Multiple Subtypes of HER-2/Neu-Positive Metastatic Breast Cancer.

Abstract

Abstract Background: Using IHC or FISH to select patients for trastuzumab-based therapy, only half of HER2-positive patients show evidence of response. In vitro data implicate HER2:HER3 heterodimers and p95HER2 (p95), the truncated 95-kilodalton C-terminal fragment of HER-2 lacking the trastuzumab binding site, as mediators of resistance to trastuzumab at the receptor level. We have previously reported that central FISH-positive patients with low HER2 protein expression by VeraTag had significantly reduced response to trastuzumab compared to patients who had FISH-positive tumors with high HER2 protein expression (Lipton, SABCS 2008). Adding quantitative measurements of HER3 and p95, we offer evidence for the existence of multiple sub-types of HER2-positive tumors that respond differently to trastuzumab.Methods: Using the VeraTag assay, quantitative protein measurements of HER2, HER3, and p95 were made in FFPE specimens from a cohort of patients with metastatic breast cancer (MBC) and correlated with time to progression (TTP) and overall survival (OS) following treatment with first-line trastuzumab using Kaplan-Meier (KM) and Cox proportional hazards regression analyses.Results: Measurements of HER2 (H2T), HER3 (H3T) and p95 were made in FFPE tumor samples from 95 patients treated with first-line trastuzumab for metastatic breast cancer. Within the group that overexpressed HER2 by the VeraTag Assay (n=60), a group with highly overexpressed HER2 (n=15) had shorter TTP and OS than those that had moderate HER2 overexpression (median TTP 4.6 vs. 12 mos, HR=2.1; p=0.011; median OS 29 vs. 40 mos, HR=2.0; p=0.047). Within the subgroup with moderate H2T overexpression (n=45), bivariate Cox analyses demonstrated that p95 and H3T were independent predictors of TTP (p95 HR=2.1; p=0.031; H3T HR=3.5; p=0.0037). For OS, p95 was significant and H3T showed a strong trend (p95 HR=2.5; p=0.025, H3T HR=2.2; p=0.089). Univariate KM analysis with the p95+ and H3T+ groups combined, gives the results in the table below. These data suggest that HER2-positive breast cancer patients can be classified into at least 4 sub-groups with different outcomes following trastuzumab treatment.Conclusions: These data suggest the existence of multiple subgroups of HER2-positive patients expressing varying HER2, p95, and HER3 levels that experience different clinical outcomes following treatment with trastuzumab. Furthermore, the association of HER3 and p95 overexpression with poor response to trastuzumab in otherwise HER2-positive tumors suggests possible treatment approaches with combinations of targeted therapies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2030.