Breast Cancer Patients with Very High Tumor HER2 Expression Levels Might Not Benefit from Treatment with Trastzumab Plus Chemotherapy: A Retrospective Exploratory Analysis of the FinHer Trial.

Abstract

Abstract Background: FinHer (NEJM 2006) is one of the several prospective randomized clinical trials that show a clinical benefit from trastuzumab added to adjuvant chemotherapy. We have previously reported that patients with metastatic breast cancer who had very high levels of HER2 protein expression as measured by the HERmark assay and who were treated with trastuzumab had similar time-to-progression (TTP) compared to a group of patients who had FISH-negative and HER2 normal cancer suggesting reduced efficacy of trastuzumab when tumor HER2 content is very high (Sperinde, ASCO 2009). Here we investigate the relationship between clinical benefit from trastuzumab and quantitative HER2 protein expression (H2T) as determined by the HERmark assay.Methods: H2T was quantitated by the HERmark assay in 899 formalin-fixed paraffin-embedded specimens from patients enrolled in the FinHer trial; 196 of the samples were HER2-positive by chromogenic in situ hybridization (CISH). Focusing on the HER2-positive patients who were randomized to trastuzumab treatment or control, Cox proportional hazards analyses, sub-population treatment effect pattern plots (STEPP analyses), positional scanning analyses, and Kaplan-Meier analyses were used to identify sub-populations of HER2 over-expressing patients who experienced different clinical outcomes on trastuzumab.Results: Using time to distant recurrence (TDR) and overall survival (OS) as endpoints, Cox proportional hazards analyses treating H2T as a continuous variable failed to show a relationship between HER2 expression levels and clinical benefit from trastuzumab (HR=1, p=ns for both). STEPP analyses were performed to look for non-linear relationships between H2T and clinical outcome. At the highest levels of H2T, the hazard ratio comparing trastuzumab treatment to control approached and exceeded 1. Positional scanning analyses were conducted to identify the optimal cutoff discriminating the very high H2T group. Patients with very high H2T values (>= 125.9) did not benefit from trastuzumab plus chemotherapy treatment relative to controls (HR=1.23, p=0.75 for TDR, HR=1.05, p=0.95 for OS), while those with H2T values <125.9 did (HR=0.52, p=0.05 for TDR, HR=0.48, p=0.1 for OS). The very high H2T group represented 13% of the HER2-positive population compared with 16% in the prior study from Sperinde et al.Discussion: In this exploratory analysis of a prospectively randomized controlled trial of trastuzumab in the adjuvant setting, the 13% of patients with the highest H2T values showed no evidence of clinical benefit from trastuzumab. Potential explanations include insufficient trastuzumab dose, steric hindrance preventing access of trastuzumab to its epitope target under conditions of HER2 over-crowding, or the existence of trastuzumab-resistant forms of HER2 at the highest levels of over-expression (e.g. p95/HER2, HER2:HER3 heterodimers). Although these results are in agreement with prior observations from the metastatic setting, they need to be confirmed in larger randomized trials of trastuzumab in early breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5083.