone or in continuously plus 1,500 mg/m2 of capecitabine for 2 weeks
combination with trastuzumab, inhibitors of every 21 days).
immunocheckpoints, and others) are also being tested In part two, the ORR was 64% for patients with no prior
in HER2-positive breast cancer. lapatinib exposure and 57% for patients previously treated with
lapatinib. Median PFS was approximately 9 and 8 months,

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MARTIN AND LOPEZ-TARRUELLA

respectively. The most common side effects of the combination that, in combination with standard therapy, meet a high
were diarrhea (88%) and palmar-plantar erythrodysesthesia Bayesian predictive probability of statistical significance in a
syndrome (48%). This study showed that the combination of future phase III neoadjuvant trial performed among the same
neratinib and capecitabine possesses significant antitumor population. Patients with HER2-positive breast cancer were
activity in trastuzumab-pretreated metastatic HER2-positive randomly assigned to receive 12 weekly administrations of
breast cancer. A randomized registration trial (NALA; paclitaxel plus trastuzumab or paclitaxel plus neratinib, fol-
NCT01808573) comparing neratinib plus capecitabine with lowed by four cycles of doxorubicin hydrochloride plus cy-
lapatinib plus capecitabine is underway. clophosphamide (AC) before surgery. Neratinib met the
A randomized phase II trial (NEFERTT; NCT00915018), predictive probability criterion in the population with HR-
which included 479 patients with HER2-positive breast negative/HER2-positive tumors. A phase III confirmatory trial
cancer without any therapy for metastatic disease, com- with neratinib is planned for patients with HER2-positive breast
pared paclitaxel plus trastuzumab with paclitaxel plus ner- cancer (I-SPY 3, a phase III registration trial).
atinib. No statistically significant differences in PFS (the Neratinib has been evaluated in an adjuvant phase III trial,
primary endpoint) or ORR (one of the trials secondary the ExteNET study. Eligible patients had operable-stage
endpoints) were seen.9 Grade 3 diarrhea was reported for HER2-positive breast cancer with no relapse after surgery,
approximately 30% of patients receiving neratinib plus chemotherapy, and up to 2 years after the completion of
paclitaxel compared with approximately 4% of patients in 1 year of trastuzumab. Patients were randomly assigned to
the paclitaxel plus trastuzumab arm. Central nervous system receive neratinib or placebo for 1 year (together with
(CNS) progression occurred in 8.3% of patients in the ner- hormonal therapy for patients with HR-positive tumors). In
atinib arm versus 17.3% in the trastuzumab arm (RR 0.48; the initial design, the trial had a 90% power to detect a
p = .002). However, the proportion of patients with CNS hazard ratio of 0.7 for invasive disease-free survival (iDFS),
involvement at study initiation was superior in the paclitaxel at a two-sided 5% significance level. The study design suf-
arm (12 patients; 5.1%) compared with the neratinib arm fered from some modifications over time because the drug
(6 patients; 2.5%). owner changed and three different sponsors assumed re-
The significant activity of neratinib observed in metastatic sponsibility. In the initial design, patients who were T$1c
HER2-positive breast cancer has prompted the evaluation of node negative were eligible, a sample size of 3,850 patients
the drug in earlier stages. A phase II trial conducted by the was established, and iDFS was the main endpoint. In view of
NSABP group (NSABP FG-7 Trial) compared weekly paclitaxel the good outcome of node-negative patients with standard
plus neratinib or trastuzumab or the combination of ner- trastuzumab-containing chemotherapy later reported in
atinib and trastuzumab followed by standard doxorubicin other adjuvant trials (particularly the BCIRG 006 study), an
and cyclophosphamide as neoadjuvant therapy among initial amendment restricted recruitment to patients with
126 patients with HER2-positive locally advanced, operable node-positive disease with trastuzumab completion 1 year
breast cancer.10 The proportions of patients with inflam- or earlier before randomization. In October 2011, the new
matory breast cancer (a bad prognostic feature) were 16.7% sponsor introduced two key changes: cessation of enroll-
(neratinib arm) and 9.5% (in both the trastuzumab and the ment (only 2,842 patients of the initially planned of 3,850
trastuzumab plus neratinib arms). The pCR rates (breast plus had been enrolled at that time) and shortening of follow-up
axillary lymph nodes) were 38.1% (trastuzumab arm), 33.3% to 2 years from randomization. In January 2014, a new
(neratinib arm), and 50% (neratinib plus trastuzumab arm). amendment re-established the extension of data collection
The apparent superiority of the combination arm was for disease events and deaths to 5 years postrandomization
mainly attributable to the effect on patients with hormone for consenting patients and the primary endpoint of iDFS at
receptor (HR)negative disease (pCR rates of 57.1%, 46.2%, 2 years of follow-up was resumed. Treatment allocation
and 73.7%, in the trastuzumab, neratinib, and combination remained blinded to the sponsor prior to the first analysis
arms, respectively). For patients with HR-positive disease, and an independent statistical evaluation by a reputed
the pCR rates were not significantly different among arms biostatistician who had access to all data was performed.
(29.6%, 27.6%, and 30.4%, respectively). Grade 3 diarrhea The detailed analyses showed that the results remained
was the most relevant side effect of neratinib (31% in both consistent throughout the trial and were trustable. The
neratinib arms vs. 0% in the trastuzumab arm). Intensive primary analysis was first reported in 201512 and published
primary prophylaxis with loperamide in neratinib-treated in detail in 2016.13 At 2 years from randomization, the hazard
patients implemented at European sites apparently reduced ratio for iDFS in the neratinib group compared with the
the incidence of grade 3 diarrhea (17% in the neratinib placebo group was 0.67 (p = .009), with 2-year iDFS rates of
arm and 24% in the neratinib plus trastuzumab arm across 93.9% and 91.6%, respectively. A preplanned subgroup
all cycles). analysis according to HR status showed that patients
Neratinib has also been evaluated in the I-SPY 2 program, with HR-positive tumors (the majority of whom were re-
a multicenter neoadjuvant trial among women with oper- ceiving concurrent hormonal therapy) obtained the greatest
able breast cancer using adaptive randomization within benefit with neratinib (hazard ratio for iDFS of 0.51, p = .001),
biomarker subtypes to evaluate novel antitumor drugs added whereas patients with HR-negative tumors had little or
to conventional therapy.11 I-SPY 2 intends to identify new drugs no benefit (hazard ratio for iDFS, 0.93; p = .735; interaction

