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.

Tumour heterogeneity and a long-standing paucity of effective therapies other than chemotherapy have contributed to triple-negative breast cancer (TNBC) being the subtype with the least favourable outcomes. In the past few years, advances in omics technologies have shed light on the relevance of the TNBC microenvironment heterogeneity, unveiling a close dynamic relationship with cancer cell features. An improved understanding of tumour-immune system co-evolution supports the need to adopt a more comprehensive view of TNBC as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody-drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease. The current therapeutic scenario is only the tip of the iceberg, as hundreds of new compounds and combinations are in development. The translation of these experimental therapies into clinical benefit is a welcome and ongoing challenge. In this Review, we describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can define different levels of risk and provide improved opportunities for tailoring treatment.

Metastatic breast cancers are immunologically more inert than the corresponding primary tumors but some immune-oncology targets and macrophage and angiogenesis signatures show preserved expression and suggest therapeutic combinations for clinical testing.

Purpose: We report a retrospective exploratory analysis of the association of the research-based prediction analysis of microarray 50 (PAM50) subtype predictor with pathologic complete response (pCR) and event-free survival (EFS) in women enrolled in the NeOAdjuvant Herceptin (NOAH) trial.Experimental Design: Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded core biopsies from 114 pretreated patients with HER2-positive (HER2 þ ) tumors randomized to receive neoadjuvant doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF), or the same regimen in combination with trastuzumab for one year. A control cohort of 42 patients with HER2-negative tumors treated with AT-CMF was also included. The PAM50 subtypes, the PAM50 proliferation score, and the PAM50 risk of relapse score based on subtype (RORS) and subtype and proliferation (RORP) were evaluated.Results: HER2-enriched (HER2-E) tumors predominated within HER2 þ disease, although all PAM50 intrinsic subtypes were identified across the three cohorts. The OR for achieving pCR with trastuzumabbased chemotherapy for HER2 þ /HER2-E and HER2 þ /RORP-high were 5.117 (P ¼ 0.009) and 8.469 (P ¼ 0.025), respectively, compared with chemotherapy only. The pCR rates of HER2 þ /HER2-E and HER2 þ / RORP-high after trastuzumab-based chemotherapy were 52.9% and 75.0%, respectively. A statistically nonsignificant trend was observed for more pronounced survival benefit with trastuzumab in patients with HER2 þ /HER2-E and HER2 þ /RORP-high tumors compared with patients with HER2 þ /non-HER2-E and HER2þ /non-RORP-high tumors, respectively. Conclusions: As determined by EFS and pCR, patients with HER2þ