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Guideline Summary
Guideline Title
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.
Bibliographic Source(s)
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010 Jun 1;28(16):2784-95. [34 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)

Breast cancer

Guideline Category
Diagnosis
Evaluation
Technology Assessment
Clinical Specialty
Family Practice
Obstetrics and Gynecology
Oncology
Pathology
Intended Users
Clinical Laboratory Personnel
Physicians
Guideline Objective(s)
  • To develop a guideline to improve the accuracy of immunohistochemical (IHC) estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer and the utility of these receptors as predictive markers
  • To assist physicians and patients in clinical decision making and to identify questions and settings for further research
Target Population

Patients with in situ and invasive breast cancer

Interventions and Practices Considered
  1. Immunohistochemical estrogen receptor testing (invasive and recurrent breast cancer)
  2. Immunohistochemical progesterone receptor testing (invasive and recurrent breast cancer)
  3. Large multiple core biopsies of tumor for testing
  4. Tissue handling requirements (time, fixation, slide storage)
  5. Internal validation procedure
  6. Quality assurance procedures
  7. External proficiency assessment
  8. Laboratory accreditation
Major Outcomes Considered
  • Estrogen receptor status
  • Progesterone receptor status
  • Sensitivity and specificity of specific tests
  • Clinical utility

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Literature Review and Analysis

American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO) Systematic Review

ASCO and College of American Pathologists (CAP) commissioned a systematic review of the literature on hormone receptor testing published since 1990. That review conducted by ASCO and CCO is being published separately (manuscript in preparation) and served as the primary source of the evidence for this guideline. Articles were selected for inclusion in the systematic review if they met the following prospective criteria. Studies comparing immunohistochemistry (IHC) in paraffin-embedded female breast cancer sections with another assay and comparative studies whose objectives were to improve or validate the quality of IHC studies that linked test performance to clinical outcome were specifically sought. Systematic reviews, consensus statements, and practice guidelines from 1990 onward were included if they addressed hormone receptor testing in female breast cancer using IHC in paraffin-embedded sections or gene expression signatures for estrogen receptor (ER) and progesterone receptor (PgR). A cutoff date of 1990 was chosen because this was the time that IHC began to come into common use. Additional details of the literature search strategy are provided in the Systematic Review (manuscript in preparation).

Number of Source Documents

337

Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus
Rating Scheme for the Strength of the Evidence

Not applicable

Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

The Panel reviewed all data from the systematic review, as well as additional studies obtained from personal files.

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

The American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines Committee (CPGC) and the College of American Pathologists (CAP) Council on Scientific Affairs (CSA) jointly convened an Expert Panel (hereafter referred to as the Panel) consisting of experts in clinical medicine and research relevant to hormone receptor testing, including medical oncology, pathology, epidemiology, statistics, and health services research. Academic and community practitioners, a patient representative, and experts from the U.S. National Cancer Institute (NCI) and international organizations were also part of the Panel. Representatives from the U.S. Federal Drug Administration (FDA) and the U.S. Centers for Medicare and Medicaid Services served as ex-officio members. The opinions of Panel members associated with official government agencies like the U.S. National Cancer Institute represent their individual views and not necessarily those of the agency with which they are affiliated. Representatives of commercial laboratories and assay manufacturers were invited as guests to attend the open portion of the 2-day meeting held at ASCO headquarters in Alexandria, VA, in December 2008. The planning, deliberations, and manuscript drafting were led by a six-member steering committee composed of two ASCO representatives (Drs Hayes and Wolff), two CAP representatives (Drs Hammond and Schwartz), and two additional experts in testing and evaluation of estrogen receptors (ER) (Drs Allred and Dowsett).

The entire Panel met in December 2008, and additional work on the guideline was completed through e-mail and teleconferences of the Panel. The purpose of the Panel meeting was to refine the questions addressed by the guideline, draft guideline recommendations, and distribute writing assignments. All members of the Panel participated in the preparation of the draft guideline document, which was then disseminated for review by the entire Panel.

Rating Scheme for the Strength of the Recommendations

Not applicable

Cost Analysis

A formal cost analysis was not performed and published cost analyses were not reviewed.

Method of Guideline Validation
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

The guideline was submitted to Journal of Clinical Oncology and Archives of Pathology & Laboratory Medicine for peer review. Feedback from external reviewers was also solicited. The content of the guidelines and the manuscript were reviewed and approved by the American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines Committee (CPGC) and Board of Directors, and by the College of American Pathologists (CAP) Council on Scientific Affairs (CSA) and Board of Governors before publication.

