Transcript Slide 1

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?
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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)
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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 +
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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, ER.2.123+1D5; PgR:
1294, 1A6, 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
Clinical Question 2.3. What is the optimal internal quality management regimen
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
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
Washington University School of Medicine , St. Louis,
D. Craig Allred, MD*
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
Robert L. Becker, MD, Ex-Officio
ECOG, Indiana University, IN
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
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
Guideline Methodology:
Panel Members, cont’d
Panel 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
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
Guideline Methodology:
Panel Members, cont’d
Panel 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)
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved
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
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, “What 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 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.
www.asco.org/guidelines. ©American Society of Clinical Oncology 2010. All rights reserved