dc.contributor.author | Tutt, A | |
dc.contributor.author | Tovey, H | |
dc.contributor.author | Cheang, MCU | |
dc.contributor.author | Kernaghan, S | |
dc.contributor.author | Kilburn, L | |
dc.contributor.author | Gazinska, P | |
dc.contributor.author | Owen, J | |
dc.contributor.author | Abraham, J | |
dc.contributor.author | Barrett, S | |
dc.contributor.author | Barrett-Lee, P | |
dc.contributor.author | Brown, R | |
dc.contributor.author | Chan, S | |
dc.contributor.author | Dowsett, M | |
dc.contributor.author | Flanagan, JM | |
dc.contributor.author | Fox, L | |
dc.contributor.author | Grigoriadis, A | |
dc.contributor.author | Gutin, A | |
dc.contributor.author | Harper-Wynne, C | |
dc.contributor.author | Hatton, MQ | |
dc.contributor.author | Hoadley, KA | |
dc.contributor.author | Parikh, J | |
dc.contributor.author | Parker, P | |
dc.contributor.author | Perou, CM | |
dc.contributor.author | Roylance, R | |
dc.contributor.author | Shah, V | |
dc.contributor.author | Shaw, A | |
dc.contributor.author | Smith, IE | |
dc.contributor.author | Timms, KM | |
dc.contributor.author | Wardley, AM | |
dc.contributor.author | Wilson, G | |
dc.contributor.author | Gillett, C | |
dc.contributor.author | Lanchbury, JS | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Rahman, N | |
dc.contributor.author | Harries, M | |
dc.contributor.author | Ellis, P | |
dc.contributor.author | Pinder, SE | |
dc.contributor.author | Bliss, JM | |
dc.date.accessioned | 2018-05-31T10:45:36Z | |
dc.date.accessioned | 2019-02-28T14:07:03Z | |
dc.date.issued | 2018-04-30 | |
dc.identifier.citation | Nature medicine, 2018, 24 (5), pp. 628 - 637 | |
dc.identifier.issn | 1078-8956 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3109 | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.doi | 10.1038/s41591-018-0009-7 | |
dc.description.abstract | Germline 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 628 - 637 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.relation.replaces | https://repository.icr.ac.uk/handle/internal/1695 | |
dc.relation.replaces | internal/1695 | |
dc.relation.replaces | internal/1623 | |
dc.relation.replaces | https://repository.icr.ac.uk/handle/internal/1623 | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Humans | |
dc.subject | Carboplatin | |
dc.subject | BRCA1 Protein | |
dc.subject | BRCA2 Protein | |
dc.subject | Treatment Outcome | |
dc.subject | Mutation | |
dc.subject | Female | |
dc.subject | Homologous Recombination | |
dc.subject | Triple Negative Breast Neoplasms | |
dc.subject | Progression-Free Survival | |
dc.title | Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-03-02 | |
rioxxterms.versionofrecord | 10.1038/s41591-018-0009-7 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature medicine | |
pubs.issue | 5 | |
pubs.notes | Not 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/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/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Medicine (Brown Epigenetic Therapy) | |
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/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 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/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/Closed research teams | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Closed research teams/Medicine (Brown Epigenetic Therapy) | |
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/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 24 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | Genomic Analysis – Clinical Trials | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Medicine (Brown Epigenetic Therapy) | |
icr.researchteam | Genetic Susceptibility | |
icr.researchteam | Endocrinology | |
dc.contributor.icrauthor | Tutt, Andrew | |
dc.contributor.icrauthor | Tovey, Holly | |
dc.contributor.icrauthor | Cheang, Chon | |
dc.contributor.icrauthor | Kernaghan, Sarah | |
dc.contributor.icrauthor | Kilburn, Lucy | |
dc.contributor.icrauthor | Brown, Robert | |
dc.contributor.icrauthor | Fox, Lisa | |
dc.contributor.icrauthor | Bliss, Judith | |