Abstract

Triple-negative breast cancer (TNBC) represents one of the most aggressive and therapeutically challenging breast cancer subtypes, characterised by the absence of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) amplification. Comprising approximately 15-20% of all breast cancer diagnoses, TNBC disproportionately affects younger women, particularly those with BRCA1 mutations, and exhibits rapid progression, high recurrence rates, and historically limited therapeutic options. Recent advances in molecular profiling have revealed significant heterogeneity within TNBC, leading to the identification of distinct molecular subtypes, including basal-like (BL1 and BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR) subtypes, each presenting unique therapeutic vulnerabilities. This comprehensive review synthesises current knowledge on targeted therapeutic strategies for TNBC, examining established approaches such as PARP inhibitors for BRCA-mutated tumours and immune checkpoint inhibitors for PD-L1-positive cases, while extensively covering emerging targets including EGFR inhibitors, JAK/STAT pathway modulators, developmental signalling pathways (Notch, Wnt, Hedgehog), epigenetic regulators (HDAC and DNMT inhibitors), and tumour-associated antigens (GPNMB, LIV-1). Unlike previous reviews, this work provides an integrated perspective on precision medicine approaches, emphasising biomarker-driven patient selection strategies and clinical translation of molecular discoveries. We analyse recent clinical trial outcomes, regulatory approvals, and emerging therapeutic combinations while addressing current challenges, including tumour heterogeneity, drug resistance mechanisms, and healthcare accessibility. The review concludes with a strategic roadmap for next-generation TNBC drug development, highlighting the transition from conventional chemotherapy to personalised, molecularly-guided therapeutic approaches that promise to improve outcomes for patients with this challenging disease.

Key words: Triple-negative breast cancer; Targeted therapy; PARP inhibitors; Immune checkpoint blockade; Biomarkers; Precision medicine; Molecular subtypes; Clinical trials.