Recommendations

Major Recommendations

What Is the Optimal Testing Algorithm for the Assessment of Estrogen Receptor (ER) and Progesterone Receptor (PgR) Status?

The Panel reviewed the literature on ER and PgR testing and discussed its implications for patients diagnosed with breast cancer. The purpose of both tests is to help determine likelihood of patients responding to endocrine therapy. Therefore, the optimal threshold to define clinical benefit should be based on thresholds that are clinically validated against patient outcome in patients treated with endocrine therapy compared with those who were not.

What Are the Clinically Validated Methods That Can Be Used in This Assessment?

Refer to Table 2 in the original guideline document for significant correlations between ER levels determined by immunohistochemistry (IHC) and clinical outcome in patients with less advanced disease treated with adjuvant hormonal therapy.

Refer to Table 3 in the original guideline document for a detailed list of clinically validated assays including reagents, thresholds, and publications.

A thorough discussion of these topics appears in the unabridged version of the original guideline document (see the "Availability of Companion Documents" field).

What Strategies Can Ensure Optimal Performance, Interpretation, and Reporting of Established Assays?

The Panel considered those strategies that would ensure optimal performance of ER/PgR testing, interpretation, and reporting and was heavily influenced by the previous experience with the implementation of the elements included in the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) HER2 testing guideline. This guideline included measures to improve standardization of preanalytical variables, type of fixative and duration of tissue fixation, antibodies and controls, and assay interpretation.

What Are the Preanalytic, Analytic, and Postanalytic Variables That Must Be Controlled to Ensure That the Assays Reflect the Tumor ER and PgR Status?

For information regarding the Panel's discussion of tissue handling standardization (i.e., time, fixation, slide storage, etc.), refer to the original guideline document.

What Are the Optimal External Quality Assurance Methods to Ensure Ongoing Accuracy in ER/PgR Testing?

The guideline is based on regulatory requirements of the Clinical Laboratory Improvement Amendments of 1998 (CLIA 88), published studies, previous CAP experience, experience of other groups, and the Panel's consensus.

Currently there are no regulatory requirements for proficiency testing of ER or PgR assays in the United States. CLIA regulations require alternative assessment schemes for ER and PgR as substitutes for mandated successful performance on external proficiency testing. However, proficiency testing can be used to meet the alternative assessment requirement if it is available. The current guideline will make successful performance in proficiency testing mandatory. There are mandatory requirements for successful performance in proficiency testing in Australia and New Zealand, which had been in place since 2001.

The guidelines also require enhanced levels of scrutiny at the time of laboratory inspection beyond those required by CLIA. The Panel recommends that ER and PgR testing be performed in a CAP accredited laboratory or in a laboratory that meets the additional accreditation requirements set out within this guideline.

Refer to Table 7 in the original guideline document for a CAP checklist of laboratory requirements.

Reporting Results

Taking these issues into consideration, the Panel recommends that ER and PgR results be reported with three required result elements and two optional result elements (refer to Table 1 in the original guideline document). The three required elements are as follows.

