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

Rinath Jeselsohn, Roman Yelensky, Gilles Buchwalter, Garrett Frampton, Funda Meric-Bernstam, Ana Maria Gonzalez-Angulo, Jaime Ferrer-Lozano, Jose A. Perez-Fidalgo, Massimo Cristofanilli, Henry Goḿez, Carlos L. Arteaga, Jennifer Giltnane, Justin M. Balko, Maureen T. Cronin, Mirna Jarosz, James Sun, Matthew Hawryluk, Doron Lipson, Geoff Otto, Jeffrey S. RossAddie Dvir, Lior Soussan-Gutman, Ido Wolf, Tamar Rubinek, Lauren Gilmore, Stuart Schnitt, Steven E. Come, Lajos Pusztai, Philip Stephens, Myles Brown*, Vincent A. Miller

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

489 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1757-1767
Number of pages11
JournalClinical Cancer Research
Issue number7
StatePublished - Apr 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer'. Together they form a unique fingerprint.

Cite this