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EMERGING THERAPEUTIC OPTIONS FOR HER2 BREAST CANCER

p = .054). Another preplanned analysis of iDFS for 1,463 the MARIANNE trial, in which T-DM1 plus pertuzumab was not
patients with centrally confirmed HER2-positive disease superior to taxane plus trastuzumab as a first-line treatment for
showed a hazard ratio of 0.51 (95% CI, 0.330.77; p = .002). patients in the metastatic setting.
The 3-year update of the ExteNET trial was recently reported The ADAPT trial19 is a phase II trial that enrolled 375 patients
and confirmed the earlier findings.14 OS data were not with HR-positive, operable, HER2-positive tumors and ran-
mature but will continue to be monitored. domly assigned them to receive neoadjuvant T-DM1, T-DM1
Diarrhea was the most frequent side effect of neratinib in plus endocrine therapy, or trastuzumab plus endocrine therapy
the ExteNET trial and occurred among most patients (grade 2 for 12 weeks prior to surgery. The pathologic complete re-
in 32.5%, grade 3 in 39.8%, and grade 4 in 0.1%). Ustaris sponse rates (breast plus axilla) were 41%, 41.5%, and 15.1%,
et al15 recently reviewed the characteristics and treatment respectively.
of neratinib-induced diarrhea. This side effect usually starts The phase III KATHERINE trial (NCT01772472) compares
during the first month of therapy and resolves or decreases adjuvant trastuzumab versus adjuvant T-DM1 for patients with
later among most patients either spontaneously or with HER2-positive tumors in which the tumor persisted in the
loperamide or dose reductions. Diarrhea is a cause of dose breast or axilla after neoadjuvant chemotherapy plus trastu-
reduction for 10%15% of patients. Permanent discontin- zumab. The KRISTINE trial (TRIO-021; NCT02131064) is an
uation of neratinib because of diarrhea occurs in a minority ongoing phase III trial in which patients are randomly assigned
of patients (0%14% of patients in the reviewed trials) and to neoadjuvant standard docetaxel, carboplatin, trastuzumab,
seems to be reduced by the introduction of early, intense and pertuzumab or to T-DM1 plus pertuzumab, with pCR as the
loperamide prophylaxis. A prospective clinical trial is eval- main endpoint.
uating the efficacy of prophylactic loperamide among pa-
tients with HER2-positive operable breast cancer receiving
extended adjuvant neratinib (NCT02400476). Loperamide is MM-302
administered at a dose of 4 mg three times a day for the first MM-302 is an ADC composed of a HER2-directed antibody
2 weeks of neratinib and 4 mg twice a day until week 8. (lacking anti-HER2 activity) linked to pegylated liposomal
doxorubicin. The antibody acts as a carrier delivering pegylated
liposomal doxorubicin into HER2-positive breast cancer cells.
ONT-380 The drug has been tested in a phase I trial with 69 patients
ONT-380 is an oral, small-molecule, HER2-selective inhibitor in with HER2-positive metastatic breast cancer after a median of
clinical development. It is speculated that the lack of inhibition four prior regimens for metastatic disease. Patients were
of HER1 could translate into a lower frequency of skin and treated with either MM-302 alone, MM-302 plus trastuzumab,
gastrointestinal toxicity with respect to HER2/HER1 dual in- or MM-plus trastuzumab and cyclophosphamide. The most
hibitors (i.e., lapatinib, or neratinib). In fact, a phase I trial with frequent adverse events (. 20% of patients) were con-
ONT-380 as a single agent showed no treatment-related grade stipation, cough, decreased appetite, diarrhea, dyspnea, fa-
3 diarrhea and only minimal skin toxicity. In a phase Ib trial of tigue, nausea, neutropenia, stomatitis, and vomiting. As a
ONT-380 in combination with T-DM1 among patients who single agent, a maximum tolerated dose was not reached at
received prior taxane and trastuzumab treatment, a 41% ORR 50 mg/m2. Cardiotoxicity was seen only among patients with
was reported.16 A second study reported the CNS activity of extensive prior exposure to regular anthracyclines. Antitumor
ONT-380 in combination with either T-DM1 or trastuzumab or activity was observed for 49 patients treated with 30 mg/m2 of
capecitabine. Patients with brain metastases assessable for MM-302 or greater, alone or in combination with trastuzumab,
response were included in the combined analysis. Responses with a response rate of 12% and median PFS of 7.6 months.
and clinical benefit in the CNS were reported with the three Responses were seen for patients pretreated with trastuzu-
combinations tested, supporting future development of the mab, T-DM1, and pertuzumab. The median PFS among the 13
drug for this particular indication.17 patients receiving MM-302 plus trastuzumab and cyclophos-
phamide was 10.6 months.20 In view of these data, a ran-
ANTIBODY-DRUG CONJUGATES domized phase II study (the HERMIONE trial; NCT02213744) is
T-DM1 ongoing. The study includes patients with metastatic HER2-
T-DM1 is the first antibody-drug conjugate (ADC) approved for positive breast cancer who received prior trastuzumab, T-DM1,
metastatic HER2-positive breast cancer for the indication of and pertuzumab treatment (but not anthracyclines in any
patients pretreated with taxanes and trastuzumab.18 The role setting) and randomly assigns patients to receive MM-302 plus
of T-DM1 in earlier stages of the disease is currently under trastuzumab or trastuzumab plus a single chemotherapy agent
evaluation. The KAITLIN trial (NCT01966471) is an adjuvant at the physicians choice.
study in operable HER2-positive breast cancer. After surgery,
patients are randomly assigned to receive four cycles of INHIBITORS OF DOWNSTREAM SIGNALING
anthracycline-containing chemotherapy followed by combi- PATHWAYS
nation treatment with taxane, trastuzumab, and pertuzumab mTOR/Phosphoinositide 3-Kinase/Akt Inhibitors
or with T-DM1 and pertuzumab. The study enrollment has The mTOR/phosphoinositide 3-kinase (PI3K)/Akt pathway
stopped and the protocol was amended in view of the results of plays an important role in the downstream signaling of

