title: ActivatingESR1Mutations Differentially Affect the Efficacy of ER Antagonists.
abstract: Recent studies have identified somaticESR1mutations 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 ofESR1mutations from more than 900 patients.ESR1mutations 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 resistancein vivoCorrespondingly, 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 certainESR1mutants.Significance:A diversity of activatingESR1mutations 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Toy
authors.affiliation: AstraZeneca, iMED Oncology, Cambridge, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Weir
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Pedram
authors.initials: P
authors.lastname: Razavi
authors.affiliation: AstraZeneca, iMED Oncology, Cambridge, UK.
authors.forename: Mandy
authors.initials: M
authors.lastname: Lawson
authors.affiliation: AstraZeneca, Discovery Sciences, IMED Biotech Unit, Cambridge, UK.
authors.forename: Anne U
authors.initials: AU
authors.lastname: Goeppert
authors.affiliation: AstraZeneca, iMED Oncology, Waltham, Massachusetts.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Mazzola
authors.affiliation: AstraZeneca, iMED Oncology, Cambridge, UK.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.affiliation: AstraZeneca, iMED Oncology, Cambridge, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wilson
authors.affiliation: AstraZeneca, iMED Oncology, Cambridge, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Morrow
authors.affiliation: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Wai Lin
authors.initials: WL
authors.lastname: Wong
authors.affiliation: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Stanchina
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carlson
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Martin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sharmeen
authors.initials: S
authors.lastname: Uddin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
authors.forename: Sean
authors.initials: S
authors.lastname: Fanning
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: John A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Greene
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. chandars@mskcc.org.|Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002934:Cinnamates / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D000072417:Protein Domains; D023041:Xenograft Model Antitumor Assays
chemical_list: C000604573:AZD9496; D018931:Antineoplastic Agents, Hormonal; D002934:Cinnamates; C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D007211:Indoles; D000077267:Fulvestrant; D004958:Estradiol