estrogen progesterone receptors in breast cancer // asco / cap

8/9/2019 Estrogen Progesterone Receptors In Breast Cancer // ASCO / CAP

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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 forImmunohistochemical Testing of

Estrogen/Progesterone Receptors in Breast

Cancer


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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 firstever evidence-based ER-PgR testing guideline,

based on a systematic review


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Background

Hormone receptor-positive is the most

common breast cancer phenotype worldwide

Access to accurate and reliable ER/PgR

testing and to established and relativelyaffordable endocrine therapies could have a

profound impact on breast cancer outcomes

in high and low/middle income countriesacross the globe


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Guideline Methodology:Systematic Review ASCO and Cancer Care Ontario jointly

conducted a systematic review of the medicalliterature available from 1990-May 2008

Ovid (Medline)

EMBASE

Cochrane Database of Systematic Reviews

Primary outcome: correlation of hormone

receptor status and outcome of endocrinetreatment

ASCO/CAP Expert Panel maderecommendations based on this review


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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 toensure that assay results reflect tumor ER and PgR

status?


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Clinical Questions, contd

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 permitsapplication 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?


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Special Questions

1. Should ER/PgR be done in DCIS or recurrent

tumor?

2. Does PgR influence the choice of endocrine

therapy?


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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 areimmunoreactive 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?


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Recommendations

Optimal testing conditions

Large, preferably multiple core biopsies of tumorare preferred for testing if they are representativeof 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?


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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 relativeto positive controls on same batch

3. Interpretation of the assay (+, -, oruninterpretable)


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Optional report elements, contd

2. -Pathologist may also provide a composite

score e.g. the H score, Allred score, or

Quick score

-Using the percent and intensitymeasurements provided

-Since each of these is somewhat differently

calculated and may lead to confusion acrossinstitutions

-Scoring is not required


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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 marginsdesignation 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 ERand PgR status?


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Recommendations- Optimal tissuehandling requirements, contd

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 tissuehandling requirements, contd

Storage of unstained slides for more than 6

weeks prior to analysis is not recommended

Time tissue is removed from patient, timetissue 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 VariablesAntibody 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 orPgR negative category

Include: ER: 1D5, 6F11, SP1, 1D5; PgR: 1294, 312


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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 achange 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?


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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 leastsemiannually. 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?


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Recommendations

Optimal external proficiency assessment

Mandatory participation in external proficiency testingprogram 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-siteinspection?

Clinical Question 2.5. How can internal and external control efforts be

implemented and their effects measured?


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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


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

tumor?ER and PgR statusshould be determined on all

newly diagnosed invasive breast cancers (primary

and/or metastaticsite)

Lack of validation studies on testing for people with

DCIS. Panelsaw value, but could not make formal

recommendation.

Women with breast recurrences accessible tobiopsyshould also always be tested

To check prior negative results not false negative

To checkspecimen for emergence of negative clones


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Special Questions

2. Does PgR correlate with or influence thechoice 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, PgRpoor tumor

Women w/ER-/PgR+ tumors may respond to

endocrine therapy


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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 ofSurgeons, the American Joint Committee on

Cancer, and patient advocacy groups

CAP will:

Review and publish results of proficiency testing andlaboratory accreditation

Inclusion of quality monitoring activities on ER/PgR

testing in ongoing quality assessment programs


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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


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Panel Members, contdPanel Member InstitutionNeal 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 Womens 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


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Panel Members, contdPanel Members InstitutionHironobu 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 MercyHospital, 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)


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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


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Additional ASCO Resources

The full text of the guideline, an abridgedversion 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


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ASCO Guidelines

It is im ortant to realize that man y managem ent uestions have not eencom rehensively addressed in randomized trials and guidelines cannot alwaysaccount for individual variation am ong atients. A guideline is not intended tosu lant hysic ian udgment with res ect to art icular atients or s ecia l c lin icalsituations and cannot e considered inclusive of all ro er methods of care ore clusive of other treatments reasona ly directed at o taining the same results.

Accordingly, ASCO considers adherence to this guideline to e voluntary, withthe ultimate determination regarding its a lication to e made y the hysicianin light of each atients individua l circumstances. In add ition, the guidelinedescri es administration of thera ies in clinical ractice; it cannot e assumed toa ly to interventions erformed in the conte t of clinical trials, given that clinicalstudies are designed to test innovative and novel thera ies in a disease andsett ing for which etter thera y is needed. ecause guideline develo mentinvolves a review and synthesis of the latest literature, a ractice guideline also

serves to identify im ortant uestions for further research and those settings inwhich investigational thera y should e considered.

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