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MARTIN AND LOPEZ-TARRUELLA

the HER2 pathway and is a potential target for combined study is exploring the combination of palbociclib and T-DM1
therapies.21 The BOLERO 3 trial studied adding the mTOR in metastatic HER2-positive breast cancer after prior tras-
inhibitor everolimus to conventional chemotherapy tuzumab or other HER2-directed therapies (NCT01976169).
(vinorelbine-trastuzumab) among patients with metastatic The PATRICIA trial (NCT02448420) is a phase II study of
HER2-positive breast cancer who were pretreated with palbociclib and trastuzumab with or without letrozole among
trastuzumab and taxanes. The addition of everolimus sig- patients with HER2-positive metastatic breast cancer who
nificantly improved PFS compared with vinorelbine- have received chemotherapy and treatment with trastu-
trastuzumab alone.22 The BOLERO 3 trial provided the zumab for their metastatic disease.
proof of principle that the blockade of mTOR can play a role Abemaciclib, another CDK4/6, has been safely combined
in the management of HER2-positive breast cancer; how- with trastuzumab in a phase Ib study (NCT02057133). Di-
ever, the significant increase in toxicity associated with arrhea was a dose-limiting toxicity. The recommended dose
everolimus administration makes this combination un- for further studies is 150 mg/12 hours.28
attractive. The BOLERO 1 trial, a first-line study comparing
paclitaxel plus trastuzumab with or without everolimus, VACCINES AND OTHER FORMS OF
failed to show any significant advantage in PFS with ever- IMMUNOTHERAPY
olimus in the overall group of 719 patients. However, the HR- Tumor Vaccines
negative subpopulation obtained an apparent benefit with This strategy aims to amplify the patients immune response
the addition of everolimus (median PFS of 20.27 months vs. against HER2-positive breast cancer. The majority of breast
13.08 months with placebo, p = .0049), although the pre- cancer vaccine trials were initially performed in advanced
planned protocol-specified significance threshold (p = .0044) stages of the disease and the results were somewhat dis-
was not crossed.23 Slamon et al24 used next-generation appointing.29 The high genomic instability and the loss of
sequencing (NGS) and immunohistochemistry (IHC) to es- antigens,30 together with defects in the antitumor immune
tablish the status of the PI3K pathway in tumor samples response (T-cell activation/function and regulation) found in
(mainly primary tumors) from patients from the BOLERO metastatic breast cancer, can explain these negative results.
1 and 3 trials. Exons of 282 cancer-related genes were an- Afterward, the cornerstones of clinical development of
alyzed by NGS, whereas PTEN (phosphatase and tensin cancer vaccines were redefined,31 emphasizing the need for
homolog) levels were determined by IHC. Patients with low selecting an appropriate clinical context; herein, early or
PTEN or known PIK3CA or AKT1 E17K mutations were minimal residual disease stages were proposed as more
considered to have PI3K pathway activation. Patients with suitable scenarios to be explored. Several vaccine formu-
PI3K pathway hyperactivity showed a significantly better PFS lations have been tested among patients with HER2-positive
with exemestane, but the remaining patients did not.24 The breast cancer.32
role of everolimus in the routine therapy of metastatic HER2- Peptide-based vaccines use antigen epitopes of cancer
positive breast cancer is therefore currently undefined. cells combined with different adjuvants to elicit immune
Clinical trials of PI3K pathway inhibitors (both pan-class responses. The main advantages of this approach include
I and alpha-specific inhibitors) for the treatment of meta- their easy manufacture at low cost, storage stability, safety,
static HER2-positive breast cancer are underway. In a phase and measurable antigen-specific immune response in the
Ib trial of buparlisib plus trastuzumab for patients with HER2- blood (direct monitoring of T-cell response).33
positive metastatic breast cancer that progressed while they E75 is an immunogenic peptide derived from the extra-
