Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update
Summary (4 min read)
Introduction
- ASCO/CAP convened an Update Committee that included coauthors of the 2007 guideline to conduct a systematic literature review and update recommendations for optimal HER2 testing.
- If the pathologist or oncologist observes an apparent histopathologic discordance after HER2 testing, the need for additional HER2 testing should be discussed.
- Therefore, the need for an updated ASCO/CAP guideline on accurate HER2 testing to ensure that the right patient receives the right treatment is now more critical than ever.22,24–27,38.
METHODS
- The HER2 testing Update Committee met 3 times via Webinars coordinated by its Steering Committee to review the data published from January 2006 to January 2013 and to revise the recommendations.
- Additional data were gathered from in-press publications and personal correspondence with researchers to address the issue of mandatory testing if a test result is 0 or 1þ.
- Draft manuscripts were circulated by e-mail, and the Update Committee approved the final manuscript.
- This guideline was reviewed by external reviewers and approved by the ASCO Clinical Practice Guideline Committee and relevant CAP entities.
Literature Search Strategy
- The MEDLINE and the Cochrane Collaboration Library electronic databases were searched with the date parameters of January 2006 through January 2013 for articles in English.
- The MEDLINE search terms are included in Data Supplement 3, and a summary of the literature search results is provided in Data Supplement 4.
Inclusion and Exclusion Criteria
- ASCO and CAP believe that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
- Letters, commentaries, and editorials were reviewed for any new information.
- The clinical questions addressed in the update are available in Data Supplement 5.
- This information was used to help the Update Committee develop new algorithms (for pathologists and oncologists) for testing, specify testing requirements and exclusions, and facilitate the necessary quality assurance monitoring that will make HER2 testing less variable and ensure more analytic consistency between laboratories.
ASCO Guideline Disclaimer
- The clinical practice guideline and other guidance published herein are provided by ASCO to assist practitioners in clinical decision making.
- With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read.
- Furthermore, the information is not intended to substitute for the independent professional judgment of the treating physician, because the information does not account for individual variation among patients.
- The use of terms like must, must not, should, and should not indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases.
- ASCO provides this information on an as-is basis and makes no warranty, express or implied, regarding the information.
CAP Guideline Disclaimer
- Clinical practice guidelines reflect the best available evidence and expert consensus supported in practice.
- They are intended to assist physicians and patients in clinical decision making and to identify questions and settings for further research.
- Furthermore, guidelines and statements 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, relying on independent experience and knowledge, to determine the best course of treatment for the patient.
- CAP makes no warranty, express or implied, regarding guidelines and statements and specifically excludes any warranties of merchantability and fitness for a particular use or purpose.
Guideline and Conflicts of Interest
- The Update Committee was assembled in accordance with CAP and ASCO Conflicts of Interest Management Procedures for Clinical Practice Guidelines (ASCO procedures are summarized at http://www.asco.org/guidelinescoi).
- Members of the Update Committee completed the ASCO disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the guideline.
- Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony.
- In accordance with the procedures, the majority of the members of the Update Committee did not disclose any such relationships.
Literature Update and Discussion
- The competency of the laboratory professionals and pathologists interpreting assays must be continuously addressed as required under the Clinical Laboratory Improvements Amendments (CLIA 88).
- In practice they are rare and if encountered should be considered ISH equivocal (see Data Supplement 2E).
HER2 Assay Exclusions
- Each assay type has diagnostic pitfalls to be avoided.
- The Update Committee agreed that there were situations in which one assay type was preferred because of assay or sample considerations.
- Exclusion criteria to perform or interpret an IHC or any ISH assay for HER2 are unchanged but can be viewed in the original guideline.
- 1,2 The pathologist who reviews the histologic findings should determine the optimal assay (IHC or ISH) for determination of HER2 status.
Ongoing Communication, Education, and Evaluation Efforts by CAP
- CAP has undertaken comprehensive efforts to educate pathologists about ways to improve laboratory performance of HER2, ER, and PgR assays.
- Numerous live and online educational offerings are available from CAP and other organizations.
