Differential impact of tumor-derived ESR1 mutations on elacestrant benefit in metastatic breast cancer

BACKGROUND: ESR1 mutations are a well-established mechanism of endocrine therapy resistance in estrogen receptor (ER)-positive metastatic breast cancer and are a biomarker for treatment benefit from oral selective estrogen receptor degraders (SERDs) such as elacestrant. However, variant-specific and context-dependent effects on therapy response remain poorly understood. METHODS: Breast tumors carrying ESR1 mutations that underwent DNA sequencing at Caris Life Sciences were studied (n=3,344), with whole-transcriptome sequencing available for a subset (n=1,663). Time-on-treatment (TOT) was obtained from insurance claims and defined as the interval from initiation to discontinuation of elacestrant. Cox proportional hazards models were used to calculate hazard ratios (HRs), and log-rank tests assessed statistical significance. RESULTS: ESR1 mutation frequency increased with longer duration of prior endocrine therapy including combined treatment regimens, particularly those including CDK4/6 inhibitors. Heterogeneity in treatment benefit was observed across ESR1 variants. Tumors harboring ESR1-L536 mutations demonstrated reduced elacestrant benefit, with significantly shorter TOT compared to more common mutations such as Y537 and D538G (HR=2.089, p=0.001). L536-mutated tumors had lower expression of GREB1, a key estrogen-responsive gene, and reduced enrichment of estrogen response pathways, suggesting reduced ER pathway activation compared to other variants. Additionally, patients with multiple ESR1 mutations had significantly shorter TOT compared to those with single mutations (adjusted HR=1.62, p=0.038). CONCLUSIONS: ESR1 mutations are likely not functionally equivalent in their impact on elacestrant benefit. These findings highlight the importance of variant-specific stratification in optimizing endocrine therapy and suggest that biomarkers of ER signaling activity may further refine patient selection for SERD treatment.