The rise of selective estrogen receptor modulators (SERMs) in breast cancer therapy: a promising horizon.

Despite advancements in breast cancer treatment, breast cancer is still among the major causes of cancer-related deaths worldwide, with most breast cancers being estrogen receptor positive (ER+). Selective estrogen receptor modulators (SERMs) have been the core drug class used in endocrine therapy for ER+ breast cancer through tissue-specific conformational changes to the estrogen receptor. The present study critically evaluates the pharmacologic development, thermodynamics, and clinical effectiveness of SERMs. We systematically analyze approved agents (e.g., tamoxifen, raloxifene, bazedoxifene), investigational drugs (e.g., endoxifen, lasofoxifene), and historically discontinued compounds to understand the structural basis of their clinical successes and failures. Furthermore, we explore the molecular drivers of SERM resistance, including ESR1 mutations, epigenetic reprogramming, and growth factor cross-talk. By highlighting the limitations of early-generation SERMs, such as paradoxical partial agonism, thromboembolic risks, and acquired resistance, we provide a rationale for the current paradigm shift toward Complete Estrogen Receptor Antagonists (CERANs) and oral Selective Estrogen Receptor Degraders (SERDs), offering critical insights into the future of precision endocrine oncology.