were taking trastuzumab, the combination was well toler- cellular domain of HER2. Small-size phase I trials tested E75
ated and showed some activity; at the recommended dose with different immune-adjuvants in metastatic breast and
for phase II trials, there were two partial responses (17%) ovarian cancer, demonstrating that the peptide was able to
and seven disease stabilizations of 6 weeks or longer induce specific cytotoxic T-lymphocyte responses with a
(58%).25 Several studies are testing the activity of other favorable safety profile. However, no meaningful antitumor
PI3K inhibitors, including alpelisib (NCT02038010), taselisib activity was seen. Because the metastatic studies showed
(NCT02390427), and pictilisib (NCT00960960). that this active immunization could last several years after
the vaccination process, the vaccine was later tested in the
adjuvant setting. E75, in combination with granulocyte-
CDK4/6 Inhibitors macrophage colony-stimulating factor (GM-CSF), was eval-
CDK4/6 controls a key pathway downstream of HER2. The uated in a small randomized trial of patients with high-risk
activated cyclin DCDK4/6 heterodimer promotes cell cycle breast cancer with any level of HER2 and HLA-A2+, dem-
progression. Deregulation of cell cycle control is not un- onstrating its safety and effectiveness in eliciting immune
common in estrogen receptorpositive and HER2-positive response in vivo in node-positive breast cancer. Recurrence
breast cancer; therefore, inhibition of CDK4/6 could be a rates were lower in the vaccination arm (21% in the ob-
way to augment the effectiveness of standard anti-HER2 servation group vs. 8% in the vaccine group at a median
therapies. 22 months of follow-up).34 The final results of the phase I/II
Palbociclib, a CDK4/6 inhibitor, is synergistic with trastuzumab clinical trial of E75 among 195 patients with early breast
and T-DM1 in HER2-positive preclinical models.26,27 A phase Ib cancer were recently reported with a 60-month follow-up

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EMERGING THERAPEUTIC OPTIONS FOR HER2 BREAST CANCER

time. A nonstatistically significant difference in 5-year autologous or from cell-line cultures), and dendritic cell
disease-free survival (DFS) in favor of the vaccine group was vaccines.36,37
reported (89.7% vs. 80.2%, p = .08). A phase III clinical trial The synergy of trastuzumab and vaccines was explored in a
with E75 is currently ongoing (NCT01479244). phase I/II trial obtaining prolonged and robust T-cell re-
GP2 is a peptide from the transmembrane HER2 protein sponses with very low toxicity.38 Ongoing trials are even
domain found to be able to stimulate CD8 lymphocytes to considering the addition of chemotherapy to vaccine/
destroy HER2-overexpressing cells. The preliminary results antibody combinations (NCT00266110). A further step in
of a phase II trial among patients with HLA-A2+ with any level the HER2 vaccination field is the generation of HER2 vaccine-
of expression of HER2 were recently reported.35 The com- primed autologous T cells for therapeutic infusion reported
bination of GP2 plus GM-CSF was compared with GM-CSF to be feasible and well tolerated in early phase I trials.39
alone in patients with breast cancer whose tumors had
diverse expression of HER2. The treatment was well toler-
ated. In the subset of patients with HER2-overexpressing Immune Checkpoint Inhibitors
tumors treated with trastuzumab, the combination of GP2 The clinical testing of immune checkpoint inhibitors in breast
vaccine plus GM-CSF was associated with a numerically cancer, initially focused on triple-negative breast cancer, has
superior DFS (94% vs. 89% in the GM-CSF group, p = .86). recently been extended to the HER2-positive subtype.
Other immunogenic approaches are also under clinical PANACEA (NCT02129556) is a phase IB/II trial evaluating the
testing, including peptides derived from the HER2 intracellular efficacy of pembrolizumab and trastuzumab in trastuzumab-
domain, DNA-based and whole tumor cell vaccines (either resistant metastatic breast cancer.

