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dc.contributor.authorKingston, B
dc.contributor.authorCutts, RJ
dc.contributor.authorBye, H
dc.contributor.authorBeaney, M
dc.contributor.authorWalsh-Crestani, G
dc.contributor.authorHrebien, S
dc.contributor.authorSwift, C
dc.contributor.authorKilburn, LS
dc.contributor.authorKernaghan, S
dc.contributor.authorMoretti, L
dc.contributor.authorWilkinson, K
dc.contributor.authorWardley, AM
dc.contributor.authorMacpherson, IR
dc.contributor.authorBaird, RD
dc.contributor.authorRoylance, R
dc.contributor.authorReis-Filho, JS
dc.contributor.authorHubank, M
dc.contributor.authorFaull, I
dc.contributor.authorBanks, KC
dc.contributor.authorLanman, RB
dc.contributor.authorGarcia-Murillas, I
dc.contributor.authorBliss, JM
dc.contributor.authorRing, A
dc.contributor.authorTurner, NC
dc.date.accessioned2021-06-11T11:37:28Z
dc.date.available2021-06-11T11:37:28Z
dc.date.issued2021-04-23
dc.identifier.citationNature communications, 2021, 12 (1), pp. 2423 - ?
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4614
dc.identifier.eissn2041-1723
dc.identifier.eissn2041-1723en_US
dc.identifier.doi10.1038/s41467-021-22605-2
dc.identifier.doi10.1038/s41467-021-22605-2en_US
dc.description.abstractThe genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.
dc.formatElectronic
dc.format.extent2423 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectReceptor, erbB-2
dc.subjectReceptors, Estrogen
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectSequence Analysis, DNA
dc.subjectGenomics
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectClass I Phosphatidylinositol 3-Kinases
dc.subjectBiomarkers, Tumor
dc.subjectCirculating Tumor DNA
dc.subjectProgression-Free Survival
dc.titleGenomic profile of advanced breast cancer in circulating tumour DNA.
dc.typeJournal Article
dcterms.dateAccepted2021-03-16
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-021-22605-2
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2021-04-23
rioxxterms.licenseref.startdate2021-04-23en_US
dc.relation.isPartOfNature communications
pubs.issue1
pubs.notesNot known
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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/17/18 Starting Cohort
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/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Genomics/Translational Genomics (hon.)
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/17/18 Starting Cohort
pubs.publication-statusPublished
pubs.volume12en_US
pubs.embargo.termsNot known
icr.researchteamMolecular Oncology
icr.researchteamClinical Trials & Statistics Unit
icr.researchteamTranslational Genomics
icr.researchteamMolecular Oncologyen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamTranslational Genomicsen_US
dc.contributor.icrauthorMoretti, Lauraen
dc.contributor.icrauthorKernaghan, Sarahen
dc.contributor.icrauthorBliss, Judithen
dc.contributor.icrauthorKilburn, Lucyen
dc.contributor.icrauthorGarcia-Murillas, Isaacen
dc.contributor.icrauthorTurner, Nicholasen
dc.contributor.icrauthorHubank, Michaelen
dc.contributor.icrauthorKingston, Belindaen


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