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dc.contributor.authorTutt, Aen_US
dc.contributor.authorTovey, Hen_US
dc.contributor.authorCheang, MCUen_US
dc.contributor.authorKernaghan, Sen_US
dc.contributor.authorKilburn, Len_US
dc.contributor.authorGazinska, Pen_US
dc.contributor.authorOwen, Jen_US
dc.contributor.authorAbraham, Jen_US
dc.contributor.authorBarrett, Sen_US
dc.contributor.authorBarrett-Lee, Pen_US
dc.contributor.authorBrown, Ren_US
dc.contributor.authorChan, Sen_US
dc.contributor.authorDowsett, Men_US
dc.contributor.authorFlanagan, JMen_US
dc.contributor.authorFox, Len_US
dc.contributor.authorGrigoriadis, Aen_US
dc.contributor.authorGutin, Aen_US
dc.contributor.authorHarper-Wynne, Cen_US
dc.contributor.authorHatton, MQen_US
dc.contributor.authorHoadley, KAen_US
dc.contributor.authorParikh, Jen_US
dc.contributor.authorParker, Pen_US
dc.contributor.authorPerou, CMen_US
dc.contributor.authorRoylance, Ren_US
dc.contributor.authorShah, Ven_US
dc.contributor.authorShaw, Aen_US
dc.contributor.authorSmith, IEen_US
dc.contributor.authorTimms, KMen_US
dc.contributor.authorWardley, AMen_US
dc.contributor.authorWilson, Gen_US
dc.contributor.authorGillett, Cen_US
dc.contributor.authorLanchbury, JSen_US
dc.contributor.authorAshworth, Aen_US
dc.contributor.authorRahman, Nen_US
dc.contributor.authorHarries, Men_US
dc.contributor.authorEllis, Pen_US
dc.contributor.authorPinder, SEen_US
dc.contributor.authorBliss, JMen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2018-05-31T10:45:36Z
dc.date.accessioned2019-02-28T14:07:03Z
dc.date.issued2018-05en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29713086en_US
dc.identifier10.1038/s41591-018-0009-7en_US
dc.identifier.citationNat Med, 2018, 24 (5), pp. 628 - 637en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3109
dc.identifier.eissn1546-170Xen_US
dc.identifier.doi10.1038/s41591-018-0009-7en_US
dc.description.abstractGermline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.en_US
dc.format.extent628 - 637en_US
dc.languageengen_US
dc.language.isoengen_US
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/1695
dc.relation.replacesinternal/1695
dc.relation.replacesinternal/1623
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/1623
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectBRCA1 Proteinen_US
dc.subjectBRCA2 Proteinen_US
dc.subjectCarboplatinen_US
dc.subjectFemaleen_US
dc.subjectHomologous Recombinationen_US
dc.subjectHumansen_US
dc.subjectMutationen_US
dc.subjectProgression-Free Survivalen_US
dc.subjectTreatment Outcomeen_US
dc.subjectTriple Negative Breast Neoplasmsen_US
dc.titleCarboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-03-02en_US
rioxxterms.versionofrecord10.1038/s41591-018-0009-7en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-05en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfNat Meden_US
pubs.issue5en_US
pubs.notesNot knownen_US
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/Endocrinology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Genetic Susceptibility
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/Genomic Analysis – Clinical Trials
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)
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/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Genetic Susceptibility
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/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Medicine (Brown Epigenetic Therapy)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublisheden_US
pubs.volume24en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamGenomic Analysis – Clinical Trialsen_US
icr.researchteamMedicine (RMH Smith Cunningham)en_US
icr.researchteamGenetic Susceptibilityen_US
icr.researchteamEndocrinologyen_US
icr.researchteamMedicine (Brown Epigenetic Therapy)en_US
dc.contributor.icrauthorBliss, Judithen_US
dc.contributor.icrauthorTutt, Andrewen_US
dc.contributor.icrauthorTovey, Hollyen_US
dc.contributor.icrauthorCheang, Chonen_US
dc.contributor.icrauthorBrown, Roberten_US
dc.contributor.icrauthorSmith, Ianen_US
dc.contributor.icrauthorKilburn, Lucyen_US
dc.contributor.icrauthorKernaghan, Sarahen_US
dc.contributor.icrauthorFox, Lisaen_US
dc.contributor.icrauthorDowsett, Mitchen_US
dc.contributor.icrauthorRahman, Saberaen_US


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