Abstract 4552: Utilization of pathway activation and somatic mutation analysis in combination in fine needle aspirates to identify candidate drugs for effective treatment of breast cancer

Abstract

Abstract A critical hurdle in implementing prognostic and predictive biomarkers in clinical trials is our inability to perform an efficient molecular characterization of the limited amounts of available clinical samples. Here we report a comprehensive molecular analysis of fine needle aspirate (FNA) samples collected from metastatic sites of 58 breast cancer (BCA) patients. The analysis included interrogation of key receptor tyrosine kinases and their downstream signaling molecules including HER1, HER2, p95HER2, HER3, cMET, IGF1R, PI3K, Shc, AKT and ERK as well as oncogenic somatic mutational profiling. A multiplexed immunoarray CEER™ (Collaborative Enzyme Enhanced Reactive-immunoassay) platform was utilized to determine the levels of pathway protein expression and phosphorylation. All FNA collections provided sufficient materials for the combined analysis of multiplexed pathway expression/activation and somatic mutation analysis. All the FNA from metastatic sites (mFNA) collected from HER2 positive primary tumors (determined by IHC) were also CEER-HER2 positive. Over-expression of HER2 was found in 10% of mFNAs collected from BCA patients with HER2 negative primary tumors. PIK3CA mutations were found in 20% of the samples in this cohort. Statistically significant higher levels of phosphorylated AKT, ERK (downstream effector targets) as well as HER1, HER2, HER3 and IGF1R (PI3K membrane recruiter proteins) were found in mFNAs with PIK3CA mutations. Subset of PIK3CA wildtype patients also showed robust pathway signature. Hence, evaluation of biomarkers in BCA patients should include both pathway proteins as well as mutation analysis. A comprehensive disease profiling can provide insightful information on efficacy of specific agents on its intended target protein inhibition. As CEER requires minimal amount of specimen, performance of routine pathway profiling can be achieved in clinical settings. A multiplexed pathway analysis can also provide valuable information about potential drug resistance mechanisms. Furthermore, a combined mutational and pathway activation profiling can guide therapeutic strategies in clinical setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4552. doi:1538-7445.AM2012-4552