This is the current release of the guideline.

Breast cancer

Diagnosis
Evaluation
Technology Assessment

Oncology
Pathology

Clinical Laboratory Personnel
Physicians

To improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker

Patients with invasive breast cancer

1. Human epidermal growth factor receptor 2 (HER2) testing in breast cancer
   • Immunohistochemistry
   • Fluorescent in situ hybridization (FISH)
2. Tissue handling requirements
3. Internal validation procedure
4. Quality assurance procedures
5. External proficiency assessment
6. Laboratory accreditation

• Human epidermal growth factor receptor 2 (HER2) status and benefit from anti-HER2 therapy
• Positive predictive value and negative predictive value of fluorescent in situ hybridization and immunohistochemistry to determine HER2 status, alone and in combination and concordance across platforms
• Accuracy in determining HER2 status, sensitivity, and specificity of specific tests

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data

The following electronic databases were searched from January 1987 through February 2006: MEDLINE, PreMEDLINE, and the Cochrane Collaboration Library. In addition, abstracts presented at American Society of Clinical Oncology (ASCO) or College of American Pathologists (CAP) from 2000 to 2005 and at the San Antonio Breast Cancer Symposium from 2003 to 2005 were identified. Results were supplemented with hand searching of selected reviews and personal files. The following MeSH terms were used in a MEDLINE search: "immunohistochemistry," "in situ hybridization, fluorescence," "genes, erbB2," "receptor, erbB2," "receptor, epidermal growth factor," "breast neoplasms," and the substance name "epidermal growth factor receptor-neu receptor." The search was expanded by the addition of the following text words, in varying combinations: immunohistochemistry, immunocytochemistry, "IHC," fluorescence in situ hybridization, "FISH," chromogenic hybridization, "CISH," gold-facilitated hybridization, autometallographic, bright field, "GOLDFISH," HER2, erbB2, breast cancer, and breast tumor. All searches were limited to the English language.

Study design was not limited to randomized controlled trials, but was expanded to include any study type, including cohort designs, case series, evaluation studies, comparative studies, and prospective studies. Also included were testing guidelines and proficiency strategies of various United States and international organizations. Letters, commentaries, and editorials were reviewed for any new information. Case reports were excluded.

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, the negative predictive value (NPV) or positive predictive value (PPV) of fluorescent in situ hybridization (FISH) or immunohistochemistry (IHC); the study described technical comparisons across various assay platforms; the study examined potential testing algorithms for human epidermal growth factor receptor 2 (HER2) testing; or the study examined the correlation of HER2 status in primary versus metastatic tumors from the same patients; and (2) the study population consisted of patients with a diagnosis of invasive breast cancer; and (3) the primary outcomes included the PPV and NPV of FISH and IHC to determine HER2 status, alone and in combination; concordance across platforms; accuracy in determining HER2 status and benefit from anti-HER2 therapy, sensitivity, and specificity of specific tests. Consideration was given to studies that directly compared results across assay platforms.

The panel reviewed the results of randomized controlled trials in breast cancer testing anti-human epidermal growth factor receptor 2 (HER2) therapies like trastuzumab and lapatinib. The panel also reviewed unblinded trials comparing various testing methods, describing test characteristics, and defining strategies for quality assurance of testing in the literature. Individuals representing regulatory agencies (Centers for Medicare and Medicaid Services and US Food and Drug Administration) also provided information about the regulatory framework. Individuals involved with quality assurance in the United States (CAP), Great Britain, and Canada (Province of Ontario) also provided information about programs to measure and improve HER2 testing. Survey data from the maker of trastuzumab (Genentech) was also evaluated as well as testimony provided by testing manufacturers (Ventana, Dako, Abbott) and large clinical laboratories (Clarient, Mayo Medical Labs, Phenopath, Quest, and US Labs) to define the current status of training and testing for HER2. This information was used to help the panel define the best algorithm for testing, specify testing requirements and exclusions, and the necessary quality assurance monitoring that will make the testing less variable and more accurate.

American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) expert panel literature review and analysis. An initial abstract screen was performed by ASCO staff. The ASCO/CAP panel reviewed all remaining potentially relevant abstracts identified in the original literature searches to select studies pertinent to its deliberations. Two panel members independently reviewed each abstract for its relevance to the clinical questions, and disagreements were resolved by third-party review. Full-text articles were then reviewed for all selected abstracts. Evidence tables were developed based on selected studies that met the criteria for inclusion.

