Segal and Dowsett , p . 1724 Emergence of Constitutively Active Estrogen Receptor-a Mutations in Pretreated Advanced Estrogen Receptor – Positive Breast Cancer

Purpose: We undertook this study to determine the prevalence of estrogen receptor (ER) a (ESR1) mutations throughout the natural history of hormone-dependent breast cancer and to delineate the functional roles of the most commonly detected alterations. Experimental Design: We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER-positive (ERþ/HER2 ) and, as controls, 115 ER-negative (ER ) tumors. The ERþ samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next-generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes. Results: Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ERþ metastatic disease. Overall, the frequency of these mutations was 12% [9/76; 95% confidence interval (CI), 6%–21%] in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25; 95%CI, 7%–41%). These mutations were not detected in primary or treatment-na€ ve ERþ cancer or in any stage of ER disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments. Conclusions: In this study, we show evidence for the temporal selection of functional ESR1mutations as potential drivers of endocrine resistance during the progression of ERþ breast cancer.Clin Cancer Res; 20(7);