Molecular alterations in triple-negative breast cancer-the road to new treatment strategies

Triple-negative breast cancer is a heterogeneous disease and specific therapies have not been available for a long time. Therefore, conventional chemotherapy is still considered the clinical state of the art. Different subgroups of triple-negative breast cancer have been identified on the basis of protein expression, mRNA signatures, and genomic alterations. Important elements of triple-negative breast cancer biology include high proliferative activity, an increased immunological infiltrate, a basal-like and a mesenchymal phenotype, and deficiency in homologous recombination, which is in part associated with loss of BRCA1 or BRCA2 function. A minority of triple-negative tumours express luminal markers, such as androgen receptors, and have a lower proliferative activity. These biological subgroups are overlapping and currently cannot be combined into a unified model of triple-negative breast cancer biology. Nevertheless, the molecular analysis of this disease has identified potential options for targeted therapeutic intervention. This has led to promising clinical strategies, including modified chemotherapy approaches targeting the DNA damage response, angiogenesis inhibitors, immune checkpoint inhibitors, or even anti-androgens, all of which are being evaluated in phase 1-3 clinical studies. This Series paper focuses on the most relevant clinical questions, summarises the results of recent clinical trials, and gives an overview of ongoing studies and trial concepts that will lead to a more refined therapy for this tumour type.