A gene expression signature of MEK pathway activation to predict survival in triple-negative breast cancer.

Abstract

1024 Background: Tumor cell proliferation measured by Ki67 in the surgically removed tumor after neoadjuvant chemotherapy (NAC) has been shown to predict patient outcome in breast cancer. It is unclear from these studies if breast cancer subtype may account in part for the predictive ability of Ki67. Thus, we tested whether Ki67 score in the surgically-resected residual tumor (RT) after NAC predicted outcome in a cohort of triple negative breast cancer (TNBC). Gene expression profiling was performed to identify molecular subtype and test the association with gene modules indicative of signaling pathway activation. Methods: Ki67 was scored in the RT of 89 patients with stage II-III TNBC (ER/PR/HER2 negative by IHC at diagnosis) that had been treated with NAC. Expression levels for 450 genes were quantified by Nanostring. Ki67, node and menopause status, age, therapy type (± taxanes), molecular subtype, and gene expression scores were tested for association to RFS and OS using univariate and multivariate CoxPH models. Results: Ki67 score in the post-NAC RT demonstrated a wide range (1.5-77.7%; median: 36.2%). Twenty seven % of RTs were 3+ HER2 by IHC. Molecular subtype in the RT was as follows: 64% Basal-like; 20% HER2-enriched; 6% LumA; 6% LumB; 4% Normal-like. In univariate analyses to respectively predict RFS and OS, node status (p=0.005 and p=0.02), number of nodes (p=0.003 and p<0.001), and the score of a gene expression module of MEK pathway activation (p=0.04 and p=0.01,) were significant. Basal-like subtype approached significance for RFS (p=0.1) and OS (p=0.05). In multivariate analyses, node status (p=0.002 for RFS and p<0.001 for OS) and MEK pathway activation score (p=0.04 and p=0.01) were significant predictors. Conclusions: Ki67 in the RT after NAC was not predictive of outcome in a cohort of TNBC. However, a gene expression signature of activated MEK was negatively associated with outcome. These data are consistent with the reported preclinical activity of MEK inhibitors against basal-like breast cancer cells and a possible role of this signaling pathway in chemotherapy resistance. They also support deep sequencing studies to identify genetic alterations in the RAS/MEK/MAPK pathway in TNBC.