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

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.

Figure 1. The heterogenous landscape of triple-negative breast cancer

Different approaches to dissect the complex molecular landscape of TNBCs are presented. a | Histological subtypes. Some rare but relevant subtypes are shown for illustrative purposes. b | Gene-expression-based subtypes of triple-negative breast cancer (TNBC) according to PAM50. c | Gene-expression-based subtypes defined by Lehmann et al.. d | Integrative clusters (IntClust) of genomic and transcriptomic data applied to basal-like breast cancer (BLBC) defined by gene-expression. e | Heterogeneity of tumour-infiltrating lymphocytes. Tumours with low, intermediate and high lymphocyte infiltration are shown for illustrative purposes. BL1, basal-like 1; BL2, basal-like 2; IM, immunomodulatory; LAR, luminal androgen receptor; M, mesenchymal; MSL, mesenchymal stem-like; UNC, unclassified; UNS, unstable.

Figure 2. Active pharmacological interventional trials in TNBC

An overview of the clinical trials for triple-negative breast cancer (TNBC) active as of July 2015 is depicted (trials including immunotherapies were updated in November 2015). Targets of molecularly targeted therapies included angiogenesis (VEGF, VEGFR, integrins), homologous repair (poly(ADP-ribose) polymerase (PARP)), serine/threonine-protein kinase (Chk1/2), PI3K/mTOR, growth factor receptors (EGFR, MET), hormone receptors (androgen receptor (AR)), Ras/MAPK, and Notch/γ-secretase, among others. Immune-checkpoint inhibitors included anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte protein 4 (CTLA 4) monoclonal antibodies (mAbs).

Figure 3. Histological characteristics of luminal androgen receptor (LAR) triple-negative breast cancer

a | On low magnification, infiltrative nests and cords of eosinophilic tumour cells surrounded by a desmoplastic tumour stroma devoid of tumour-infiltrating lymphocytes can be observed. b | Tumour cells contain large epithelioid nuclei with prominent nucleoli and abundant granular eosinophilic cytoplasm. As depicted, rates of mitosis are frequently low in LAR. c | Nuclear expression of androgen receptors, detectable by immunohistochemistry, is a hallmark of LAR.