Oral selective estrogen receptor degraders and biomarker-driven therapy in ER-positive breast cancer: mechanisms, clinical evidence, and future directions.

Breast cancer (BC) remains one of the most prevalent malignancies worldwide, with approximately 70% of cases being estrogen receptor-positive (ER+). Endocrine therapy targeting the estrogen receptor has revolutionized BC treatment, evolving from surgical oophorectomy to selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). Selective estrogen receptor degraders (SERDs) represent the latest advancement in hormonal therapy, offering complete receptor blockade and degradation. This review comprehensively examines the mechanisms of SERD action, their role in overcoming resistance to conventional endocrine therapy, and clinical applications of approved agents including fulvestrant, elacestrant, imlunestrant, and vepdegestrant, the first FDA-approved PROTAC estrogen receptor degrader. We discuss emerging oral SERDs such as giredestrant and camizestrant, novel PROTAC-based approaches, and combination strategies with CDK4/6 inhibitors, PI3K inhibitors, and other targeted agents. Special attention is given to ESR1 mutations as biomarkers for patient selection and therapy optimization. The review highlights key clinical trials including EMERALD, EMBER-3, SERENA-6, and lidERA that have shaped current treatment guidelines and points toward future directions in SERD development.