Abstract A32: MCL1 gene amplification in breast cancer is associated with TNBC status and can respond to a sorafenib/vorinostat regimen

Abstract

Abstract Background: MCL1 encodes the induced myeloid leukemia cell differentiation protein Mcl-1, a member of the BCL-2 family which functions to inhibit apoptosis. Mcl-1 over-expression has been associated with high tumor grade and adverse prognosis in triple negative breast cancer (TNBC) but therapies specifically leading to inhibition of MCL-1 have not been identified. Methods: Comprehensive genomic profiling (CGP) using hybridization capture of 3,769 exons from 315 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥50ng of DNA extracted from 2,824 consecutive BC and sequenced to high, uniform median coverage (>600X). The original primary BC was assayed in 44% of cases and a sample from a metastatic focus was assayed in 56% of cases. Results: Of 2824 consecutive BC cases, 200 (7.1%) cases harbored MCL1 amplification. Of these MCL1-amplified cases, 146 (73%) were TNBC and 54 were non-TNBC (p<0.0001). Twelve of the latter cases (22%) were ERBB2 (HER2) amplified and slide-based HER2 status concordance with CGP was 99%. MCL1 amplification was also observed in the TCGA dataset for 32/123 (26%) of TNBC (p=0.008). Of the MCL1 amplified TNBC cases, 88% were high grade and 98% were stage IV at the time of CGP. Genes co-altered within MCL1 amplified TNBC included TP53 (86%), MYC (41%), MYST3 (21%), LYN (20%), CCNE1 (19%), PIK3CA (18%), and AKT3 (15%). Two MCL1 amplified TNBC patients were treated with a multi-drug regimen based on sorafenib and vorinostat and experienced significant clinical benefit. Conclusions: MCL1 amplification is a frequent feature in advanced stage and high grade TNBC, and correspondingly such MCL1 amplified tumors very seldom harbor co-amplifications of ERBB2. Clinical observation suggests that treatment with sorafenib and vorinostat in heavily pre-treated MCL1 amplified patients may be correlated with clinical benefit, consistent with historic preclinical investigation. These preliminary findings suggest that MCL1 amplified TNBC may be able to benefit from combination targeted therapy, and warrant further systematic investigation. Citation Format: JS Ross, K Wang, A Johnson, J Watson, C Hatzis, L Pusztai, J Chmielecki, R Yelensky, D Lipson, JA Elvin, J Vergilio, J Suh, VA Miller, K Dicke, PJ Stephens, SM Ali. MCL1 gene amplification in breast cancer is associated with TNBC status and can respond to a sorafenib/vorinostat regimen. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A32.