- Examples in North America include the American Society of Clinical Pathology (ASCP) and United States and Canadian Academy of Pathology .
- In follow-up surveys, participants routinely report they made changes to their practice as a result of the educational experience.
- Many of these learning opportunities have a scored assessment component, allowing participants to test their knowledge as part of completing the courses, and can be used to meet the American Board of Pathology (ABP), the US pathologist certifying organization, Maintenance of Certification requirements.
STUDY QUALITY, LIMITATIONS OF THE LITERATURE, AND FUTURE RESEARCH
- Whether in the context of trastuzumab clinical trials or of studies comparing HER2 testing platforms, interpretation of the literature in the field of HER2 testing is still complicated by a lack of standardization across trials in assay utilization and interpretation, presence or absence of confirmatory testing, and local versus central laboratory testing, among other considerations.
- An important gap in the literature identified by the Update Committee concerns those patients with test results reported as equivocal.
- Because the retrospective evaluation of the benefit from trastuzumab in patients with apparent discordance between IHC and FISH who were enrolled onto the first generation of trastuzumab trials included only a small number of patients in each of the discordant subsets, patients who would have qualified for enrollment in those trials should be considered for HER2-targeted therapy.
- Specifically in regard to ISH assays, it expected that additional but rare categories of HER2 status by ISH could be created that are not covered by the definitions illustrated in Figures 2 and 3.
PATIENT AND CLINICIAN COMMUNICATION
- Patients (and family members or caregivers) should be educated about the results of pathology tests and how they are used to develop a treatment plan tailored to the biology of their cancers.
- Because many newly diagnosed patients are under emotional stress and/or may be unaccustomed to complex medical terminology, the use of easily understood language (at an educational level that the patient can understand) is key to clear communication.
- Asking patients to repeat back key pieces of information, providing written or recorded notes, and using visual aids can help ensure information is effectively communicated.
- Patients should be given a copy of their pathology report and HER2 test results.
- The clinician should review the results with the patient, discuss any issues with the test interpretation or performance, and ask if he or she has any additional questions about the results.
Key Points for Clinicians to Discuss With Patients Regarding HER2 Status
- Explain the importance of determining the biologic characteristics of breast cancer.
- Unfortunately, some results remain indeterminate or inconsistent with other histopathologic findings.
- In such cases, a final treatment decision to consider treatment with HER2-targeted therapy should be made after consultation between the pathologist and oncologist and a discussion with the patient.
- —Patients should understand that HER2 status may occasionally be different when comparing a previous primary tumor and a site of recurrence or in the setting of multiple simultaneous metastatic sites.
- —Patients should be assured that HER2 testing guidelines were followed.
HEALTH DISPARITIES
- It is important to note that some racial/ ethnic minority patients have limited access to optimal medical care and/or accredited pathology laboratories.
- At the same time, some Medicaid or uninsured patients may have access to accredited pathology laboratories by virtue of receiving some or all of their care in an academic medical center.
- In the United States, Lund et al151 used data from the National Cancer Institute Metropolitan Atlanta SEER Registry in conjunction with the Georgia Comprehensive Cancer Registry to examine HER2 testing among all cases of primary invasive breast cancer diagnosed among female residents during 2003 to 2004.
- Awareness of possible disparities in access to care should be considered in the context of this clinical practice guideline, and health care providers should strive to deliver the highest level of cancer care to these vulnerable populations.
ADDITIONAL RESOURCES
- Data Supplements, including evidence tables, and clinical tools and resources can be found at www.asco.org/ guidelines/her2.
- Information for patients is available at http://www.cancer.net.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
- The following author(s) and/or an author’s immediate family member(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 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.
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"Recommendations for Human Epidermal..." refers background in this paper
...Trastuzumab had previously been shown to improve progression-free survival and overall survival when combined with chemotherapy in the metastatic setting.(28) Since 2005, several of the first-generation adjuvant trials have been updated and have confirmed the disease-free and overall survival benefit offered by 1 year of trastuzumab administered with or after adjuvant chemotherapy....
