HER2 Testing in Breast Cancer: NCCN Task Force Report and Recommendations

Abstract

<jats:p>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 <jats:italic>HER2</jats:italic> gene/chromosome 17 ratio of less than 1.8, or an average number of <jats:italic>HER2</jats:italic> 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 <jats:italic>HER2</jats:italic> gene/chromosome 17 ratio of greater than 2.2 by FISH, or an average number of <jats:italic>HER2</jats:italic> 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 <jats:italic>HER2</jats:italic> gene/chromosome ratio of 1.8 to 2.2 or average number of <jats:italic>HER2</jats:italic> 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. (<jats:italic>JNCCN</jats:italic> 2006;4(Suppl 3):S1–S22)</jats:p>

Screening Mammography for Women in Their 40s: A Retrospective Study of the Potential Impact of the U.S. Preventive Service Task Force's 2009 Breast Cancer Screening Recommendations

“…However, at the same time, the cancers detected were potentially treatable ones. The expression of ER and PR is well recognized as a predictive factor for response to tamoxifen [21] and 82% of the screening-detected cancers in women in their 40s were ER-positive and 67% were PR-positive; these findings are similar to the distributions noted in previous studies [21][22][23]. Although almost half our patients with screening-detected breast cancers in their 40s had unknown (n = 18) or indeterminate (n = 1) HER2/neu status (likely because of its relatively recent discovery), 18% had HER2/ neu-positive cancers; this finding is consistent with several studies that have reported HER2/neu positivity in 15-20% of breast cancers [24,25].…”

Pathological Complete Response to Neoadjuvant Trastuzumab Is Dependent on HER2/CEP17 Ratio in HER2-Amplified Early Breast Cancer

“…Trial design, inclusion criteria, and the main clinical results of these trials have been reported previously (19). Briefly, in ABCSG-24, 536 patients with invasive breast cancer were randomly assigned 1:1 to receive six cycles of preoperative epirubicine/docetaxel (both 75 mg/m 2 ) every 3 weeks with or without capecitabine (1,000 mg/m 2 , bid, days [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Patients with HER2-positive disease were further randomized to receive neoadjuvant trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks; n ¼ 44) or not (n ¼ 49).…”

“…IHC detects the level of HER2 protein expression on the cell surface and allows for a semi-quantitative score ranging from 0 to 3þ, with 3þ indicating a positive HER2 status. ISH, in contrast, identifies the number of HER2 gene copies on chromosome 17 as well as the number of centromere 17 (CEP17) copies per nucleus (14). According to current ASCO/CAP clinical practice guidelines (15), a tumor exhibits HER2 amplification if the HER2/ CEP17 ratio exceeds 2, or absolute HER2 copy number exceeded 6.…”

Quality in Cancer Diagnosis

“…Errors may be caused if the period of time for the formalin fixation of tissues is too short or if insufficient quantities of formalin are used 154–157. Other pitfalls related to immunohistochemical testing are nonspecific binding of tissue altered by crush artifact and cautery artifact, factors related to tissue procurement failures 154–160. The American Society of Clinical Oncology (ASCO)‐CAP practice guidelines were published to address these issues 152, 154…”