Advances and challenges of estrogen receptor-targeted agents in breast cancer

Estrogen receptors (ERs) are expressed in approximately 70% of breast cancer patients and serve as pivotal therapeutic targets. ER-targeting agents like selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) have harvested encouraging clinical outcomes. However, the expansion of their clinical utility remains limited by adverse effects, acquired resistance, and suboptimal pharmacokinetic properties. Recent advancements in ER biology have driven the development of novel ER-targeted agents, including third-generation SERMs, oral SERDs, complete ER antagonists, selective ER covalent antagonists, SERM/SERD hybrids, selective human ER partial agonists, and dual-mechanism ER inhibitors. Moreover, innovative technologies, such as proteolysis-targeting chimeras, molecular glue degraders, and lysosome-targeting chimeras have revolutionized ER degradation strategies, offering possibilities to circumvent drug resistance and enhance therapeutic efficacy. Despite these advances, only two ER-targeted drugs have been officially approved to date, indicating the barriers on the road to clinical translation. This review summarizes the recent progresses and challenges in the development of ER-targeted drugs, aiming to offer a perspective into the future of anti-ER therapies in breast cancer management.