title: Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer: A Secondary Analysis of the BOLERO-2 Clinical Trial.
abstract: OBJECTIVE
  Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent receptor activation and resistance to estrogen-deprivation therapy in laboratory models. The prevalence of these mutations and their potential impact on clinical outcomes has not been established.
  
  
  OBJECTIVE
  To determine the prevalence of ESR1 mutations (Y537S and D538G) in estrogen receptor (ER)-positive MBC and determine whether mutation is associated with inferior outcomes.
  
  
  METHODS
  From December 16, 2014, to August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples from participants in the BOLERO-2 double-blind phase 3 study that randomized patients from 189 centers in 24 countries with MBC to exemestane plus placebo or exemestane plus everolimus. The study enrolled postmenopausal women with a diagnosis of MBC and prior exposure to an aromatase inhibitor. Baseline plasma samples were available from 541 of 724 patients (74.7%). We assessed the effect of mutation on overall survival of the population and the effect of mutation on progression-free survival (PFS) by treatment arm.
  
  
  METHODS
  Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo.
  
  
  METHODS
  The 2 most frequent mutations in ESR1 (Y537S and D538G) were analyzed from cfDNA using droplet digital polymerase chain reaction and samples scored as wild-type, D538G, Y537S, or double mutant. Cox-proportional hazards model was used to assess PFS in patient subgroups defined by mutations, and the effect of each mutation on overall survival.
  
  
  RESULTS
  Of 541 evaluable patients, 156 (28.8%) had ESR1 mutation D538G (21.1%) and/or Y537S (13.3%), and 30 had both. These mutations were associated with shorter overall survival (wild-type, 32.1 months [95% CI, 28.09-36.40 months]; D538G, 25.99 months [95% CI, 19.19-32.36 months]; Y537S, 19.98 months [13.01-29.31 months]; both mutations, 15.15 months [95% CI, 10.87-27.43 months]). The D538G group (hazard ratio, 0.34 [95% CI, 0.02-0.57]) derived a similar PFS benefit as wild type from addition of everolimus to exemestane.
  
  
  CONCLUSIONS
  ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00863655.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sung
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Aliaksandra
authors.initials: A
authors.lastname: Samoila
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Daoqi
authors.initials: D
authors.lastname: You
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Trusha
authors.initials: T
authors.lastname: Bhatt
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Parul
authors.initials: P
authors.lastname: Patel
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.affiliation: Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.affiliation: University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Hortobagyi
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Moynahan
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D015337:Multicenter Studies as Topic; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic
chemical_list: D004273:DNA, Neoplasm; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha