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Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists
- Source :
- Cancer Discovery. 7:277-287
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
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
- Subjects :
- 0301 basic medicine
Mutation
Fulvestrant
Mutant
Cancer
Pharmacology
Biology
medicine.disease
medicine.disease_cause
Estrogen Receptor Antagonists
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Oncology
In vivo
030220 oncology & carcinogenesis
medicine
Receptor
Estrogen receptor alpha
medicine.drug
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi...........58815192271c7208356e21745f2adb1f