title: Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.
abstract: Acquired ESR1 mutations are a major mechanism of resistance to aromatase inhibitors (AIs). We developed ultra high-sensitivity multiplex digital polymerase chain reaction assays for ESR1 mutations in circulating tumor DNA (ctDNA) and investigated the clinical relevance and origin of ESR1 mutations in 171 women with advanced breast cancer. ESR1 mutation status in ctDNA showed high concordance with contemporaneous tumor biopsies and was accurately assessed in samples shipped at room temperature in preservative tubes. ESR1 mutations were found exclusively in estrogen receptor-positive breast cancer patients previously exposed to AI. Patients with ESR1 mutations had a substantially shorter progression-free survival on subsequent AI-based therapy [hazard ratio, 3.1; 95% confidence interval (CI), 1.9 to 23.1; P = 0.0041]. ESR1 mutation prevalence differed markedly between patients who were first exposed to AI during the adjuvant and metastatic settings [5.8% (3 of 52) versus 36.4% (16 of 44), respectively; P = 0.0002]. In an independent cohort, ESR1 mutations were identified in 0% (0 of 32; 95% CI, 0 to 10.9) tumor biopsies taken after progression on adjuvant AI. In a patient with serial sampling, ESR1 mutation was selected during metastatic AI therapy to become the dominant clone in the cancer. ESR1 mutations can be robustly identified with ctDNA analysis and predict for resistance to subsequent AI therapy. ESR1 mutations are rarely acquired during adjuvant AI but are commonly selected by therapy for metastatic disease, providing evidence that mechanisms of resistance to targeted therapy may be substantially different between the treatment of micrometastatic and overt metastatic cancer.
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hrebien
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Isaac
authors.initials: I
authors.lastname: Garcia-Murillas
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Cutts
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Pearson
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Noelia
authors.initials: N
authors.lastname: Tarazona
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Lopez-Knowles
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribas
authors.affiliation: Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Nerurkar
authors.affiliation: Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Osin
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sarat
authors.initials: S
authors.lastname: Chandarlapaty
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.affiliation: The Breast Cancer Now Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Breast Unit, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK. nicholas.turner@icr.ac.uk.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D047072:Aromatase Inhibitors / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D006801:Humans; D060885:Multiplex Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha