Heterogeneity of triple negative breast cancer: Current advances in subtyping and treatment implications

Abstract

As the field of translational 'omics has progressed, refined classifiers at both genomic and proteomic levels have emerged to decipher the heterogeneity of breast cancer in a clinically-applicable way. The integration of 'omics knowledge at the DNA, RNA and protein levels is further expanding biologic understanding of breast cancer and opportunities for customized treatment, a particularly pressing need in clinically triple negative tumors. For this group of aggressive breast cancers, work from multiple groups has now validated at least four major biologically and clinically distinct omics-based subtypes. While to date most clinical trial designs have considered triple negative breast cancers as a single group, with an expanding arsenal of targeted therapies applicable to distinct biological pathways, survival benefits may be best realized by designing and analyzing clinical trials in the context of major molecular subtypes. While RNA-based classifiers are the most developed, proteomic classifiers proposed for triple negative breast cancer based on new technologies have the potential to more directly identify the most clinically-relevant biomarkers and therapeutic targets. Phospho-proteomic data further identify targetable signalling pathways in a unique subtype-specific manner. Single cell profiling of the tumor microenvironment represents a promising way to allow a better characterization of the heterogeneity of triple negative breast cancer which could be integrated in a spatially resolved context to build an ecosystem-based patient classification. Multi-omic data further allows in silico analysis of genetic and pharmacologic screens to map therapeutic vulnerabilities in a subtype-specific context. This review describes current knowledge about molecular subtyping of triple negative breast cancer, recent advances in omics-based genomics and proteomics diagnostics addressing the diversity of this disease, key advances made through single cell analysis approaches, and developments in treatments including targeted therapeutics being tested in major clinical trials.

Keywords: Biomarkers; Clinical trials; Genomics; Molecular subtyping; Proteomics; Single cell profiling; Therapeutic targets; Tripe negative breast cancer.

Fig. 1

Overview of the characteristic mutation profile, copy number, gene expression and pathway enrichment for the different triple negative breast cancer subtypes Triple negative breast cancer subtypes of luminal androgen receptor (LAR), basal-like immune suppressed (BLIS), basal-like immune activated (BLIA), mesenchymal (MES) and the possible addition of mesenchymal stem-like (MSL) are shown at the core. Genes and pathways denoted in red (indicate high expression) while those denoted in green (indicate low expression). Data are aggregated from Lehmann et al.[57], Burstein et al.[7], Jiang et al.[6], Bareche et al.[35], Bareche et al.[64], Lehmann et al.[58], Gong et al.[76] and Asleh et al.[60]. Abbreviations: TNBC, triple negative breast cancer; HRD,