  • The percentage/proportion of tumor cells staining positively should be recorded and reported; all tumor containing areas of the tissue section on the slide should be evaluated to arrive at this percentage. The percentage can be arrived at either by estimation or by quantification, either manually by counting cells or by image analysis. Image analysis holds promise for improving inter- and intraobserver reproducibility, but controversy exists about how imaging should be implemented at this time. Standards of system performance have not yet been developed. If the sample is a cytology specimen, at least 100 cells should be counted or used to estimate the percentage of hormone receptor–positive tumor cells, particularly if the tumor specimen is limited and if the positive staining seems to involve only a minority of tumor cells.
  • The intensity of staining should be recorded and reported as weak, moderate, or strong; this measurement should represent an estimate of the average staining of the intensity of the positively stained tumor cells on the entire tissue section relative to the intensity of positive controls run with the same batch. Intensity is provided as a measure of assay quality over time and also allows for optional composite scoring.
  • An interpretation of the assay should be provided, using one of three mutually exclusive interpretations. The reader should provide an interpretation of the assay based on the following criteria.
    • Receptor positive (either ER or PgR). The Panel recommends a cutoff of a minimum of 1% of tumor cells positive for ER/PgR for a specimen to be considered positive. There is no agreement about a range for receptor equivocal, so this term should not be used.
    • Receptor negative. Tumors exhibiting less than 1% of tumor cells staining for ER or PgR of any intensity should be considered negative based on data that such patients do not receive meaningful benefit from endocrine therapy. The sample should only be considered negative in the presence of appropriately stained extrinsic and intrinsic controls. Any specimen lacking intrinsic elements (normal breast epithelium) that is negative on ER and/or PgR assay should be repeated using another tumor block or another tumor specimen and reported as uninterpretable rather than as negative.
    • Receptor uninterpretable. The Panel agreed that there are no absolute assay exclusions. Nevertheless, a result should be considered uninterpretable if a sample did not conform to preanalytic specifications of the guideline, was processed using procedures that did not conform to guideline specifications or the laboratory's standard operating procedure, or the assay used to analyze the specimen was not validated and controlled as specified in the guideline. Examples of circumstances that may lead to uninterpretable results include testing of needle biopsies or cytology samples fixed in alcohol, use of fixatives other than 10% neutral buffered formalin ([NBF] unless that fixative has been validated by the laboratory before offering the assay), biopsies fixed for intervals shorter than 6 hours or longer than 72 hours, samples where fixation was delayed for more than 1 hour, samples with prior decalcification using strong acids, and samples with inappropriate staining of internal assay controls (including intrinsic normal epithelial elements) or extrinsic assay controls. These conditions are not absolute because they depend on which conditions have been validated by the laboratory and which are subject to the judgment of the circumstances by the pathologist. The reason for an uninterpretable result should be specified (e.g., fixation for <6 hours), and an alternative potential sample for retesting should be suggested, if appropriate.

Two optional report elements are recommended by the Panel, but not required.

  1. A cautionary statement may be added to negative ER and PgR interpretations when the histopathology of the tumor is almost always associated with ER-positive and PgR-positive results. These include tubular, lobular, and mucinous histologic types or tumors with a Nottingham score of 1. The cautionary statement should indicate that although the patient's tumor tested as ER negative, tumors with the same histologic type or Nottingham score almost always test positive.
  2. Using the percentage and intensity measurements provided, the pathologist may also provide a composite score such as the H score, Allred score, or quick score (refer to Table 3 in the original guideline document). Because each of these is somewhat differently calculated and may lead to confusion across institutions, scoring is not required.

Appropriate Populations to Be Tested

The Panel developed consensus that ER and PgR status should be determined on all newly diagnosed invasive breast cancers. For patients with multiple synchronous tumors, testing should be performed on at least one of the tumors, preferably the largest. The Panel acknowledges that all newly diagnosed ductal carcinomas in situ (DCISs) are also commonly being tested for ER and PgR. This practice is based on the results of a retrospective subset analysis of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 clinical trial comparing tamoxifen versus placebo after lumpectomy and radiation, which has thus far been reported only in abstract form. There was a significant 40% to 50% reduction in subsequent breast cancer (ipsilateral and contralateral) restricted to patients with ER positive DCIS at 10 years of follow-up, and a full manuscript has recently been submitted for peer review. Because the results are scientifically reasonable and consistent with previous studies of invasive/metastatic breast cancer, the Panel sees value in assessing ER in patients with DCIS. However, because there are unlikely to be any validation studies, the Panel leaves it up to patients and their physicians to decide on testing, rather than making a formal recommendation. Breast recurrences should also always be tested to ensure that prior negative results of ER and/or PgR were not falsely negative and to evaluate the specimen for biologic changes since the previous testing.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

The evidence supporting each recommendation is presented in the original guideline document. In general, the literature review supporting these recommendations centered on consensus conferences held in the United States (U.S.), single institution studies, experience from reference laboratories, international reports, regulations currently in force in the U.S. (Clinical Laboratory Improvement Amendment [CLIA] 88 and U.S. Food and Drug Administration [FDA] regulations), and expert consensus at the panel meeting.

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Improved accuracy of estrogen and progesterone receptor testing in breast cancer

Potential Harms

False positive/false negative test results

Qualifying Statements

Qualifying Statements

The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) practice guidelines reflect expert consensus based on the best available evidence. They are intended to assist physicians and patients in clinical decision making and to identify questions and settings for further research. With the rapid flow of scientific information in oncology, new evidence may emerge between the time an updated guideline was submitted for publication and when it is read or appears in print. Guidelines are not continually updated and may not reflect the most recent evidence. Guidelines address only the topics specifically identified in the guideline and are not applicable to interventions, diseases, or stages of diseases not specifically identified. Furthermore, guidelines cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances and preferences. ASCO/CAP guidelines describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of interventions in the context of clinical trials. ASCO and CAP assume no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO/CAP's guidelines or for any errors or omissions.

