Abstract P2-07-02: Uncovering TNBC molecular heterogeneity by applying integrative “omics” analyses with potential clinical implications

Abstract

Abstract Introduction: Triple-negative breast cancer (TNBC), representing about 10-20% of all breast cancers (BC), is a heterogeneous disease characterized by a clinically aggressive course, higher relapse rates and worse overall survival as compared to other BC subtypes. Recent efforts of genome-wide gene expression profiling have improved our understanding of the biological diversity of TNBCs reporting at least 6 different molecular subtypes namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). Little is known regarding the potential driving molecular events characterizing each subtype, their difference in survival and response to therapy. Moreover, limited progress has been made so far in the development of effective therapeutic strategies in TNBC partly due to the lack of obvious genetic targets. Further insight into the underlying genomic alterations is therefore needed. Aims: Here, we aimed to study the genomic aberrations that drive each of the TNBC molecular subtypes as defined by Lehmann et al. by applying an integrative analysis combining somatic mutation, copy number aberrations and gene expression profiles of 272 TNBC derived from METABRIC consortium. Methods: In silico analyses were performed using microarray, copy number aberrations profiles (CNA) and mutation profiles data retrieved from 272 TNBC patients from the METABRIC consortium. Somatic mutation profiles were derived from targeted sequencing of 173 cancer genes. CNAs at the gene level were computed using GISTIC 2.0.22. The relationship between TNBC molecular subtypes and genomic aberrations were analysed using Fisher test. Survival analyses were performed using Cox proportional hazard models adjust for standard clinical and pathologic variables. Results: Using a multivariate model, IM and M subtypes were significantly associated with good (HR=0.53; FDR=0.01) and poor (HR=1.8; FDR=0.01) prognosis respectively. BL1 subtype was found to be the most genomically instable subtype with high frequency of TP53 mutations (93%) and copy-number deletions in genes involved in DNA repair mechanisms (BRCA2, MDM2, RB1 and TP53) and MYC overexpression. BL2 subtype was enriched with TP53 (95%) and PIK3CA mutations (52%), whereas LAR subtype was characterized by high frequency of PI3KCA mutations (44%). Of interest, for these two subtypes, mutations in genes in the PI3K signalling pathway were mutually exclusive. IM subtype was enriched in NCOR2 mutations (13%), a co-repressor of the Notch pathway, associated with lower gene expression (p=0.035). M and MSL subtypes were significantly associated with higher signature scores for angiogenesis. In addition, M subtype was associated with higher frequency of NOTCH1 mutations (M p=2.4E-2). Conclusions: This integrative analysis combining somatic mutation, copy number and gene expression profiles shed new light on TNBC molecular heterogeneity, highlighting TNBC subtype-specific genomic aberrations which could potentially open new avenues for the development of effective targeted therapies in each TNBC molecular subtype such as DNA repair, Notch and angiogenesis. Citation Format: Bareche Y, Venet D, Rothe F, Sotiriou C. Uncovering TNBC molecular heterogeneity by applying integrative “omics” analyses with potential clinical implications [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-02.