Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes in Metastatic Breast Cancer

Abstract

IMPORTANCE 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. DESIGN, SETTING, AND PARTICIPANTS 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. INTERVENTIONS Patients were randomized to treatment with exemestane (25 mg oral daily) together with everolimus (10 mg oral daily) or with placebo. MAIN OUTCOMES AND MEASURES 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 AND RELEVANCE ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated MBC. Both Y537S and D538G mutations are associated with more aggressive disease biology. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00863655

Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer

“…The recent discoveries of hotspot ER mutations in metastatic breast cancer further strengthen the key role of ER in drug resistance and disease development. The recurrent mutations, mainly occurring on tyrosine-537 and aspartic acid-538 located in the ligand-binding domain, are enriched in nearly 30% of endocrine-therapy resistant metastases and are associated with more aggressive disease biology with shorter overall survival relative to the wild-type ER [13]. Furthermore, ER mutations induce ligand-independent activation of the ER pathway and confer partial resistance to existing classes of endocrine therapies [7][8][9][10][11][12][13]30].…”

“…The hotspot mutations in ER, which are enriched in nearly 30% of endocrine therapy-resistant metastases, induce ligand-independent activation of the ER pathway [7][8][9][10][11][12], confer partial resistance to existing classes of endocrine therapies, and are associated with more aggressive disease biology with shorter overall survival in patients relative to the wild-type ESR1 [13].…”

Pushing estrogen receptor around in breast cancer

“…Gain-of-function mutations in ESR1, the gene encoding the ER, are a relatively rare event in primary breast cancer (Cancer Genome Atlas Network 2012), but can be detected using next-generation sequencing in approximately 20% of patients with metastatic ER-positive disease who had received prior endocrine therapies , Toy et al 2013, Jeselsohn et al 2015. A higher prevalence (up to 55%) of ESR1 mutations has been reported in circulating free DNA (cfDNA) in metastatic ER-positive breast cancers with prior AI therapy when using digital droplet PCR to increase mutation detection sensitivity (Chandarlapaty et al 2016, Fribbens et al 2016, Spoerke et al 2016. These mutations cluster in the ligand-binding domain of the ER and lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy and potentially enhanced metastatic capacity.…”

Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer

“…Additionally, recent digital PCR assays on plasma cell-free DNA (cfDNA) of several cohorts demonstrated the difference in the clinical features between the representative hotspot mutations in MBC, PIK3CA and ESR1 mutations [6][7][8][9][10]. In the BOLERO-2 study, Chandarlapaty and colleagues demonstrated that progression free survival (PFS) benefit of mammalian target of rapamycin (mTOR) inhibitor everolimus was maintained irrespective of PIK3CA mutations, but that was decreased according to the presence of ESR1 mutations [6,7]. In another two phase III randomized trials, Fribbens and colleagues reported the effectiveness of the target drug by having the mutations or not.…”