Implementation of the Guideline

Description of Implementation Strategy

The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) will provide educational opportunities (print, online, and society meetings) to educate health care professionals, patients, third-party payers, and regulatory agencies. In addition, CAP is producing a certificate program for pathologists that will assess their competency in following both the hormone receptor and the HER2 guideline recommendations. CAP will urge its members and participants in accreditation and proficiency testing programs to optionally append a statement to individual results or laboratory informational or promotional materials indicating that the laboratory's estrogen receptor (ER)/progesterone receptor (PgR) assays have been validated and performed in accordance with ASCO/CAP ER testing guidelines, provided that all of the guideline conditions are met.

ASCO and CAP will also work to coordinate these recommendations with those of other organizations, such as the National Comprehensive Cancer Network, the Commission of Cancer of the American College of Surgeons, the American Joint Committee on Cancer, and patient advocacy organizations.

Implementation Tools
Chart Documentation/Checklists/Forms
Patient Resources
Quick Reference Guides/Physician Guides
Slide Presentation
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010 Jun 1;28(16):2784-95. [34 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2010 Apr
Guideline Developer(s)
American Society of Clinical Oncology - Medical Specialty Society
College of American Pathologists - Medical Specialty Society
Source(s) of Funding

American Society of Clinical Oncology

College of American Pathologists

Guideline Committee

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

Composition of Group That Authored the Guideline

Panel Members: M. Elizabeth H. Hammond; Daniel F. Hayes; Mitch Dowsett; D. Craig Allred; Karen L. Hagerty; Sunil Badve; Patrick L. Fitzgibbons; Glenn Francis; Neil S. Goldstein; Malcolm Hayes; David G. Hicks; Susan Lester; Richard Love; Pamela B. Mangu; Lisa McShane; Keith Miller; C. Kent Osborne; Soonmyung Paik; Jane Perlmutter; Anthony Rhodes; Hironobu Sasano; Jared N. Schwartz; Fred C.G. Sweep; Sheila Taube; Emina Emilia Torlakovic; Paul Valenstein; Giuseppe Viale; Daniel Visscher; Thomas Wheeler; R. Bruce Williams; James L. Wittliff; Antonio C. Wolff

Financial Disclosures/Conflicts of Interest

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about the American Society of Clinical Oncology's (ASCO's) conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: Jared N. Schwartz, Aperio (C)

Consultant or Advisory Role: Mitch Dowsett, Dako (C); D. Craig Allred, Genomic Health (C), Clarient (C), Dako (C); Sunil Badve, Dako (C); Neal S. Goldstein, Clarient (C); Giuseppe Viale, Dako (C)

Stock Ownership: D. Craig Allred, Clarient

Honoraria: Glenn Francis, Roche Ventana Medical Systems; Giuseppe Viale, Dako

Research Funding: Hironobu Sasano, Ventana Japan

Expert Testimony: None

Other Remuneration: Glenn Francis, Roche Ventana Medical Systems

After the guideline manuscript was completed, Jared N. Schwartz assumed an Employment or Leadership Position with Aperio and resigned as co-chair of the Expert Panel.

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available from the American Society of Clinical Oncology (ASCO) Web site External Web Site Policy.

Print copies: Available from American Society of Clinical Oncology, Cancer Policy and Clinical Affairs, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; E-mail: guidelines@asco.org.

Availability of Companion Documents

The following are available:

  • American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Unabridged. American Society of Clinical Oncology/College of American Pathologists. 2010 Jun. 23 p. Available in Portable Document Format (PDF) from the ASCO Web site External Web Site Policy.
  • ASCO/CAP guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Guideline summary. 2010 Jul. 5 p. Electronic copies: Available in PDF from the ASCO Web site External Web Site Policy.
  • ASCO/CAP guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Slide set. 2010. 29 p. Electronic copies: Available in PDF External Web Site Policy and PowerPoint External Web Site Policy from the ASCO Web site.
  • ASCO/CAP guideline recommendations for immunohistochemical (IHC) testing of estrogen and progesterone receptors in breast cancer. Reporting elements for IHC: checklist. 2010. 1 p. Electronic copies: Available in PDF from the ASCO Web site External Web Site Policy.
Patient Resources

The following is available:

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

NGC Status

This summary was completed by ECRI Institute on November 15, 2010.

Copyright Statement

This summary is based on the original guideline, which is subject to the American Society of Clinical Oncology's copyright restrictions.

Disclaimer

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