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

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

American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP)

Guideline Recommendations for Immunohistochemical Testing of

Estrogen/Progesterone Receptors in Breast Cancer


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


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


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


Clinical Questions1. 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?


Clinical Questions, cont’d2.2. 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?


Special Questions1. Should ER/PgR be done in DCIS or recurrent

tumor?

2. Does PgR influence the choice of endocrine therapy?


Recommendations

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

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


Recommendations

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 guideline-

detailed elements

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?


Required reporting elements1. 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)


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 +


Optional report elements, cont’d2. -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


Recommendations

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

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?


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


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


Additional information in re: Clinical Question 2.1Standardization 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, ER.2.123+1D5; PgR: 1294, 1A6, 312


Recommendations

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.

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


Recommendations

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

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


Recommendations

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

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?


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


Special Questions1. 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


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


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


Guideline Methodology: Panel MembersPanel Member Institution

M. Elizabeth H. Hammond, MD, Co-Chair*Intermountain Health Care, University of Utah School of Medicine, UT

Daniel F. Hayes, MD, Co-Chair*University of Michigan Comprehensive Cancer Center, University of Michigan Health and Health System, MI

Mitch Dowsett, PhD* Royal Marsden Hospital, UK

D. Craig Allred, MD*Washington University School of Medicine , St. Louis,

MO

Jared N. Schwartz, MD, PhD, FACP, Co-Chair* Presbyterian Hospital, NC

Antonio C. Wolff, MD, FACP, Co-Chair*The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, MD

Sunil Badve, MD ECOG, Indiana University, IN

Robert L. Becker, MD, Ex-Officio

US Food and Drug Administration, Center for Devices and Radiological Health, Office of In Vitro Diagnostic Device Evaluation and Safety

Patrick L. Fitzgibbons, MD, FACP St. Jude Medical Center, CA

Glenn Francis, MBBS, FRCPA, MBA Princess Alexandra Hospital, Australia *Steering Committee Member


Guideline Methodology: Panel Members, cont’dPanel Member Institution

Neal S. Goldstein, MD Advanced Diagnostics Laboratory, MI

Malcolm Hayes, MD University of British Columbia, Canada

David G. Hicks, MD, FCAP University of Rochester, NY

Susan Lester, MD Brigham and Women’s Hospital, MA

Richard Love, MD Ohio State University, OH

Lisa McShane, PhD NCI, Biometric Research Branch, DCTD

Keith Miller, MD UK NEQAS

C. Kent Osborne, MD Baylor College of Medicine, TX

Soonmyung Paik, MD National Surgical Adjuvant Breast and Bowel Project, PA

Jane Perlmutter, PhD, Patient Representative Gemini Group, MI

Anthony Rhodes, PhD University of the West of England, Bristol, UK NEQAS


Guideline Methodology: Panel Members, cont’dPanel Members Institution

Hironobu Sasano, MD Tohoku University School of Medicine, Japan

Fred C. G. J. Sweep, PhD Radboud University, Nijmegen, Netherlands

Sheila Taube, PhD ST Consulting, MD

Emina Emilia Torlakovic, MD, PhD Royal University Hospital, Saskatoon, Canada

Paul Valenstein, MD, FCAP St. Joseph Mercy Hospital, Ann Arbor, MI

Giuseppe Viale, MD, FRCPath European Institute of Oncology, Milan, Italy

Daniel Visscher, MD University of Michigan, Ann Arbor, MI

Thomas Wheeler, MD, FCAP Baylor College of Medicine, TX

R. Bruce Williams, MD, FCAP The Delta Pathology Group, Shreveport, LA

James L. Wittliff, MD, PhD University of Louisville, KY

Judy Yost, MA, MT (ASCP), Ex Officio CMS, Division of Laboratory Services (CLIA)


Guideline Methodology: Guests invited to open portion of meeting

Invited Guests Affiliation

Richard Bender, MD Agendia Inc

Kenneth J. Bloom, MD Clarient

Allen M. Gown, MD PhenoPath Laboratories, Seattle, WA

David L. Rimm, MD, PhD Yale University

Patrick Roche, PhD Ventana Medical Systems

Steven Shak, MD Genomic Health

Roseanne Welcher DAKO

Hadi Yaziji, MD Ancillary Pathways, Miami, FL


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, “What to Know” about this guideline, is available at: http://www.cancer.net/whattoknow


ASCO GuidelinesIt is important to realize that many management questions have not been comprehensively addressed in randomized trials and guidelines cannot always account for individual variation among patients. A guideline is not intended to supplant physician judgment with respect to particular patients or special clinical situations and cannot be considered inclusive of all proper methods of care or exclusive of other treatments reasonably directed at obtaining the same results. Accordingly, ASCO considers adherence to this guideline to be voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient’s individual circumstances. In addition, the guideline describes administration of therapies in clinical practice; it cannot be assumed to apply to interventions performed in the context of clinical trials, given that clinical studies are designed to test innovative and novel therapies in a disease and setting for which better therapy is needed. Because guideline development involves a review and synthesis of the latest literature, a practice guideline also serves to identify important questions for further research and those settings in which investigational therapy should be considered.

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