125

Expert Consensus (Committee)

Not applicable

Systematic Review with Evidence Tables

Not stated

Expert Consensus

The entire panel met in March 2006; additional work on the guideline was completed through electronic mail and teleconferences of the panel. The purposes of the panel meeting were to refine the questions addressed by the guideline and to make writing assignments for the respective sections. All members of the panel participated in the preparation of the draft guideline.

Not applicable

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

External Peer Review
Internal Peer Review

The draft guideline was disseminated for review by the entire panel. Feedback from external reviewers was also solicited. The content of the guideline and the manuscript were reviewed and approved by the American Society of Clinical Oncology (ASCO) Health Services Committee (HSC) and board of directors and by the College of American Pathologists (CAP) Council on Scientific Affairs and board of governors before dissemination.

Abbreviations: HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; FISH, fluorescent in situ hybridization; QA, quality assurance

Algorithms are provided in the original guideline document for:

• Immunohistochemistry (IHC)
• Fluorescent in situ hybridization (FISH)

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

Improved accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker

Not stated

• Whether in the context of trastuzumab clinical trials or of studies comparing human epidermal growth factor receptor 2 (HER2) testing platforms, interpretation of the literature in the field of HER2 testing is 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. Testing algorithms for HER2 were somewhat arbitrarily developed and assays used within algorithms have not always been standardized. While some assays have been carefully validated, others, especially the "home brew assays" have not, which complicates direct comparisons across trials and platforms, and we maintain this situation leads to either over- or undertreatment of a substantial percentage of patients with breast cancer.
• In addition to published studies, the panel also considered previous guidelines and position statements from national and international professional organizations. Most of these earlier guidelines simply stated that HER2 testing should be performed, without addressing specific methodology, quality control, or associations with clinical outcomes. Guidelines have also emphasized the need for individual laboratories to document their own concordance experience of fluorescent in situ hybridization (FISH) versus immunohistochemistry (IHC) (90% for IHC 0 and 3+, and 95% for IHC 1+) before limiting reflex FISH testing only to IHC 2+ results. The guidelines considered were developed before the publication of the adjuvant trastuzumab data, and thus these concordance requirement parameters were set taking into account the palliative role of trastuzumab, and not the survival advantage shown in the adjuvant trials. Finally, other organizations have recommended algorithms based on best available data, which in fact have been quite sparse. It should be noted that testing algorithms described in existing guidelines assume a high level of correlation between IHC and FISH assays, which the existing literature shows may be unfounded.
• An important gap in the literature identified by the panel concerns those patients with test results in the intermediate or equivocal range. The decision to treat with specific therapies like trastuzumab is by necessity dichotomous (yes or no). However, HER2 test results are derived from a continuous variable, which can be expected to lead to some results falling into a gray area. Adding to this confusion is the fact that there is significant variation in the intermediate ranges for both the IHC and FISH assays. The literature is lacking in this subgroup of patients with intermediate results, and there are also limited efficacy data in the subgroup tested with both high-quality IHC and FISH and found to have a discordant result. Patients with such results constitute poorly studied subgroups with less confidence in the scores and actual benefit from trastuzumab therapy. As these patient subgroups (and number of events) found within each of the individual adjuvant transtuzumab trials are relatively small, we urge those principal investigators to pool their data for a joint analysis to attempt to address some of these questions.
• It is important to emphasize that guidelines and technology assessments cannot always account for individual variation among patients. They are 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 result. Accordingly, the American Society of Clinical Oncology (ASCO) considers adherence to this guideline assessment 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, this guideline describes the use of procedures and therapies in clinical practice; it cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment is needed.

To be effective, these recommendations must be widely communicated to the medical community and to patients both by educational efforts and by modifying the regulatory oversight of laboratories doing human epidermal growth factor receptor 2 (HER2) testing. We recommend coordinated educational efforts by both College of American Pathologists (CAP) and American Society of Clinical Oncology (ASCO) to provide such education and coordinate standardized review criteria among all agencies performing laboratory accreditation. In addition, CAP will periodically publish the aggregate results of the proficiency testing results to make the oncology community aware of the improvements resulting from this strategy.

