Emergence of Constitutively Active Estrogen Receptor-alpha Mutations in Pretreated Advanced Estrogen Receptor-Positive Breast Cancer

作者：Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles; Frampton, Garrett; Meric-Bernstam, Funda; Gonzalez-Angulo, Ana Maria; Ferrer-Lozano, Jaime; Perez-Fidalgo, Jose A.; Cristofanilli, Massimo; Gomez, Henry; Arteaga, Carlos L.; Giltnane, Jennifer; Balko, Justin M.; Cronin, Maureen T.; Jarosz, Mirna; Sun, James; Hawryluk, Matthew; Lipson, Doron; Otto, Geoff; Ross, Jeffrey S.; Dvir, Addie; Soussan-Gutman, Lior; Wolf, Ido; Rubinek, Tamar; Gilmore, Lauren; Schnitt, Stuart; Come, Steven E.

来源：Clinical Cancer Research, 2014, 20(7): 1757-1767.

DOI：10.1158/1078-0432.CCR-13-2332

• POSTMENOPAUSAL WOMEN

Purpose: We undertook this study to determine the prevalence of estrogen receptor (ER) alpha ( 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 (ER+/HER2(-)) and, as controls, 115 ER-negative (ER-) tumors. The ER+ 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 ER+ 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-naive ER+ 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 ESR1 mutations as potential drivers of endocrine resistance during the progression of ER+ breast cancer.

• 出版日期2014-4-1