American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) Guideline Recommendations for Immunohistochemical Testing of Estrogen

/Progesterone Receptors in Breast Cancer
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

INTRODUCTION
‡ ASCO and the College of American Pathologists (CAP) previously collaborated on a guideline on HER2 testing, published in 2007 ‡ Subject: Estrogen (ER) and Progesterone (PgR) testing ‡ Rationale: Evidence of wide variability in test performance and inaccurate results ‡ ASCO and CAP decided to produce the first ever evidence-based ER-PgR testing guideline, based on a systematic review
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Background
‡ Hormone receptor-positive is the most common breast cancer phenotype worldwide ‡ Access to accurate and reliable ER/PgR testing and to established and relatively affordable endocrine therapies could have a profound impact on breast cancer outcomes in high and low/middle income countries across the globe

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Guideline Methodology: Systematic Review
‡ ASCO and Cancer Care Ontario jointly conducted a systematic review of the medical literature available from 1990-May 2008
± Ovid (Medline) ± EMBASE ± Cochrane Database of Systematic Reviews

‡ Primary outcome: correlation of hormone receptor status and outcome of endocrine treatment ‡ ASCO/CAP Expert Panel made recommendations based on this review
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Clinical Questions
1. What is the optimal testing algorithm for testing ER and PgR status? 1.1 What are the clinically validated methods that can be used in this assessment? 2. What strategies can ensure optimal performance, interpretation, and reporting of established assays? 2.1 What are the preanalytic, analytic and postanalytic variables that must be controlled to ensure that assay results reflect tumor ER and PgR status?
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Clinical Questions, cont¶d
2.2. What is the optimal internal quality management regimen to ensure ongoing accuracy of ER and PgR testing? 2.3. What is the regulatory framework that permits application of external controls such as proficiency testing and on-site inspection? 2.4. How can internal and external control efforts be implemented and their effects measured?

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Special Questions
1. Should ER/PgR be done in DCIS or recurrent tumor? 2. Does PgR influence the choice of endocrine therapy?

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Recommendations
Clinical Question 1. What is the optimal testing algorithm for testing ER and PgR status?

Optimal algorithm for ER/PgR testing
‡ Positive - if finding of • 1% of tumor cell nuclei are immunoreactive ‡ Negative - if finding of < 1% of tumors¶ cell nuclei are immunoreactive in the presence of evidence that the sample can express ER or PgR (positive intrinsic controls are seen) ‡ Uninterpretable - finding that no tumor nuclei are immunoreactive and that internal epithelial elements present in the sample or separately submitted from the same sample lack any nuclear staining
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Recommendations
Clinical Question 2. What strategies can ensure optimal performance, interpretation, and reporting of established assays? Clinical Question 2.1 What are the preanalytic, analytic, and postanalytic variables that must be controlled to ensure that assay results reflect tumor ER and PgR status?

Optimal testing conditions ‡ Large, preferably multiple core biopsies of tumor are preferred for testing if they are representative of the tumor (grade and type) at resection ‡ Interpretation follows guideline recommendation ‡ Accession slip and report must include guidelinedetailed elements
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Required reporting elements
1. Percent/proportion of tumor cells staining positively. Percentage either by:
1. Estimation 2. Quantitation (counting cells or image analysis) 3. If cytology specimen, count •100 cells

2. Intensity of staining ± weak, moderate, or strong ± representing an estimate of average of intensity of positive cells relative to positive controls on same batch 3. Interpretation of the assay (+, -, or
uninterpretable)
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Two optional report elements are recommended
1. If negative ER and PgR interpretations when the histopathology of the tumor is almost always associated with ER+ and PgR+ results, including: tubular, lobular, and mucinous histological types or Nottingham grade 1 tumors Then an optional cautionary statement should indicate that while the patient¶s tumor tested as ER-negative, tumors with the same histological type or Nottingham grade almost always test +
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Optional report elements, cont¶d
2. -Pathologist may also provide a composite score e.g. the H score, Allred score, or Quick score -Using the percent and intensity measurements provided -Since each of these is somewhat differently calculated and may lead to confusion across institutions -Scoring is not required
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Recommendations
Clinical Question 2.1 What are the preanalytic, analytic, and postanalytic variables that must be controlled to ensure that assay results reflect tumor ER and PgR status?