Educational Requirements and Communication Strategies

For this guideline to be effectively implemented by laboratories anywhere in the world, there will need to be effective and widespread educational efforts of pathologists, oncologists, patients, and advocacy groups. CAP will offer online and live educational sessions about clinical necessity, testing requirements, test interpretation guidelines, and methods by which acceptable performance will be measured through laboratory accreditation and proficiency testing, and organizations in other parts of the world could play a similar role. ASCO will create education materials for oncologists and patients about how laboratory quality can be evaluated through review of reports and laboratory quality assurance activities. Pathologists must actively monitor the quality of their test procedures and oncologists on behalf of their patients must seek assurance that laboratories providing test results are appropriately accredited. These actions should improve the consistency of testing for HER2, although quantifying this improvement will be difficult. One of the important outcomes resulting from accurate HER2 testing is to ensure that every breast cancer patient who might benefit from anti-HER2 therapy be accurately and promptly identified, while those who would not benefit be spared a costly and potentially harmful placebo.

This guideline will be made available for review by organizations involved in laboratory accreditation and proficiency testing services in the USA. ASCO and CAP will jointly work to facilitate the dissemination of these guidelines. Efforts will be directed at enhancing the education of laboratories by requesting publication of guideline information in Morbidity and Mortality Weekly Report published by the Centers of Disease Control and Prevention. CAP will engage in significant live and online educational activities to help pathologists understand the significance of these changes in accreditation practice, beginning at the CAP annual meeting in September 2006. ASCO and CAP will provide educational opportunities (print, online, and society meetings) to educate health care professionals, patients, third party payers, and regulatory agencies. CAP will urge its members and participants in accreditation and proficiency testing programs to provide information in its reports specifying participation in laboratory accreditation. ASCO and CAP will work to coordinate these recommendations with those of other organizations, such as the National Comprehensive Cancer Network, the National Cancer Advisory Board, and patient advocacy organizations.

We are confident that these measures will improve performance of laboratories using these and future predictive testing methods. CAP will actively review results of proficiency testing and laboratory accreditation activities and periodically publish performance results. The organization will also work to include quality monitoring activities of HER2 testing in its programs designed for ongoing quality assessment, similar to CAP's Q-tracks and Q-probes.

Living with Illness

Effectiveness
Patient-centeredness

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

2007 Jan 1

American Society of Clinical Oncology - Medical Specialty Society
College of American Pathologists - Medical Specialty Society

American Society of Clinical Oncology

College of American Pathologists

ASCO/CAP Expert Panel on Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer

Panel Members: Antonio C. Wolff; M. Elizabeth H. Hammond; Jared N. Schwartz; Karen L. Hagerty; D. Craig Allred; Richard J. Cote; Mitchell Dowsett; Patrick L. Fitzgibbons; Wedad M. Hanna; Amy Langer; Lisa M. McShane; Soonmyung Paik; Mark D. Pegram; Edith A. Perez; Michael F. Press; Anthony Rhodes; Catharine Sturgeon; Sheila E. Taube; Raymond Tubbs; Gail H. Vance; Marc van de Vijver; Thomas M. Wheeler; Daniel F. Hayes

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.

Employment: N/A

Leadership: N/A

Consultant: Richard J. Cote, Clarient, Roche, Abbott; Mitchell Dowsett, Roche, Abbott Diagnostics; Soonmyung Paik, Genentech, GlaxoSmithKline; Mark D. Pegram, Genetech; Michael F. Press, Genentech; Anthony Rhodes, European Collection of Cell Cultures; Marc van de Vijver, Roche; Daniel F. Hayes, Immunicon, Pfizer, Novartis

Stock: Richard J. Cote, Clarient

Honoraria: M. Elizabeth H. Hammond, M2 Communications, Serinomics; Mitch Dowsett, Roche; Soonmyung Paik, Genentech, GlaxoSmithKline; Mark D. Pegram, Genentech; Michael F. Press, Genentech; Raymond Tubbs, Ventana, Abbott/Vysis; Marc van de Vijver, Roche

Research Funds: Antonio C. Wolff, Roche; Richard J. Cote, Roche, Abbott; Raymond Tubbs, Ventana, Abbott/Vysis; Daniel F. Hayes, Pfizer, Novartis

Testimony: Michael F. Press, Genentech

Other: Raymond Tubbs, Nanoprobes

This is the current release of the guideline.

This NGC summary was completed by ECRI on February 21, 2007. The information was verified by the guideline developer on February 22, 2007.

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