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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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Guideline Methodology:
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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Guideline Methodology:
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.