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dc.contributor.authorRueda Palacio, Oscaren
dc.contributor.authorSammut, Stephenen
dc.contributor.authorSeoane, Jose Aen
dc.contributor.authorChin, Suet-Feungen
dc.contributor.authorCaswell-Jin, Jennifer Len
dc.contributor.authorCallari, Maurizioen
dc.contributor.authorBatra, Rajbiren
dc.contributor.authorPereira, Bernarden
dc.contributor.authorBruna, Alejandraen
dc.contributor.authorAli, Razaen
dc.contributor.authorProvenzano, Elenaen
dc.contributor.authorLiu, Binen
dc.contributor.authorParisien, Michelleen
dc.contributor.authorGillett, Cherylen
dc.contributor.authorMcKinney, Stevenen
dc.contributor.authorGreen, Andrew Ren
dc.contributor.authorMurphy, Leighen
dc.contributor.authorPurushotham, Arnieen
dc.contributor.authorEllis, Ian Oen
dc.contributor.authorPharoah, Paulen
dc.contributor.authorRueda, Cristinaen
dc.contributor.authorAparicio, Samuelen
dc.contributor.authorCaldas, Carlosen
dc.contributor.authorCurtis, Christinaen
dc.date.accessioned2019-02-22T00:30:21Z
dc.date.available2019-02-22T00:30:21Z
dc.date.issued2019-03-13en
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/289797
dc.description.abstractThe rates and routes of lethal systemic spread in breast cancer are poorly understood due to the lack of molecularly characterized cohorts with long-term, detailed follow-up. Long-term follow-up is especially essential for ER-positive (ER+) breast cancer, where tumors continue to recur up to two decades after initial diagnosis1–6 and there is a critical need to identify high-risk patients prior to lethal recurrence7–9. Here we present a statistical framework to model distinct disease stages (loco-regional recurrence (LR), distant recurrence (DR) and breast cancer-related death) and competing risks of breast cancer mortality, while yielding individual risk of recurrence predictions. Application of this model to 3240 breast cancer patients, including 1980 with molecular data, delineates the spatio-temporal patterns of relapse across the immunohistochemical (IHC), intrinsic (PAM50)10,11, and integrative (IntClust)12,13 subtypes. We identify four late-recurring integrative subtypes, comprising a quarter (26%) of ER+, human epidermal growth factor receptor 2-negative (HER2-) tumors, each with characteristic genomic copy number driver alterations and high (median 42-55%) risk of recurrence up to 20 years post-diagnosis. Additionally, we define a subgroup of triple-negative breast cancers (TNBC) that rarely recur after 5 years and a separate subgroup that remain at risk. The integrative subtypes improve prediction of late distant relapse beyond clinical covariates (nodal status, tumor size, grade and IHC subtype). These findings illuminate opportunities for improved patient stratification and biomarker-driven clinical trials.
dc.description.sponsorshipCancer Research UK (CRUK) travel grant (SWAH/047) 282 to visit Prof. Curtis’ Lab. C.R. is supported by award MTM2015-71217-R. Ca.C. is 283 supported by CRUK, ECMC and NIHR. C.C. is supported by the National Institutes 284 of Health through the NIH Director’s Pioneer Award (DP1-CA238296) and the Breast 285 Cancer Research Foundation.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherNature Publishing Group
dc.subjectHumansen
dc.subjectBreast Neoplasmsen
dc.subjectNeoplasm Metastasisen
dc.subjectNeoplasm Recurrence, Localen
dc.subjectDisease Progressionen
dc.subjectReceptor, erbB-2en
dc.subjectReceptors, Estrogenen
dc.subjectPrognosisen
dc.subjectOrgan Specificityen
dc.subjectModels, Biologicalen
dc.subjectTime Factorsen
dc.subjectFemaleen
dc.subjectTriple Negative Breast Neoplasmsen
dc.titleDynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups.en
dc.typeArticle
prism.endingPage404
prism.issueIdentifier7748en
prism.publicationDate2019en
prism.publicationNameNatureen
prism.startingPage399
prism.volume567en
dc.identifier.doi10.17863/CAM.37037
dcterms.dateAccepted2019-01-31en
rioxxterms.versionofrecord10.1038/s41586-019-1007-8en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-03-13en
dc.contributor.orcidRueda Palacio, Oscar [0000-0003-0008-4884]
dc.contributor.orcidSammut, Stephen [0000-0003-4472-904X]
dc.contributor.orcidSeoane, Jose A [0000-0002-3856-9177]
dc.contributor.orcidChin, Suet-Feung [0000-0001-5697-1082]
dc.contributor.orcidBruna, Alejandra [0000-0003-1214-9665]
dc.contributor.orcidAli, Raza [0000-0001-7587-0906]
dc.contributor.orcidGreen, Andrew R [0000-0002-0488-5913]
dc.contributor.orcidEllis, Ian O [0000-0001-5292-8474]
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.contributor.orcidCaldas, Carlos [0000-0003-3547-1489]
dc.identifier.eissn1476-4687
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (CB4140)
pubs.funder-project-idCancer Research UK (20544)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (A3086)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (60098573)
pubs.funder-project-idCancer Research UK (unknown)
pubs.funder-project-idCancer Research UK (A7199)
pubs.funder-project-idCancer Research UK (A15580)
pubs.funder-project-idCancer Research UK (C507/A16278)
pubs.funder-project-idCancer Research UK (A6306)
pubs.funder-project-idCancer Research UK (A6106)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (RG51913)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (unknown)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0515-10090)
pubs.funder-project-idCancer Research UK (A25117)
pubs.funder-project-idCancer Research UK (C14303_do not transfer)
pubs.funder-project-idCancer Research UK (C9545/A29580_do not transfer)
pubs.funder-project-idCancer Research UK (25815)
rioxxterms.freetoread.startdate2019-09-13


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