Pharmacological Challenges in Triple-Negative Breast Cancer Therapy

Abstract

Triple-negative breast cancer (TNBC) represents one of the most therapeutically challenging breast cancer subtypes owing to the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. This molecular profile eliminates the utility of conventional endocrine and HER2-targeted therapies, leaving systemic chemotherapy as the historical backbone of treatment. However, high intratumoral heterogeneity, early metastatic dissemination, adaptive drug resistance, and substantial treatment-related toxicity continue to compromise durable clinical benefit. Advances in molecular profiling have revealed actionable vulnerabilities including DNA damage repair defects, immune checkpoint susceptibility, and dysregulated growth factor signaling, enabling the emergence of poly (ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and antibody–drug conjugates. Despite these advances, variable biomarker predictability, resistance evolution, and limited access to precision diagnostics constrain optimal patient stratification. Pharmacokinetic challenges such as poor tumor penetration, dose-limiting toxicities, and interpatient variability further complicate therapeutic optimization. This review critically examines the pharmacological barriers in TNBC therapy, integrating mechanistic insights into tumor biology, resistance pathways, immunomodulation, and emerging targeted platforms. Key clinical trial evidence and translational strategies aimed at overcoming therapeutic resistance are highlighted. The synthesis underscores the necessity of integrated biomarker-driven treatment algorithms, rational drug combinations, and innovative delivery technologies to improve survival outcomes and minimize systemic toxicity in TNBC patients.