Triple-Negative Breast Cancer: Molecular Subtypes and New Targets for Therapy

Abstract

Triple-negative breast cancer (TNBC) is a molecularly diverse disease. This heterogeneity has limited the success of targeted therapy in unselected patients to date. Recent transcriptional analysis has divided TNBC into transcriptionally similar subtypes that may have different sensitivity to neoadjuvant chemotherapy and targeted therapy. At present, chemotherapy is the mainstay of treatment for early-stage and advanced TNBC; however, several actionable targets show promise in preclinical studies. Novel therapeutic strategies are currently being tested in phase II and phase III trials and will likely require patient stratification before therapy. Examples of these tailored approaches include poly(ADP-ribose) polymerase inhibitors for BRCA-mutated TNBC, antiandrogens for androgen receptor (AR)–positive TNBC, fibroblast growth factor receptor (FGFR) inhibitors for TNBC harboring FGFR amplifications, and gamma-secretase inhibitors for TNBC with mutations in the PEST domain of NOTCH proteins. Treatment of TNBC based on molecular subsets represents a potential algorithm for the future. Well-designed clinical trials with incorporation of integrated biomarkers are necessary to advance the development of molecularly targeted therapy for different subgroups of TNBC.