The Evolution of Triple-Negative Breast Cancer: From Biology to Novel Therapeutics

Abstract

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as "immune-activated," consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.