Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.


PURPOSE We undertook this study to determine the prevalence of estrogen receptor (ER) α (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-naïve 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.

DOI: 10.1158/1078-0432.CCR-13-2332

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@article{Jeselsohn2014EmergenceOC, title={Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.}, author={Rinath Jeselsohn and Roman Yelensky and Gilles Buchwalter and Garrett Frampton and Funda Meric-Bernstam and Ana Maria Gonzalez-Angulo and Jaime Ferrer-Lozano and Jose A Perez-Fidalgo and Massimo Cristofanilli and Henry G{\'o}mez and Carlos L Arteaga and Jennifer Giltnane and Justin M Balko and Maureen T Cronin and Mirna Jarosz and James Sun and Matthew Hawryluk and Doron Lipson and Geoff Otto and Jeffrey S Ross and Addie Dvir and Lior Soussan-Gutman and Ido Wolf and Tamar Rubinek and Lauren Gilmore and Stuart Schnitt and Steven E Come and Lajos Pusztai and Philip Stephens and Myles Brown and Vincent A Miller}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2014}, volume={20 7}, pages={1757-1767} }