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dc.contributor.authorSchiavon, G
dc.contributor.authorHrebien, S
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorCutts, RJ
dc.contributor.authorPearson, A
dc.contributor.authorTarazona, N
dc.contributor.authorFenwick, K
dc.contributor.authorKozarewa, I
dc.contributor.authorLopez-Knowles, E
dc.contributor.authorRibas, R
dc.contributor.authorNerurkar, A
dc.contributor.authorOsin, P
dc.contributor.authorChandarlapaty, S
dc.contributor.authorMartin, L-A
dc.contributor.authorDowsett, M
dc.contributor.authorSmith, IE
dc.contributor.authorTurner, NC
dc.coverage.spatialUnited States
dc.date.accessioned2022-08-16T13:37:10Z
dc.date.available2022-08-16T13:37:10Z
dc.date.issued2015-11-11
dc.identifierARTN 313ra182
dc.identifier7/313/313ra182
dc.identifier.citationScience Translational Medicine, 2015, 7 (313), pp. 313ra182 -
dc.identifier.issn1946-6234
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5275
dc.identifier.eissn1946-6242
dc.identifier.eissn1946-6242
dc.identifier.doi10.1126/scitranslmed.aac7551
dc.description.abstractAcquired 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.
dc.formatPrint
dc.format.extent313ra182 -
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC ADVANCEMENT SCIENCE
dc.relation.ispartofScience Translational Medicine
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.subjectAntineoplastic Agents
dc.subjectAromatase Inhibitors
dc.subjectBreast Neoplasms
dc.subjectEstrogen Receptor alpha
dc.subjectFemale
dc.subjectHumans
dc.subjectMultiplex Polymerase Chain Reaction
dc.titleAnalysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2015-11-11
dc.date.updated2022-08-16T13:12:51Z
rioxxterms.versionAM
rioxxterms.versionofrecord10.1126/scitranslmed.aac7551
rioxxterms.licenseref.startdate2015-11-11
rioxxterms.typeJournal Article/Review
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/26560360
pubs.issue313
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Molecular Oncology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Endocrinology
pubs.publication-statusPublished
pubs.volume7
icr.researchteamMolecular Oncology
icr.researchteamEndocrinology
icr.researchteamMedicine (RMH)
dc.contributor.icrauthorGarcia-Murillas, Isaac
dc.contributor.icrauthorCutts, Rosalind
dc.contributor.icrauthorPearson, Alex
dc.contributor.icrauthorLopez Knowles, Elena
dc.contributor.icrauthorMartin, Lesley-Ann
dc.contributor.icrauthorTurner, Nicholas
icr.provenanceDeposited by Dr Elena Lopez Knowles on 2022-08-16. Deposit type is initial. No. of files: 1. Files: scitranslmed.aac7551.pdf
icr.provenanceDeposited by Mr Arek Surman (impersonating Dr Elena Lopez Knowles) on 2022-08-16. Deposit type is subsequent. No. of files: 1. Files: nihms-803731 (1).pdf


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