Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2 + advanced breast cancer patients receiving trastuzumab-containing therapy

摘要

Background. Patients with human epidermal growth factor receptor (HER)-2 + breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) inHER-2 + advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy forHER-2 + metastatic breast cancer. HER-2/ neu gene copy number was quantified as the HER-2/ centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark? assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab- containing therapy. Results. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p =.013, 28, and 25, respectively). In the subset of patients that was centrally determined by FISH to beHER-2 +, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p =.005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p =.4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p =.024). Conclusions. These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse inHER-2 + advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.