References
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Eur J Cancer. 2013;49:3763-3772. 14-20.
8. Saura C, Garcia-Saenz JA, Xu B, et al. Safety and efficacy of neratinib in 17. Murthy RK, Hamilton E, Borges VF, et al. ONT-380 in the treatment of
combination with capecitabine in patients with metastatic human HER2+ breast cancer central nervous system (CNS) metastases (mets).
epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. Presented at: San Antonio Breast Cancer Symposium. San Antonio, TX;
2014;32:3626-3633. 2015. Abstract P4-14-19.
9. Awada A, Colomer R, Bondarenko I, et al. Efficacy and CNS progression 18. Krop IE, Kim SB, Gonza lez-Martn A, et al; TH3RESA Study Collab-
analysis from the randomized phase 2 trial of neratinib + paclitaxel vs orators. Trastuzumab emtansine versus treatment of physicians
trastuzumab + paclitaxel as first-line treatment for HER2+ MBC choice for pretreated HER2-positive advanced breast cancer
(NEfERTT). J Clin Oncol. 2015;33 (suppl; abstr 610). (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol.
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20. LoRusso P, Krop I, Miller K, et al. A phase I study of MM-302, a HER2- 29. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving
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73:3817-3820. 31. Hoos A, Parmiani G, Hege K, et al; Cancer Vaccine Clinical Trial Working
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(BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 32. Milani A, Sangiolo D, Montemurro F, et al. Active immunotherapy in
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trastuzumab plus paclitaxel as first-line treatment for patients with 33. Clifton GT, Mittendorf EA, Peoples GE. Adjuvant HER2/neu peptide
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mised, double-blind, multicentre trial. Lancet Oncol. 2015;16:816-829. 34. Peoples GE, Gurney JM, Hueman MT, et al. Clinical trial results of a
24. Slamon DJ, Hurvitz SA, Chen D, et al. Predictive biomarkers of ever- HER2/neu (E75) vaccine to prevent recurrence in high-risk breast cancer
olimus efficacy in HER2+ advanced breast cancer: combined exploratory patients. J Clin Oncol. 2005;23:7536-7545.
analysis from BOLERO-1 and BOLERO-3. J Clin Oncol. 2015;33 (suppl; 35. Schneble EJ, Perez SA, Murray JL, et al. Primary analysis of the pro-
abstr 512). spective, randomized, phase II trial of GP2+GMCSF vaccine versus GM-
25. Saura C, Bendell J, Jerusalem G, et al. Phase Ib study of buparlisib plus CSF alone administered in the adjuvant setting to high-risk breast
trastuzumab in patients with HER2-positive advanced or metastatic cancer patients. J Clin Oncol. 2014;32 (suppl 26; abstr 134).
breast cancer that has progressed on tsrastuzumab-based therapy. Clin 36. Disis ML, Schiffman K, Guthrie K, et al. Effect of dose on immune re-
Cancer Res. 2014;20:1935-1945. sponse in patients vaccinated with an HER-2/neu intracellular domain
26. Cadoo KA, Gucalp A, Traina TA. Palbociclib: an evidence-based review of proteinbased vaccine. J Clin Oncol. 2004;22:1916-1925.
its potential in the treatment of breast cancer. Breast Cancer (Dove Med 37. Morse MA, Hobeika A, Osada T, et al. Long term disease-free survival
Press). 2014;6:123-122. and T cell and antibody responses in women with high-risk Her2+ breast
27. Knudsen E, Cox D, Franco J, et al. Targeting CDK4/6 in HER2 positive cancer following vaccination against Her2. J Transl Med. 2007;5:42.
breast cancer: therapeutic effect, markers, and combination strategies. 38. Disis ML, Wallace DR, Gooley TA, et al. Concurrent trastuzumab and
Ann Oncol. 2014;25(suppl 1):i21-i22. HER2/neu-specific vaccination in patients with metastatic breast can-
28. Goetz MP, Beeram M, Beck T, et al. Abemaciclib, an inhibitor of CDK4 cer. J Clin Oncol. 2009;27:4685-4692.
and CDK6, combined with endocrine and HER2-targeted therapies for 39. Disis ML, Dang Y, Coveler AL, et al. HER-2/neu vaccine-primed autol-
women with metastatic breast cancer. Presented at: San Antonio Breast ogous T-cell infusions for the treatment of advanced stage HER-2/neu
Cancer Symposium. San Antonio, TX; 2015. Abstract P4-13-25. expressing cancers. Cancer Immunol Immunother. 2014;63:101-109.

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CANCER PREVENTION, HEREDITARY GENETICS,
AND EPIDEMIOLOGY

Controversies in Genetic
Evaluation

CHAIR
Noah D. Kauff, MD
Memorial Sloan Kettering Cancer Center
New York, NY

SPEAKERS
Claudine Isaacs, MD, FRCPC
Georgetown Lombardi Comprehensive Cancer Center
Washington, DC

