Molecularly Targeted Therapies for Triple Negative Breast Cancer: History, Advances, and Future Directions

Triple negative breast cancer (TNBC) remains the subtype with poorest prognosis. Despite the subtype's heterogeneity, there is still a paucity in effective targeted therapeutics that offer both good efficacy and tolerability, and chemotherapy remains the backbone of modern TNBC therapy. In the past few years, immunotherapy as well as novel therapeutic modalities like antibody-drug conjugates (ADCs) have shown clinical benefit and have been FDA approved in various clinical stages of unselected TNBC. However, there has not been similar advancement in molecularly targeted therapies, especially when compared to advancements seen in hormone receptor (HR)-positive or HER2-positive breast cancer. PARP inhibitors have been approved for BRCA- mutated TNBC, but responses are short-lived, and resistance remains a barrier for current treatment. PI3K pathway inhibitors approved in HR + breast cancer has not worked for TNBC and continue to have significant dose-limiting adverse effects. EGFR inhibition has been thoroughly explored in TNBC, but all trials so far have shown minimal efficacy. Nevertheless, despite these setbacks, current research in targeted therapy for TNBC holds great promise in overcoming the barriers of the past and developing novel therapeutic approaches for the future. In this review, we describe molecular targets both identified and validated in the treatment of TNBC, discuss the historical efforts towards development of targeted agents and current areas of improvement, and address promising advances that have the potential to improve outcomes in this heterogenous and aggressive breast cancer subtype. Immunotherapy, ADCs, and AR targeting will be discussed in separate reviews of this edition.