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"Recommendations for Human Epidermal..." refers background or methods in this paper
...Inclusion and Exclusion Criteria Articles were selected for inclusion in the systematic review of the evidence if they met the following criteria : (1) the study compared, prospectively or retrospectively, fluorescent ISH (FISH) and immunohistochemistry (IHC) results or other tests; described technical comparisons across various assay platforms; examined potential testing algorithms for HER2 testing; or examined the correlation of HER2 status in primary versus metastatic tumors from the same patients; (2) the study population consisted of patients with a diagnosis of invasive breast cancer; or (3) the primary outcomes included the negative predictive value (NPV) or positive predictive value (PPV) of ISH and IHC assays used to determine HER2 status, alone and in combination; negative and positive concordance across platforms; and accuracy in determining HER2 status and benefit from anti-HER2 therapy and in determining sensitivity and specificity of individual tests....
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...Exclusion criteria to perform or interpret an IHC or any ISH assay for HER2 are unchanged but can be viewed in the original guideline.(1,2) The pathologist who reviews the histologic findings should determine the optimal assay (IHC or ISH) for determination of HER2 status....
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Frequently Asked Questions (11)
Q2. What are the future works in "Recommendations for human epidermal growth factor receptor 2 testing in breast cancer american society of clinical oncology/college of american pathologists clinical practice guideline update" ?
Although FDA-approved assays have been carefully validated, not all LDTs may have, which complicates direct comparisons across trials and platforms, and the authors maintain that this situation leaves open the possibility that a substantial percentage of some patients with breast cancer could be either over- or undertreated with HER2-targeted therapies. The decision to treat with specific therapies like trastuzumab is by necessity dichotomous ( yes or no ) and will not be informed by an equivocal diagnosis with respect to HER2 status without repeat testing, if possible. However, HER2 test results are derived from a continuous variable, which can be expected to lead to some results falling into a gray area.
Q3. What is the method of obtaining tissue from the primary tumor?
Tissue from the primary tumor can be obtained through a core needle biopsy, as well as from an incisional and excisional surgical procedure.
Q4. What is the term ratio used in the guideline recommendations and algorithms?
The term ratio, as used in the guideline recommendations and algorithms, always applies to the HER2/CEP17 ratio, which means the ratio of HER2 signals per cell (numerator) over CEP17 signals per cell (denominator).
Q5. How did Lund et al examine HER2 testing among female residents?
In the United States, Lund et al151 used data from the National Cancer Institute Metropolitan Atlanta SEER Registry in conjunction with the Georgia Comprehensive Cancer Registry to examine HER2 testing among all cases of primary invasive breast cancer diagnosed among female residents during 2003 to 2004.
Q6. What are the learning opportunities for HER2?
Many of these learning opportunities have a scored assessment component, allowing participants to test their knowledge as part of completing the courses, and can be used to meet the American Board of Pathology (ABP), the US pathologist certifying organization, Maintenance of Certification requirements.
Q7. What is the reason for the small number of patients affected by HER2?
Aside from the very small number of patients affected (as few as 0.15% of all newly diagnosed patients, as previously discussed),5 the Update Committee was also of the opinion that improvements in analytic performance of HER2 testing in clinical practice since 2007 have further reduced the already small number of patients potentially at risk of receiving a false-negative test result.
Q8. What is the definition of amplification in a dual-probe ISH assay?
Amplification in a dual-probe ISH assay is defined by examining first the HER2/CEP17 ratio followed by the average HER2 copy number (see Data Supplement 2E for more details).
Q9. What is the FDA’s recommendation for HER2 testing?
The product package inserts for trastuzumab and pertuzumab prepared by the FDA indicate that ‘‘HER2 testing should be performed using US Food and Drug Administration-approved tests by laboratories with demonstrated proficiency.
Q10. What are the new interpretation requirements for HER2 assays?
New interpretation requirements relate to the definition of tumor samples with genomic heterogeneity as well as the examination of specimens and interpretation of results in these samples.
Q11. What is the responsibility of the treating physician to determine the course of treatment for the patient?
It is the responsibility of the treating physician, relying on independent experience and knowledge, to determine the best course of treatment for the patient.