Victoria Raymond, MS, CGC


University of Michigan Medical School
Ann Arbor, MI
LYNCE AND ISAACS

How Far Do We Go With Genetic Evaluation? Gene, Panel, and


Tumor Testing
Filipa Lynce, MD, and Claudine Isaacs, MD, FRCPC

OVERVIEW

The traditional model by which an individual was identified as harboring a hereditary susceptibility to cancer was to test for a mutation
in a single gene or a finite number of genes associated with a particular syndrome (e.g., BRCA1 and BRCA2 for hereditary breast and
ovarian cancer or mismatch repair genes for Lynch syndrome). The decision regarding which gene or genes to test for was based on
a review of the patients personal medical history and their family history. With advances in next-generation DNA sequencing
technology, offering simultaneous testing for multiple genes associated with a hereditary susceptibility to cancer is now possible.
These panels typically include high-penetrance genes, but they also often include moderate- and low-penetrance genes. A number of
the genes included in these panels have not been fully characterized either in terms of their cancer risks or their management options.
Another way some patients are unexpectedly identified as carrying a germline mutation in a cancer susceptibility gene is at the time
they undergo molecular profiling of their tumor, which typically has been carried out to guide treatment choices for their cancer. This
article first focuses on the issues that need to be considered when deciding between recommending more targeted testing of a single
or a small number of genes associated with a particular syndrome (single/limited gene testing) versus performing a multigene panel.
This article also reviews the issues regarding germline risk that occur within the setting of ordering molecular profiling of tumors.

T hroughout the past several decades, we have witnessed


tremendous advances in our knowledge of evaluating
and treating patients with germline mutations in hereditary
supported by the recent American Society of Clinical Oncology
(ASCO) policy statement on testing for genetic and genomic
cancer susceptibility,5 a number of criteria must be considered
cancer syndromes, with studies clearly demonstrating the when evaluating existing or emerging genetic tests. These cri-
feasibility and clinical utility of genetic testing. Perhaps most teria include analytical and clinical validity, clinical utility, and
importantly, studies have provided convincing evidence the associated ethical, legal, and social issues. In the context of
that implementing prevention strategies in some instances genetic testing, analytic validity refers to the accuracy and re-
prolongs the survival of mutation carriers. For example, for producibility by which the assay detects the presence or absence
unaffected women who carry a BRCA1 or BRCA2 mutation, of a mutation. Clinical validity focuses on whether the test ac-
risk-reducing salpingo-oophorectomy results in a significant curately and reproducibly predicts the clinically defined disorder.
reduction in all-cause mortality (3% vs. 10%; hazard ratio Clinical utility can be defined as the evidence that a genetic test
[HR] 0.40; 95% CI, 0.260.6), breast cancer-specific mor- results in improved health outcomes typically based on early
tality (2% vs. 6%; HR 0.44; 95% CI, 0.260.76) and ovarian detection or prevention strategies, and the tests usefulness
cancerspecific mortality (0.4 vs. 3%; HR 0.21; 95% CI, and added value to patient management decision making. For
0.060.8) when compared with carriers who chose not to genetic testing, particularly for moderate-penetrance genes,
clinical utility remains the fundamental issue.5 The EGAPP
undergo this procedure.1 Additionally, Markov modeling sug-
framework is key when evaluating the utility of genetic testing
gests that a 30-year old healthy BRCA1 mutation carrier
for hereditary cancer syndromes. Failure to meet some of
would gain 0.2 to 1.8 years in life expectancy with risk-
these criteria forms the basis for many concerns regarding the
reducing salpingo-oophorectomy and 0.6 to 2.1 years from
current clinical actionability of multigene panel testing.
risk-reducing mastectomies.2,3 Given these findings, genetic
testing for hereditary cancer syndromes has now become part
of standard practice. SINGLE/LIMITED GENE TESTING
As set forth in the Evaluation of Genomic Applications in For well over a century, it has been recognized that some
Practice and Prevention (known as EGAPP) initiative4 and further families harbor a hereditary predisposition to a variety of

From the Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC; Lombardi Comprehensive Cancer Center, Georgetown University,
Washington, DC.

Disclosures of potential conflicts of interest provided by the authors are available with the online article at asco.org/edbook.

Corresponding author: Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center, 3800 Reservoir Rd. NW, Washington, DC 20057; email: isaacsc@georgetown.edu.

2016 by American Society of Clinical Oncology.