Optimal tissue handling requirements ‡ Time from tissue acquisition to start of fixation process should be as short as possible ‡ Samples for ER and PgR testing are fixed in 10% neutral buffered formalin (NBF) for 6-72 hours ‡ Samples should be sliced at 5 mm intervals after appropriate gross inspection and margins designation and placed in sufficient volume of NBF formalin of a sufficient volume to allow adequate tissue penetration
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Recommendations- Optimal tissue
handling requirements, cont¶d

‡ If tumor comes from remote location, it should be bisected on removal and sent to the laboratory immersed in a sufficient volume of NBF ‡ Cold ischemia time, fixative type, and time sample placed in NBF must be recorded

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Recommendations-Optimal tissue
handling requirements, cont¶d

‡ Storage of unstained slides for more than 6 weeks prior to analysis is not recommended ‡ Time tissue is removed from patient, time tissue is placed in fixative (cold ischemia time), duration of fixation, and fixative type must be recorded and noted on accession slip or in report

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Additional information in re: Clinical Question 2.1
Standardization of Analytical Variables
Antibody Selection ‡Antibodies should have well-established specificity and sensitivity and have been clinically validated (good correlation with patient outcomes) ‡Alternatively, results of lab-selected antibodies should be •90% concordant with clinically validated antibodies for ER and PgR-positive category and •95% concordant with clinically validated antibodies for ER or PgR negative category ‡Include: ER: 1D5, 6F11, SP1, 1D5; PgR: 1294, 312
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Recommendations
Clinical Question 1.1 What are the clinically validated methods that can be used in this assessment?

Optimal internal validation procedure ‡ Validation of any test must be done before test is offered ‡ Validation must be done using a clinically validated ER or PgR test method ‡ Revalidation should be done whenever there is a significant change to the test system, such as a change in the primary antibody clone or introduction of new antigen retrieval or detection systems.
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Recommendations quality management regimen Clinical Question 2.3. What is the optimal internal
to ensure ongoing accuracy of ER and PgR testing?

Optimal internal QA procedures ‡ Initial test validation ‡ Ongoing quality control and equipment maintenance ‡ Initial and ongoing laboratory personnel training and competency assessment ‡ Use of standardized operating procedures including routine use of external control materials with each batch of testing and routine evaluation of internal normal epithelial elements or the inclusion of normal breast sections on each tested slide, wherever possible. ‡ Regular, ongoing assay reassessment should be done at least semiannually. Revalidation is needed whenever there is a significant change to the test system. ‡ Ongoing competency assessment and education of pathologists
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Recommendations
Clinical Question 2.4. What is the regulatory framework that permits application of external controls such as proficiency testing and on-site inspection? Clinical Question 2.5. How can internal and external control efforts be implemented and their effects measured?

Optimal external proficiency assessment ‡ Mandatory participation in external proficiency testing program with at least two testing events (mailings)/year ‡ Satisfactory performance requires at least 90% correct responses on graded challenges for either test ‡ Unsatisfactory performance will require laboratory to respond according to accreditation agency program requirements
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Recommendations
Optimal laboratory accreditation ‡ On-site inspection every other year with annual requirement for self-inspection ‡ Reviews laboratory validation, procedures, QA results and processes, results and reports ‡ Unsuccessful performance results in suspension of laboratory testing for ER or PgR

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Special Questions
1. Should ER/PgR be done in DCIS or recurrent tumor?
‡ER and PgR status should be determined on all newly diagnosed invasive breast cancers (primary and/or metastatic site) ‡Lack of validation studies on testing for people with DCIS. Panel saw value, but could not make formal recommendation. ‡Women with breast recurrences accessible to biopsy should also always be tested
± To check prior negative results not false negative ± To check specimen for emergence of negative clones
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Special Questions
2. Does PgR correlate with or influence the choice of endocrine therapy?
‡The precise role of PgR in patient management has not been strongly established ‡Do not withhold endocrine treatment from women w/ ER-rich, PgR poor tumor ‡Women w/ ER-/PgR+ tumors may respond to endocrine therapy

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

How can these efforts be implemented and the effects measured?
‡ Educational opportunities from ASCO and CAP ‡ CAP certification program for pathologists ‡ Coordination of recommendations with NCCN, Commission of Cancer of the American College of Surgeons, the American Joint Committee on Cancer, and patient advocacy groups ‡ CAP will:
± Review and publish results of proficiency testing and laboratory accreditation ± Inclusion of quality monitoring activities on ER/PgR testing in ongoing quality assessment programs
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Guideline Methodology: Panel Members
Panel Member
M. Elizabeth H. Hammond, MD, Co-Chair* Daniel F. Hayes, MD, Co-Chair* Mitch Dowsett, PhD*

