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

Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM, Ferrer-Lozano J, Perez-Fidalgo JA, Cristofanilli M, Gómez H, Arteaga CL, Giltnane J, Balko JM, Cronin MT, Jarosz M, Sun J, Hawryluk M, Lipson D, Otto G, Ross JS, Dvir A, Soussan-Gutman L, Wolf I, Rubinek T, Gilmore L, Schnitt S, Come SE, Pusztai L, Stephens P, Brown M, Miller VA
Clin Cancer Res. 2014 20 (7): 1757-1767

PMID: 24398047 · PMCID: PMC3998833 · DOI:10.1158/1078-0432.CCR-13-2332

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.

©2014 AACR.

MeSH Terms (9)

Breast Neoplasms Estrogen Receptor alpha Female High-Throughput Nucleotide Sequencing Humans MCF-7 Cells Mutation Neoplasms, Hormone-Dependent Neoplasm Staging

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