ESR1 mutations and endocrine resistance in ER-positive breast cancer: Molecular mechanisms, liquid biopsy, and emerging targeted therapies

ABSTRACT: Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common type of breast cancer, and endocrine therapy remains the cornerstone of treatment. This narrative review summarizes the biology of mutations in the ligand-binding domain of the estrogen receptor (ER), the utility of circulating tumor DNA (ctDNA) for detecting these alterations, and the evidence supporting emerging therapies for ESR1 -mutant metastatic disease to provide clinicians with a practical, evidence-based framework for managing patients with the disease. Mutations in the ligand-binding domain of ESR1 , such as Y537S and D538G, lock the receptor in a constitutively active conformation, increasing resistance to aromatase inhibitors and variably affecting sensitivity to selective ER degraders (SERDs). These mutations can be detected non-invasively by longitudinal ctDNA next-generation sequencing, often before radiographic progression is evident, although questions remain regarding optimal assay sensitivity, clonal heterogeneity, and monitoring intervals. Elacestrant, the first oral SERD approved for ESR1 -mutant disease, improved progression-free survival in the phase III EMERALD trial and subsequent trials of oral SERDs, and the proteolysis-targeting chimera vepdegestrant (EMBER-3, SERENA-6, and VERITAC-2) provides further supporting evidence. Other complete ER antagonists and covalent antagonists remain in clinical trials. ESR1 mutation testing and treatment adaptation according to ctDNA are now part of the precision management of ER+/HER2- breast cancer, but more prospective research is required for the best sequencing and monitoring strategies.