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SINGLE GENE VERSUS MULTIGENE PANEL TESTING FOR HEREDITARY CANCER

malignancies. In 1913, Warthin described a kindred known with rare high-penetrance syndromes or a more moderate
as Family G, in which he noted an aggregation of endometrial penetrance were identified.
carcinoma along with gastric and colorectal cancer.6 This Based on these findings, the general paradigm of testing
family, among others, formed the basis of the initial evolved whereby the more common genes such as BRCA1
descriptions of hereditary nonpolyposis colorectal cancer and BRCA2 were tested first, and, if negative, sequential
syndrome, now more commonly known as Lynch syn- testing for additional gene(s) was performed if the patient
drome. Similarly, astute clinicians recognized other hered- met criteria for testing for other syndromes. This process
itary cancer syndromes such as Li-Fraumeni and Cowden had both advantages and disadvantages. In terms of ad-
syndromes and hereditary breast and ovarian cancer based vantages, the genes tested in this setting typically have
on the cancer phenotype of the family.7-12 By the mid-1990s, well-described cancer risks and often have established
linkage analyses and other studies resulted in the abil- management guidelines. Additionally, through the pretest
ity to pinpoint individual genes associated with some of counseling process, patients undergoing this testing have
these hereditary cancer syndromes.13,14 These included the had the opportunity to fully consider the benefits, risks, and
identification of BRCA1 and BRCA2 associated with hered- limitations of testing in their particular situation. In terms
itary breast and ovarian cancer; MLH1, MSH2, MSH6, PMS2, of disadvantages, such testing is less comprehensive than
and more recently EPCAM associated with Lynch syndrome; multigene testing, and, if performed, sequential testing is
FAP with familial adenomatous polyposis; and TP53 with quite time-consuming and costly.
Li-Fraumeni syndrome.
However, it became apparent that many families with
striking histories consistent with either a hereditary colo- MULTIGENE PANELS
rectal or breast/ovarian cancer syndrome are not found to There has been a dramatic shift in the genetic testing
carry a mutation in one of the mismatch repair genes as- landscape over the past several years in large part because of
sociated with Lynch syndrome or in BRCA1/2. For example, two major factors. The first is the development of next-
studies indicate that a mutation in a mismatch repair gene is generation sequencing, a high-throughput approach to DNA
found in approximately 40% to 80% of families that meet sequencing that allows for massively parallel sequencing of
the Amsterdam I criteria and only about 5% to 50% of multiple genes more efficiently and at a lower cost than the
families meeting the Amsterdam II criteria.15 Similarly, only traditional Sanger sequencing methods. The second is the
about 5% to 10% of unselected patients with breast cancer16 Supreme Court decision in 2013 for Association for Mol-
and 20% to 25% of patients with hereditary breast cancer17 ecular Pathology v. Myriad Genetics, which invalidated many
are found to carry a deleterious BRCA1 or BRCA2 mutation. patents restricting BRCA1/2 testing. Very shortly after the
Additionally, a number of other genes associated either ruling, many companies and some academic institutions
announced they would offer BRCA testing in addition to the
existing genes on their multigene panels.18,19 As a result of
these two factors, offering relatively rapid turnaround times
for multigene testing in a reasonably affordable manner
KEY POINTS became feasible.
The panels differ from company to company. They may
Advances in technology have resulted in the ability to be comprehensive, tumor-specific, and focus only on highly
test for multiple genes associated with a hereditary penetrant genes, or be customizable (Table 1). The price of
predisposition to cancer.
testing also has dropped significantly. It now can range from
Multigene panel testing can allow for a more
comprehensive and efficient approach to testing, but
$249 to $6,040, with most costing $1,500 to $6,040. The cost
many of the genes included in multigene panels have varies among laboratories and differs based on the number
not been fully characterized either in terms of their of genes included. In most cases, the cost of multigene panel
cancer risks or management strategies. In many cases, testing does not significantly differ from the cost of more
single/limited gene testing remains a very appropriate single/limited gene testing. Furthermore, the cost of testing
testing option. likely will continue to diminish over time. Adding to the
The decision to pursue single or limited gene testing is complexity of testing choices is that insurance companies
complex and referral to clinicians with expertise in have different policies and may cover some but not all
cancer genetics is critical. Testing must be carried out choices.
with pre- and post-test genetic counseling. A number of studies have evaluated the utility and impact
In the tumor molecular profiling setting, secondary
of multigene testing in a variety of settings. The key ques-
incidental germline mutations may be detected. ASCO
recommends that the possibility of identifying
tions that must be addressed revolve around the clinical
secondary incidental germline information and the utility or actionability of the findings from such testing,
clinical relevance, benefits, risks, and limitations of such namely (1) the numbers of patients who are found to have a
findings be discussed with all patients before they deleterious mutation in a gene for which cancer risks are
undergo tumor sequencing. known and management strategies exist, (2) patients who
are found to have a mutation with uncertain cancer risks

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LYNCE AND ISAACS

TABLE 1. Examples of Genes Included on Some Next-Generation Sequencing Cancer Panels*