Institution
Intermountain Health Care, University of Utah School of Medicine, UT University of Michigan Comprehensive Cancer Center, University of Michigan Health and Health System, MI Royal Marsden Hospital, UK Washington University School of Medicine , St. Louis,

D. Craig Allred, MD* MO Jared N. Schwartz, MD, PhD, FACP, Co-Chair* Antonio C. Wolff, MD, FACP, Co-Chair* Sunil Badve, MD Robert L. Becker, MD, Ex-Officio Patrick L. Fitzgibbons, MD, FACP Glenn Francis, MBBS, FRCPA, MBA
*Steering Committee Member www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Presbyterian Hospital, NC The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, MD ECOG, Indiana University, IN US Food and Drug Administration, Center for Devices and Radiological Health, Office of In Vitro Diagnostic Device Evaluation and Safety St. Jude Medical Center, CA Princess Alexandra Hospital, Australia

Guideline Methodology: Panel Members, cont¶d
Panel Member
Neal S. Goldstein, MD Malcolm Hayes, MD David G. Hicks, MD, FCAP Susan Lester, MD Richard Love, MD Lisa McShane, PhD Keith Miller, MD C. Kent Osborne, MD Soonmyung Paik, MD Jane Perlmutter, PhD, Patient Representative Anthony Rhodes, PhD

Institution
Advanced Diagnostics Laboratory, MI University of British Columbia, Canada University of Rochester, NY Brigham and Women¶s Hospital, MA Ohio State University, OH NCI, Biometric Research Branch, DCTD UK NEQAS Baylor College of Medicine, TX National Surgical Adjuvant Breast and Bowel Project, PA Gemini Group, MI University of the West of England, Bristol, UK NEQAS

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Guideline Methodology: Panel Members, cont¶d
Panel Members
Hironobu Sasano, MD Fred C. G. J. Sweep, PhD Sheila Taube, PhD Emina Emilia Torlakovic, MD, PhD Paul Valenstein, MD, FCAP Giuseppe Viale, MD, FRCPath Daniel Visscher, MD Thomas Wheeler, MD, FCAP R. Bruce Williams, MD, FCAP James L. Wittliff, MD, PhD Judy Yost, MA, MT (ASCP), Ex Officio

Institution
Tohoku University School of Medicine, Japan Radboud University, Nijmegen, Netherlands ST Consulting, MD Royal University Hospital, Saskatoon, Canada St. Joseph Mercy Hospital, Ann Arbor, MI European Institute of Oncology, Milan, Italy University of Michigan, Ann Arbor, MI Baylor College of Medicine, TX The Delta Pathology Group, Shreveport, LA University of Louisville, KY CMS, Division of Laboratory Services (CLIA)

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Guideline Methodology:
Guests invited to open portion of meeting
Invited Guests
Richard Bender, MD Kenneth J. Bloom, MD Allen M. Gown, MD David L. Rimm, MD, PhD Patrick Roche, PhD Steven Shak, MD Roseanne Welcher Hadi Yaziji, MD

Affiliation
Agendia Inc Clarient PhenoPath Laboratories, Seattle, WA Yale University Ventana Medical Systems Genomic Health DAKO Ancillary Pathways, Miami, FL

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

Additional ASCO Resources
‡The full text of the guideline, an abridged version of the guideline, an Executive Summary, this slide set, and additional clinical tools and resources can be found at: http://www.asco.org/guidelines/erpr ‡A patient guide, ³What to Know´ about this guideline, is available at: http://www.cancer.net/whattoknow

www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved

ASCO Guidelines
It is im ortant to realize that m any m anagem ent uestions have not een com rehensively addressed in random ized trials and guidelines cannot always account for individual variation am ong atients. A guideline is not intended to su lant hysician udgm ent with res ect to articular atients or s ecial clinical situations and cannot e considered inclusive of all ro er m ethods of care or e clusive of other treatm ents reasona ly directed at o taining the sam e results. A ccordingly, A S C O considers adherence to this guideline to e voluntary, with the ultim ate determ ination regarding its a lication to e m ade y the hysician in light of each atient¶s individual circum stances. In addition, the guideline descri es adm inistration of thera ies in clinical ractice; it cannot e assum ed to a ly to interventions erform ed in the conte t of clinical trials, given that clinical studies are designed to test innovative and novel thera ies in a disease and setting for which etter thera y is needed. ecause guideline develo m ent involves a review and synthesis of the latest literature, a ractice guideline also serves to identify im ortant uestions for further research and those settings in which investigational thera y should e considered.

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