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Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease

Key Points

  • The routine diagnosis of triple-negative breast cancer (TNBC) depends on the accurate assessment of the status of the oestrogen receptor (ER), progesterone receptor (PgR) and HER2

  • Chemotherapy remains the standard therapeutic approach for TNBC at all stages, with platinum compounds having a relevant role, especially in patients harbouring BRCA1/2 mutations or 'BRCAness'

  • 'Omics' technologies have provided unprecedented insights into the molecular complexity and heterogeneous clinical behaviour of TNBC but, to date, none of the newly developed molecular classifications has demonstrated clinical utility

  • Several potentially actionable molecular alterations, frequently affecting PI3K/mTOR or RAS/RAF/MEK, have been found in TNBC, but none have been confirmed as a 'driver alteration', nor have any TNBC subsets been shown to be 'addicted' to them

  • Targeted agents currently under clinical investigation in TNBC include PARP inhibitors, PI3K inhibitors, MEK inhibitors, anti-androgen therapies, heat shock protein 90 inhibitors, histone deacetylase inhibitors, and their combinations

  • TNBC is remarkably heterogeneous in terms of the tumour microenvironment; tumour lymphocyte infiltration is associated with good prognosis and a response to chemotherapy, which provides a strong rationale for testing immunotherapies in TNBC

Abstract

Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations. Whether these alterations are molecular 'drivers', however, has not been clearly established. A subgroup of TNBCs shows a high degree of tumour-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. In this Review, we discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities derived from these data.

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Figure 1: The heterogenous landscape of triple-negative breast cancer.
Figure 2: Active pharmacological interventional trials in TNBC.
Figure 3: Histological characteristics of luminal androgen receptor (LAR) triple-negative breast cancer.

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Acknowledgements

This report was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC) grant to G.B. (MFGA 13428) and the Fondazione Michelangelo for the advancement of the study and treatment of cancer grant to G.B.

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G.B., J.M.B, I.A.M. and L.G. researched data for the article. M.E.S. provided histological pictures. G.B., J.M.B, I.A.M., M.E.S. and L.G. contributed to discussing the article's content. All authors wrote, reviewed and edited the manuscript before submission.

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Correspondence to Luca Gianni.

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Competing interests

G.B received honorarium from Roche. L.G. had an advisory role for Merck and Roche. J.M.B., I.A.M. and M.E.S. declare no competing interests.

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Bianchini, G., Balko, J., Mayer, I. et al. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 13, 674–690 (2016). https://doi.org/10.1038/nrclinonc.2016.66

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