Prevalence of Estrogen Receptor Alpha (ESR1) Somatic Mutations in Breast Cancer

Estrogen receptor–positive breast tumors, which initially respond effectively to endocrine therapy, progress due to acquired endocrine therapy resistance, including genomic alterations in estrogen receptor alpha (ESR1). A recent study has suggested that there is a sufficient number of preexisting ESR1 mutations acting as an intrinsic resistance mechanism to warrant primary screening. We determined the incidence of de novo ESR1 mutations in hormone-positive treatment-naïve primary breast tumors using 12 publicly available international datasets in the cBioPortal. The prevalence of mutation was statistically significantly lower in treatment-naïve primary tumors (n = 6 of 3682, 0.16%) than in metastatic (n = 156 of 1089, 14.3%, 2-sided P < .001) or previously treated primary tumors (n = 11 of 92, 12.0%, 2-sided P < .001). Pathogenic ESR1 mutations are a common mechanism of acquired but not intrinsic resistance to endocrine therapy and may not warrant universal testing of primary breast cancer populations.