Abstract
Purpose: 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 (SERD) such as elacestrant. However, variant-specific and contextdependent effects on therapy response remain poorly understood.
Experimental Design: 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 (HR), and log-rank tests were used to assess statistical significance.
Results: ESR1 mutation frequency increased with longer duration of prior endocrine therapy, including combined treatment regimens, particularly those including cyclin-dependent kinase 4/6 inhibitors. Heterogeneity in treatment benefit was observed across ESR1 variants. Tumors harboring ESR1-L536 mutations demonstrated reduced elacestrant benefit, with significantly shorter TOT compared with more common mutations such as Y537 and D538G (HR, 2.089; P . 0.001). L536-mutated tumors had lower expression of growth regulation by estrogen in breast cancer 1, a key estrogen-responsive gene, and reduced enrichment of estrogen response pathways, suggesting reduced ER pathway activation compared with other variants. Additionally, patients with multiple ESR1 mutations had significantly shorter TOT compared with those with one ESR1 mutation (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.