JNCCN HER 2 Testing in Breast Cancer : NCCN Task Force Report and Recommendations

The NCCN HER2 Testing in Breast Cancer Task Force was convened to critically evaluate the ability of the level of HER2 expression or gene amplification in breast cancer tumors to serve as a prognostic and a predictive factor in the metastatic and adjuvant settings, to assess the reliability of the methods of measuring HER2 expression or gene amplification in the laboratory, and to make recommendations regarding the interpretation of test results. The Task Force is a multidisciplinary panel of 24 experts in breast cancer representing the disciplines of medical oncology, pathology, radiation oncology, surgical oncology, epidemiology, and patient advocacy. Invited members included members of the NCCN Breast Cancer Panel and other needed experts selected solely by the NCCN. During a 2-day meeting, individual task force members provided didactic presentations critically evaluating important aspects of HER2 biology and epidemiology: HER2 as a prognostic and predictive factor; results from clinical trials in which trastuzumab was used as a targeted therapy against HER2 in the adjuvant and metastatic settings; the available testing methodologies for HER2, including sensitivity, specificity, and ability to provide prognostic and predictive information; and the principles on which HER2 testing should be based. Each task force member was charged with identifying evidence relevant to their specific expertise and presentation. Following the presentations, an evidence-based consensus approach was used to formulate recommendations relating to the pathologic and clinical application of the evidence to breast cancer patient evaluation and care. In areas of controversy, this process extended beyond the meeting to achieve consensus. The Task Force concluded that accurate assignment of the HER2 status of invasive breast cancer is essential to clinical decision making in the treatment of breast cancer in both adjuvant and metastatic settings. Formal validation and concordance testing should be performed and reported by laboratories performing HER2 testing for clinical purposes. If appropriate quality control/ assurance procedures are in place, either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) methods may be used. A tumor with an IHC score of 0 or1+, an average HER2 gene/chromosome 17 ratio of less than 1.8, or an average number of HER2 gene copies/cell of 4 or less as determined by FISH is considered to be HER2 negative. A tumor with an IHC score of 3+, an average HER2 gene/chromosome 17 ratio of greater than 2.2 by FISH, or an average number of HER2 gene copies/cell of 6 or greater is considered HER2 positive. A tumor with an IHC score of 2+ should be further tested using FISH, with HER2 status determined by the FISH result. Tumor samples with an average HER2 gene/chromosome ratio of 1.8 to 2.2 or average number of HER2 gene copies/cell in the range of greater than 4 to less than 6 are considered to be borderline, and strategies to assign the HER2 status of such samples are proposed. (JNCCN 2006;4(Suppl 3):S1–S22) HER2-Testing Task Force Meeting: Rationale The human epidermal growth factor receptor 2 (HER2) is a type of transmembrane protein receptor tyrosine kinase (RTK) known as ErbB that is important in initiating signal transduction pathways in normal and abnormal cells. The HER2 protein is overexpressed and/or its gene is amplified in 15% to 20% of invasive breast cancers. HER2 overexpression or gene amplification is associated with an aggressive phenotype of breast cancer, predicts for benefit from trastuzumab therapy (Herceptin; a recombinant humanized monoclonal antibody specific for the external region of HER2), and may predict breast cancer sensitivity to combinations of trastuzumab and selected chemotherapeutic agents, such as the anthracyclines. The identification of individual patients with breast cancers that overexpress the HER2 protein or amplify the HER2 gene is dependent on the determination of the HER2 status of invasive breast cancer cells. This single assessment of the presence or absence of the trastuzumab target is the central criterion used to direct critical decisions concerning patient eligibility for trastuzumab therapy (Figure 1). The most recent version of the NCCN Breast Cancer Clinical Practice Guidelines in Oncology incorporates tumor hormonal receptor (e.g., estrogen receptor and/or progesterone receptor) and HER2 receptor expression or gene amplification as both prognostic factors for outcome and predictive factors for responsiveness to adjuvant systemic therapy. The importance of these factors is emphasized by the stratification of patients by hormonal receptor status and HER2 status before assessment of anatomic prognostic factors such as tumor size, lymph node involvement, tumor grade, angiolymphatic invasion, or mitotic rate. A false-negative HER2 test result denies the patient access to trastuzumab therapy and its potential for substantial clinical benefit, whereas a false-positive result exposes the patient to the risks (e.g., cardiotoxicity) and expense of costly trastuzumab therapy without likelihood of therapeutic benefit. Use of the HER2 receptor and hormonal receptor biomarkers in breast cancer is an example of the successful application of genomic and proteomic technologies to cancer evaluation and treatment. Biomarkers such as HER2 and estrogen receptors allow for targeted therapy because they are direct cellular targets of therapeutic interventions with trastuzumab or endocrine therapy, they can be measured in the laboratory, and they are correlated with clinical response to therapy. Furthermore, the clinical benefits of targeted therapy in patients not selected for the presence of the target will probably be modest. Thus, accurate identification of patients with HER2-positive (i.e., HER2 overexpression/ gene amplification) versus -negative (i.e., normal/ low, non-amplified levels of HER2 protein/gene) disease has implications not only for patients with HER2-positive disease, but also for the 80% to 85% of breast cancer patients with HER2-negative disease. Clinically important effects of particular therapies in populations with HER2-negative disease may be better understood when the subset of patients with HER2-positive disease is accurately identified and selectively excluded from certain clinical studies. The NCCN HER2 Testing in Breast Cancer Task Force was convened to critically evaluate the ability of the level of HER2 expression or gene amplification of breast cancer tumors to serve as a prognostic and a predictive factor in the metastatic and adjuvant settings, to assess the reliability of methods of measuring HER2 expression or gene amplification in the laboratory, and to make recommendations regarding the interpretation of test results. The need for this evaluation intensified after reports of HER2 testing problems encountered in clinical studies involving adjuvant breast cancer therapies targeted to the HER2 receptor. The task force generated recommendations to guide the overall process of HER2 testing to limit test variability. The consensus of the task force was that the HER2 receptor is a biomarker used in the setting of breast cancer for which laboratory testing processes must undergo intense scrutiny and reevaluation. The important roles of both the clinician and the pathologist in assuring the accurate quantification of breast cancer biomarkers, the correct interpretation of biomarker test results, and the appropriate application of targeted therapy were overarching themes the task force acknowledged. HER2-Testing Task Force Meeting: Process Task Force members came from both NCCN and nonNCCN institutions, and include some members of the NCCN Breast Cancer Clinical Practice Guidelines Panel. Additionally, breast cancer experts with special expertise in HER2 biology, testing, or trastuzumab were invited. In all, 24 Task Force members represented medical oncology, pathology, radiation oncology, surgical oncology, epidemiology, and patient advocacy. All Task Force members were identified and invited solely by NCCN. Topics for discussion were elaborated in a formal agenda developed by the task force chair, and individual members were assigned topics for focused, didactic presentations based on high-level scientific evidence whenever possible. Substantial time was allowed for discussion after each scientific presentation. An evidence-based consensus approach was used to formulate recommendations relating to the pathological and clinical application of the evidence to S-2 Supplement NCCN Task Force Report © Journal of the National Comprehensive Cancer Network | Volume 4 | Supplement 3 | July 2006 Figure 1 Pivotal role of the HER2 test result in selecting therapy in breast cancer. breast cancer patient evaluation and care. In areas of controversy, this process extended beyond the meeting to achieve consensus. Draft versions of this report were circulated among all of the task force members for review and comment.