Number
Company Test of Genes Genes Included
20
Comprehensive Ambry Genetics CancerNext 32 APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4,
Panels CDKN2A, CHEK2, EPCAM, GREM1, MLH1, MRE11A, MSH2, MSH6,
MUTYH, NBN, NF1, PALB2, PMS2, POLD1, POLE, PTEN, RAD50,
RAD51C, RAD51D, SMAD4, SMARCA4, STK11, TP53
GeneDx OncoGene Dx Compre- 32 APC, ATM, AXIN2, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1,
hensive Cancer Panel21 CDK4, CDKN2A, CHEK2, EPCAM, FANCC, MLH1, MSH2, MSH6,
MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D,
SCG5/GREM1, SMAD4, STK11, TP53, VHL, XRCC2
Myriad Genetics MyRisk22 25 BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH,
CDKN2A, CDK4, TP53, PTEN, STK11, CDH1, BMPR1A, SMAD4, PALB2,
CHEK2, ATM, NBM, BARD1, BRIP1, RAD51C, RAD51D
Invitae Invitae Multi-Cancer 79 ALK, APC, ATM, AXIN2, BAP1, BARD1, BLM, BMPR1A, BRCA1, BRCA2,
Panel23 BRIP1, CASR,CDC73, CDH1, CDK4, CDKN1B, CDKN1C, CDKN2A,
CEBPA, CHEK2, DICER1, DIS3L2, EGFR, EPCAM, FH, FLCN, GATA2,
GPC3, GREM1, HOXB13, HRAS, KIT, MAX, MEN1, MET, MITF, MLH1,
MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2,PDGFRA, PHOX2B,
PMS2, POLD1, POLE, PRKAR1A, PTCH1, PTEN, RAD50,RAD51C,
RAD51D, RB1, RECQL4, RET, RUNX1, SDHA, SDHAF2, SDHB, SDHC,
SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TERC,
TERT, TMEM127, TP53, TSC1, TSC2, VHL, WRN, WT1
Breast/Ovarian Ambry Genetics BRCAplus24 6 BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53
Panels
BreastNext25 17 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MRE11A, MUTYH,
NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, TP53
OvaNext26 23 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1,
MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN,
RAD50, RAD51C, RAD51D, SMARCA4, STK11, TP53
Invitae Breast and Gynecologic 14 ATM, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6,
Cancers Guidelines PALB2, PMS2,PTEN, STK11, TP53
Based Panel27
Breast Cancer Guidelines 9 ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53
Based Panel28
Color Color 19 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MHL1,
Genomics29 MSH2, MSH6, NBM, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11,
TP53
GeneDx Breast Cancer High/Mod- 9 ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53
erate Risk Panel21
Breast/Ovarian Cancer 21 ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FANCC,
Panel21 MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D,
STK11, TP53, XRCC2
Gastrointestinal Ambry Genetics ColoNext30 17 APC, BMPR1A, CDH1, CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH6,
Panels MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4, STK11, TP53
Invitae Colorectal Cancer Guide- 12 APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN,
lines Based Panel31 SMAD4, STK11, TP53
Myriad Genetics COLARIS32 6 MLH1, MSH2, EPCAM, MSH6, PMS2, MUTYH
COLARIS AP33 APC, MUTYH
GeneDx Colorectal Cancer Panel21 19 APC, ATM, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2,
MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SCG5/GREM1, SMAD4,
STK11, TP53
Lynch/Colorectal High Risk 7 APC, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2
Panel21
Abbreviation: VUS, variants of uncertain significance.
*Current as of February 2, 2016.

and/or no evidence-based recommendations for manage- future because of the rapid accumulation of data from
ment, and (3) the rate detection of variants of uncertain multigene panel testing.
significance (VUS). As summarized in Tables 2 and 3, the rate Given the high rate of VUS and the detection of genes for
of VUS varies between 3.3% and 42%, and many patients which the cancer risks are not well-defined, several regis-
were reported to have two or more VUS. The VUS rate is still tries have been created to catalog and curate these vari-
high in some reports, but it is expected to fall in the near ants with the goal of advancing our knowledge about their

e74 2016 ASCO EDUCATIONAL BOOK | asco.org/edbook


SINGLE GENE VERSUS MULTIGENE PANEL TESTING FOR HEREDITARY CANCER

TABLE 2. Rate of Deleterious Mutations and VUS Reported in Multigene Testing Associated with Hereditary Breast
Cancer

BRCA Mutations Non-BRCA Mutations


Publication No. of Participants Panel Tested Detected (%) Detected (%) VUS Rate (%)
38
Kapoor et al 337 Ambry Genetics; different 3.6% 3.9%; gene mutations more often 3.3% BRCA1/2 and
panel types and genes detected: PALB2, CHEK2, ATM 13.4% non-BRCA1/2
tested
Slavin et al39 348 Not provided 3.4% 16.4% 42%
40
Tung et al 2,158 Cohort 1: Referred for 9.3% 4.2% 41.7%
commercial BRCA1/2
gene testing and
Cohort 2: Previously 3.7% 41.6%
tested negative for
BRCA1/2 mutations
Chong et al41 3,000 BRCAPlus: 6-gene panel 4.6% 1% 7.6%
(BRCA1, BRCA2, TP53,
CDH1, PTEN, SKT11)
Kurian et al42 198 (57 BRCA1/2, Invitae 11.4% 2.1% VUS/average per
141 BRCA1/2 neg) participant
LaDuca et al43 2,079 (874 had Ambry Genetics All previously underwent 7.4% gene mutations detected: 19.8%
breast panel) BRCA sequencing and CHEK2 (19), ATM (18), PALB2
BART testing and were (15), TP53 (4), PTEN (3), RAD50
negative (3), RAD51C (2), BRIP1 (1),
MRE11A (1), NBN (1)
Abbreviation: VUS, variants of uncertain significance.

clinical utility. The Prospective Registry of Multiplex Testing syndrome versus multigene panel testing. These include
(PROMPT)34 is a multi-institutional online registry that en- (1) the characteristics of the probands personal and family
courages patients to self-enter information about their history, (2) an individuals preferences and tolerance re-
genetic testing results and to complete questionnaires about garding the possibility of ambiguous results, (3) insurance-
their personal medical and family histories. Others involved related issues, and (4) the rapidity with which results are
in reclassifying variants include ENIGMA (Evidence-based