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dc.contributor.authorWongchenko, MJ
dc.contributor.authorMcArthur, GA
dc.contributor.authorDréno, B
dc.contributor.authorLarkin, J
dc.contributor.authorAscierto, PA
dc.contributor.authorSosman, J
dc.contributor.authorAndries, L
dc.contributor.authorKockx, M
dc.contributor.authorHurst, SD
dc.contributor.authorCaro, I
dc.contributor.authorRooney, I
dc.contributor.authorHegde, PS
dc.contributor.authorMolinero, L
dc.contributor.authorYue, H
dc.contributor.authorChang, I
dc.contributor.authorAmler, L
dc.contributor.authorYan, Y
dc.contributor.authorRibas, A
dc.date.accessioned2018-02-19T11:06:14Z
dc.date.issued2017-09
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (17), pp. 5238 - 5245
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1268
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-17-0172
dc.description.abstractPurpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAFV600-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66).Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.
dc.formatPrint-Electronic
dc.format.extent5238 - 5245
dc.languageeng
dc.language.isoeng
dc.subjectHumans
dc.subjectMelanoma
dc.subjectSulfonamides
dc.subjectAzetidines
dc.subjectPiperidines
dc.subjectIndoles
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectDisease-Free Survival
dc.subjectTreatment Outcome
dc.subjectProportional Hazards Models
dc.subjectDrug Resistance, Neoplasm
dc.subjectMutation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.titleGene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.
dc.typeJournal Article
dcterms.dateAccepted2017-05-18
rioxxterms.versionofrecord10.1158/1078-0432.ccr-17-0172
rioxxterms.licenseref.startdate2017-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue17
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Melanoma and Kidney Cancer/Melanoma and Kidney Cancer (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume23
pubs.embargo.termsNot known
icr.researchteamMelanoma and Kidney Canceren_US
dc.contributor.icrauthorLarkin, Jamesen
dc.contributor.icrauthorMarsden,en


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