Unravelling triple-negative breast cancer molecular heterogeneity using an integrative multiomic analysis

Abstract

BackgroundRecent efforts of genome-wide gene expression profiling analyses have improved our understanding of the biological complexity and diversity of triple-negative breast cancers (TNBCs) reporting, at least six 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.Patients and methodsThis study was carried out using copy-number aberrations, somatic mutations and gene expression data derived from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas. TNBC samples (n = 550) were classified according to Lehmann’s molecular subtypes using the TNBCtype online subtyping tool (http://cbc.mc.vanderbilt.edu/tnbc/).ResultsEach subtype showed significant clinic-pathological characteristic differences. Using a multivariate model, IM subtype showed to be associated with a better prognosis (HR = 0.68; CI = 0.46–0.99; P = 0.043) whereas LAR subtype was associated with a worst prognosis (HR = 1.47; CI = 1.0–2.14; P = 0.046). 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 and 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. Finally, IM showed high expression levels of immune signatures and check-point inhibitor genes such as PD1, PDL1 and CTLA4.ConclusionOur 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 anticancer therapeutics for TNBC.

A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

“…Moreover, our presentation of global copy number alterations highlights the specific characteristics of TNBC: 8q24 ( MYC ) focal gain, 1q, 10p gain and 8p, 5q loss . Some transcriptomic subtypes in this cohort harbored specific somatic mutations already described in other studies LAR subtype corresponds to the luminal repertoire of genomic alterations: the most frequent mutations are PIK3CA and AKT1 (40%, 2/5) and the less frequent mutations are TP53 (20%). BL1 and BL2 present a high percentage of TP53 mutations (55.5 and 75%, respectively).…”

“…Transcriptomic classifications are not used in clinical practice, but stress the importance of selection of the TNBC subtype before prescribing targeted therapy. However, except for the LAR and mesenchymal subtypes, it is difficult to demonstrate a specific correlation between transcriptomic subtype and response to targeted therapy …”

A Bayesian network meta‐analysis of the efficacy of targeted therapies and chemotherapy for treatment of triple‐negative breast cancer

“…Nowadays, with improving understanding of biological complexity and diversity of TNBC, six different molecular subtypes were identified, which helped to develop molecular drivers that can be therapeutically targeted. In view of the limited clinical benefit with targeted agents in unselected TNBC patients of some trials, Bareche et al unraveled molecular heterogeneity of six subtypes by using an integrative genomic analysis. The researchers found specific differences in mutational and copy number profiles characterizing each subtype and offered novel therapeutic avenues for these patients .…”

“…In view of the limited clinical benefit with targeted agents in unselected TNBC patients of some trials, Bareche et al unraveled molecular heterogeneity of six subtypes by using an integrative genomic analysis. The researchers found specific differences in mutational and copy number profiles characterizing each subtype and offered novel therapeutic avenues for these patients . For example, basal‐like 1 (BL1) subset characterizing with high genomic instability for BRCA1/2 may be sensitive to PARP inhibitors while mesenchymal (M) subtype tumors with high level of EGFR mRNA expression may be potential candidates to anti‐VEGF inhibitors and EGFR inhibitors .…”

“…The researchers found specific differences in mutational and copy number profiles characterizing each subtype and offered novel therapeutic avenues for these patients . For example, basal‐like 1 (BL1) subset characterizing with high genomic instability for BRCA1/2 may be sensitive to PARP inhibitors while mesenchymal (M) subtype tumors with high level of EGFR mRNA expression may be potential candidates to anti‐VEGF inhibitors and EGFR inhibitors . Thus, the application of a comprehensive genomic characterization may help to select the most appropriate treatment in TNBC and individualized treatment for TNBC patients may be extremely necessary .…”