Abstract 3698: Unraveling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis
Authors: Bareche Yacine , Venet David , Aftimos Philippe , Ignatiadis Michail , Piccart Martine , Rothe Francoise , Sotiriou Christos 
Published: August 2018

Abstract
Introduction : Triple negative breast cancers (TNBCs) represent about 10-20% of all breast cancers and show worse prognosis compared to other molecular subtypes with increased likelihood of early distant recurrence and death. Recent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of TNBCs reporting, at least 6 different molecular subtypes of TNBC namely Basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL) and luminal androgen receptor (LAR). However, little is known regarding the potential driving molecular events within each subtype, their difference in survival and response to therapy. Further insight into the underlying genomic alterations is therefore needed.
Aims : Here, we aimed to study the genomic aberrations that drive each of these TNBC subtypes by applying an integrated analysis of somatic mutation, copy number and gene expression of 550 TNBC derived from Molecular Taxonomy of Breast Cancer International (METABRIC) and The Cancer Genome Atlas (TCGA) consortia.
Methods : The METABRIC & the TCGA datasets were used, with available data for copy-number aberrations, somatic mutations and gene expression. ER, HER2 and PR status were inferred based on the bimodality of their mRNA expression level. TNBC samples (n=550) were classified according to Lehmann's molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc).
Results : We were able to globally reproduce Lehmann's classification with Basal-like 1 (BL1), Immunomodulatory (IM), Androgen-Receptor-like (LAR), Mesenchymal-like (M) and Mesenchymal Stem Cell-like (MSL) being the most stable TNBC subtypes. Each subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, the IM and LAR subtypes showed to be associated with a better prognosis (HR=0.68; CI=0.46-0.99; p=0.043) and a worst prognosis (HR=1.47; CI=1.0-2.14; p=0.046), respectively. BL1 subtype was found to be most genomically instable subtype with high TP53 mutation (92%) and copy-number deletion in genes involved in DNA repair mechanism (BRCA2, MDM2, PTEN, RB1 & TP53). LAR tumours were associated with higher mutational burden with significantly enriched mutations in PI3KCA (55%), AKT1 (13%) and CDH1 (13%) genes. M and MSL subtypes were associated with higher signature score for angiogenesis. IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.
Conclusions : Our findings highlight for the first time the substantial genomic heterogeneity that characterize TNBC molecular subtypes, allowing for a better understanding of the disease biology as well as the identification of several candidate targets paving novel approaches for the development of anti-cancer therapeutics for TNBC.
Citation Format: Yacine Bareche, David Venet, Philippe Aftimos, Michail Ignatiadis, Martine Piccart, Francoise Rothe, Christos Sotiriou. Unraveling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3698.