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Background  Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high  HER2  to  Chromosome 17  FISH ( HER2/CEP17 ) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether  HER2/CEP17  ratios might have an impact on disease-free survival (DFS).    Methods  Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007–2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts.  HER2/CEP17  ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of  HER2  amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between  HER2  gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression.    Results  A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23–89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and  HER2/CEP17  ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high  HER2/CEP17  ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact was detected for tumor size (p = 0.02), nodal status (p<0.01), proliferation index (p<0.01), level (≥20%) of estrogen receptor expression (p = 0.03) and neoadjuvant therapeutic setting (p = 0.03), respectively. Importantly, univariate and multivariable analysis revealed that standard trastuzumab containing chemotherapy resulted in impaired disease free survival among tumors with FISH ratio >8 (p<0.01). Although less pronounced, a similar association was found also with respect to high  HER2  gene copy numbers (>12) and DFS (p = 0.01).    Conclusions  In early BC patients, tumors with high  HER2  amplification ratios (>8), may less likely respond to standard trastuzumab-containing therapies. Although, we obtained a similar effect for high  HER2  gene copy numbers, this provides only an indirect speculation and not a proof that high  HER2/CEP17 ratios  may induce HER2 resistance.

HER2/CEP17 Ratios and Clinical Outcome in HER2-Positive Early Breast Cancer Undergoing Trastuzumab-Containing Therapy