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Cancer Discov. 2017 Mar;7(3):277-287. doi: 10.1158/2159-8290.CD-15-1523. Epub 2016 Dec 16.

Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
AstraZeneca, iMED Oncology, Cambridge, UK.
3
Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
4
AstraZeneca, Discovery Sciences, IMED Biotech Unit, Cambridge, UK.
5
AstraZeneca, iMED Oncology, Waltham, Massachusetts.
6
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
8
Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
9
Weill Cornell Medical College, New York, New York.
10
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. chandars@mskcc.org.

Abstract

Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation of the receptor. The degree to which all recurrent mutants can drive estrogen-independent activities and reduced sensitivity to ER antagonists like fulvestrant is not established. In this report, we characterize the spectrum of ESR1 mutations from more than 900 patients. ESR1 mutations were detected in 10%, with D538G being the most frequent (36%), followed by Y537S (14%). Several novel, activating mutations were also detected (e.g., L469V, V422del, and Y537D). Although many mutations lead to constitutive activity and reduced sensitivity to ER antagonists, only select mutants such as Y537S caused a magnitude of change associated with fulvestrant resistance in vivo Correspondingly, tumors driven by Y537S, but not D5358G, E380Q, or S463P, were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists, including AZD9496. These data point to a need for antagonists with optimal pharmacokinetic properties to realize clinical efficacy against certain ESR1 mutants.Significance: A diversity of activating ESR1 mutations exist, only some of which confer resistance to existing ER antagonists that might be overcome by next-generation inhibitors such as AZD9496. Cancer Discov; 7(3); 277-87. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 235.

PMID:
27986707
PMCID:
PMC5340622
DOI:
10.1158/2159-8290.CD-15-1523
[Indexed for MEDLINE]
Free PMC Article

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