Abstract P1-08-23: Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer

Abstract

Abstract Purpose: In 2009 we started a prospective, randomized Phase II trial to evaluate HER2-targeting without chemotherapy (CT) in HER2-positive (HER2+) metastatic breast cancer (MBC) patients (pts). Although the study was prematurely closed because of slow accrual, we decided to analyze the primary tumors in order to identify possible biomarkers that could identify, among the enrolled pts, those deriving the longest lasting benefit from HER2-targeting without CT. Experimental Design: In the HERLAP study (NCT00842998), pts with HER2+ MBC were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. CT was added to anti-HER-2 therapy in pts failing to achieve tumor regression at the 8-week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded primary tumor samples. The research-based PAM50 intrinsic subtypes (Luminal A, Luminal B, HER2-enriched and Basal-like) and the normal breast-like group were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated using the HERmark® assay and the p95 VeraTag® assay, respectively. Potential predictors of persistence on protocol (PP, time from randomization to addition of chemotherapy to anti HER2-therapy or death from any cause) were studied by univariate and multivariate analysis. Results: Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8-38.8+) with 4 pts (21.1%) persisting on single agent T or L for longer than 12 months (14.9-38.8+ months). Seventeen pts were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal-related genes such as PGR, MDM2 and PIK3CA, or the PAM50 luminal intrinsic profile, were found associated with reduced PP. Quantitative H2T and p95 expression revealed that, increasing H2T/p95 ratio significantly associated with longer PP (HR 0.969, p = 0.010). When analyzed as a multivariable model, PAM50 intrinsic subtype and H2T/p95 ratio dichotomized around the median value independently predicted for longer PP (PAM50 non-luminal vs. Luminal A+B, HR 0.164, p = 0.078 and H2T/p95 ratio higher vs. lower/equal, HR 0.294, p = 0.062 respectively). Conclusions: Our data suggest that tumors belonging to the PAM50 “HER2-enriched” subtype tumors and/or with high H2T/p95 protein expression ratio are exquisitely sensitive to anti HER2-agents. MBC pts with these tumors may be candidates for studies aimed at establishing chemotherapy-free approaches. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-23.