Evaluation of the association of HER family members with efficacy of trastuzumab therapy in metastatic breast cancer

Abstract

Background: In the current study, we performed a complete analysis of gene amplification, copy-number variations (CNV), transcriptional profiling and protein expression of all four HER family receptors, in a series of patients with metastatic breast cancer (MBC), treated with trastuzumab-based regimens. In addition, our analysis included the evaluation of several other factors, such as PTEN and mTOR protein expression by immunohistochemistry (IHC) and PIK3CA mutations. Methods: Formalin-fixed paraffin-embedded tumor tissue samples were collected from 229 patients, considered to be HER2-positive when assessed at the local laboratories. Central review of HER2 status by fluorescence in situ hybridization and/or IHC revealed that of the 229 patients, only 139 (61%) were truly HER2-positive. Results: In the multivariate analysis, HER3 gene amplification (using the 75th percentile as a cut-off point) (HR = 0.50, 95% CI 0.27-0.93, p = 0.027), HER3 mRNA expression (75th percentile as a cut-off point) (HR = 0.47, 95% CI 0.22-1.01, p = 0.052) and PTEN protein expression (HR = 0.60, 95% CI 0.37-0.98, p = 0.042) retained their favorable prognostic significance for OS in the HER2-positive subgroup. In HER2-negative patients, none of the significant factors that were identified in the univariate analysis retained prognostic ability for OS. Moreover, wild-type PIK3CAwas found to be an independent favorable prognostic factor for TTP in the HER2-positive patients (HR = 0.53, 95% CI 0.27-1.02, p = 0.059). In addition, EGFR CNVs (HR = 4.89, 95% CI 1.23-19.36, p = 0.024), HER3 gene amplification (using the median value as a cut-off point) (HR = 0.41, 95% CI 0.16-1.06, p = 0.067), HER3 protein expression (HR = 0.15, 95% CI 0.04-0.52, p = 0.003) and mTOR protein expression (HR = 0.33, 95% CI 0.13-0.84, p = 0.02) independently affected TTP in the HER2-negative subgroup. Conclusions: The present study suggests that EGFR is a negative, whereas HER3 is a positive prognostic factor in patients with MBC. Since the above associations were not restricted to HER2-positive patients only, a definitive predictive value for trastuzumab treatment is not documented. Given the retrospective nature of the current analysis, our findings should be considered as hypothesis generating.