Practical classification of triple-negative breast cancer: intratumoral heterogeneity, mechanisms of drug resistance, and novel therapies

Abstract

Triple-negative breast cancer (TNBC) is not a unique disease, encompassing multiple entities with marked histopathological, transcriptomic and genomic heterogeneity. Despite several efforts, transcriptomic and genomic classifications have remained merely theoretic and most of the patients are being treated with chemotherapy. Driver alterations in potentially targetable genes, including PIK3CA and AKT, have been identified across TNBC subtypes, prompting the implementation of biomarker-driven therapeutic approaches. However, biomarker-based treatments as well as immune checkpoint inhibitor-based immunotherapy have provided contrasting and limited results so far. Accordingly, a better characterization of the genomic and immune contexture underpinning TNBC, as well as the translation of the lessons learnt in the metastatic disease to the early setting would improve patients' outcomes. The application of multi-omics technologies, biocomputational algorithms, assays for minimal residual disease monitoring and novel clinical trial designs are strongly warranted to pave the way toward personalized anticancer treatment for patients with TNBC.

Keywords: Breast cancer.

Fig. 1. Triple-negative breast cancer molecular subtypes across studies.

Transcriptomic-based and gene expression-based subtypes of triple-negative breast cancer (TNBC) according to PAM50 (a) and defined by Lehmann et al.^, (b and d), Curtis et al. (c), Burstein et al. (e), and Jiang et al. (f). BLIA basal-like immune-activated, BLIS basal-like immunosuppressed, BL1 basal-like 1, BL2 basal-like 2, IM immunomodulatory, IntClust integrative clusters, LAR luminal androgen receptor, M mesenchymal, MES mesenchymal, MSL mesenchymal stem-like, UNS unstable. Figures was generated by reanalysis of publicly available studies and open-source platforms (cBioPortal: https://www.cbioportal.org).

Fig. 2

Biomarker-driven therapeutic approaches in triple-negative breast cancer.