Overcoming Drug Resistance in Breast Cancer: Advances in Targeted and Combination Therapies.

In 2022, the Global Cancer Observatory (GLOBOCAN) predicted that female Breast Cancers (BCs) are the second most diagnosed cancer worldwide, accounting for 11.6% of all new cancer cases and estimated to account for 6.9% of all cancer deaths glob-ally. BC treatment options depend on factors such as tumor grade, stage, molecular subtype, and personalized considerations, including age, menopausal status, overall health, safety, and treatment efficacy. The traditional assessment of BC prognosis and treatment involves evaluating hormone receptor status (HRs: ER, PR, AR), human epidermal growth factor receptor 1 and 2 (HER1/EGFR, HER2), immune checkpoint markers (e.g., PD-L1), and cell signalling molecules (e.g., CDK4/6, PARP), among others. While TNBCs (ER-, PR-, HER2-) are mainly treated with chemotherapy, targeted therapy, and immunotherapy, either alone or in combination, HRs and/or HER2 remain the primary therapeutic targets for ER/PR+HER2+ and ER/PR+HER2- BCs, respectively. However, challenges such as de novo and acquired resistance, toxicity, and side effects limit the effectiveness of targeted therapies. This review discusses the advancement of conventional targeted therapies against BCs by introducing new generations of targeted molecules, including advanced SERMs, SERDs, AIs, CDK4/6, and PARP inhibitors, various ADCs, PROTACs, CERANs, and SERCAs.