Purpose: Heterogeneity of HER2 gene amplification is found in a subset of breast cancers. However, it is not known whether breast cancers with heterogeneous HER2 amplification respond differently to HER2-targeted therapy than those with homogeneous amplification. In this study, we investigated the relationship between HER2 heterogeneity and trastuzumab resistance and clinical outcomes in patients with HER2-positive metastatic breast cancer.

Patients and methods: We studied tumor tissues from 127 patients with HER2-positive metastatic breast cancers who had received trastuzumab-based chemotherapy. Regional and genetic heterogeneity of HER2 amplification was determined in three different areas of each tumor by immunohistochemistry (IHC) and silver in situ hybridization. We also assessed the overall levels of HER2 amplification, and the proportion of tumor cells with a HER2/CEP17 ratio >2.2 or HER2 overexpression (IHC score of 3+). HER2status including HER2 heterogeneity was correlated with trastuzumab responses and survival of the patients.

Results:HER2regional and genetic heterogeneity was confirmed in 7.8% and 3.6% of cases, respectively. Poor response to trastuzumab was associated with overall low-level amplification, HER2regional heterogeneity, HER2/CEP17 ratio >2.2 in <80% of tumor cells, and HER2 IHC score of 3+ in <75% of tumor cells. In survival analyses, low-level HER2 amplification, HER2regional heterogeneity, and HER2/CEP17 ratio >2.2 in <80% of tumor cells were associated with shorter time to progression and lower overall survival in univariate and multivariate analyses.

Conclusion: Accurate assessment of HER2 status including HER2 heterogeneity is important in predicting trastuzumab responses and outcomes in patients with HER2-positive metastatic breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-38.