Retrospective study of differential impact of tumor-derived ESR1 mutations on elacestrant benefit in metastatic breast cancer

ESR1 mutations are a well-established mechanism of endocrine therapy resistance in ER-positive metastatic breast cancer (mBC) and are a biomarker for treatment benefit from oral selective estrogen degraders such as elacestrant. However, variant-specific and context-dependent effects on therapy response are poorly understood. A retrospective study at Caris Life Sciences (Phoenix, AZ) evaluated the differential impact of tumor-derived ESR1 mutations on elacestrant benefit in mBC. Breast tumors carrying ESR1 mutations that underwent DNA sequencing (n=3344) were studied, with whole-transcritome sequencing available for a subset (n=1663). Time on treatment (TOT; interval for initiation to discontinuation of elacestrant) was obtained from insurance claims. ESR1 mutation frequency increased with longer duration of prior endocrine therapy. Heterogeneity in treatment benefit was observed across ESR1 variants. Tumors harboring ESR1-L536 mutations demonstrated reduced elacestrant benefit, with significantly shorter TOT compared with Y537 and D538G mutations (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.. Patients with multiple ESR1 mutations had significantly shorter TOT compared with those with one ESR1 mutation (aHR 1.62; p=0.038). The authors conclude that ESR1 mutations are likely not functionlly equivalent in their impact on elacestrant benefit.