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dc.contributor.authorKingston, Belinda
dc.contributor.authorCutts, Rosalind J
dc.contributor.authorBye, Hannah
dc.contributor.authorBeaney, Matthew
dc.contributor.authorWalsh-Crestani, Giselle
dc.contributor.authorHrebien, Sarah
dc.contributor.authorSwift, Claire
dc.contributor.authorKilburn, Lucy S
dc.contributor.authorKernaghan, Sarah
dc.contributor.authorMoretti, Laura
dc.contributor.authorWilkinson, Katie
dc.contributor.authorWardley, Andrew M
dc.contributor.authorMacpherson, Iain R
dc.contributor.authorBaird, Richard D
dc.contributor.authorRoylance, Rebecca
dc.contributor.authorReis-Filho, Jorge S
dc.contributor.authorHubank, Michael
dc.contributor.authorFaull, Iris
dc.contributor.authorBanks, Kimberly C
dc.contributor.authorLanman, Richard B
dc.contributor.authorGarcia-Murillas, Isaac
dc.contributor.authorBliss, Judith M
dc.contributor.authorRing, Alistair
dc.contributor.authorTurner, Nicholas C
dc.date.accessioned2021-05-03T23:32:03Z
dc.date.available2021-05-03T23:32:03Z
dc.date.issued2021-04-23
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/321887
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.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://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.typeArticle
prism.issueIdentifier1
prism.publicationDate2021
prism.publicationNameNat Commun
prism.startingPage2423
prism.volume12
dc.identifier.doi10.17863/CAM.69346
dcterms.dateAccepted2021-03-16
rioxxterms.versionofrecord10.1038/s41467-021-22605-2
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-04-23
dc.contributor.orcidKingston, Belinda [0000-0002-4921-4638]
dc.contributor.orcidKilburn, Lucy S [0000-0002-1987-7545]
dc.contributor.orcidMoretti, Laura [0000-0003-0488-0140]
dc.contributor.orcidMacpherson, Iain R [0000-0003-4295-8885]
dc.contributor.orcidBaird, Richard D [0000-0001-7071-6483]
dc.contributor.orcidReis-Filho, Jorge S [0000-0003-2969-3173]
dc.contributor.orcidFaull, Iris [0000-0001-6005-077X]
dc.contributor.orcidBanks, Kimberly C [0000-0002-1290-3114]
dc.contributor.orcidLanman, Richard B [0000-0001-8122-4329]
dc.contributor.orcidGarcia-Murillas, Isaac [0000-0001-8183-7969]
dc.contributor.orcidRing, Alistair [0000-0003-1230-2973]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (C37096/A16673)
cam.issuedOnline2021-04-23


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International