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dc.contributor.authorTutt, A
dc.contributor.authorTovey, H
dc.contributor.authorCheang, M
dc.contributor.authorKernaghan, S
dc.contributor.authorKilburn, L
dc.contributor.authorGazinska, P
dc.contributor.authorOwen, J
dc.contributor.authorAbraham, J
dc.contributor.authorBarrett, S
dc.contributor.authorBarrett-Lee, P
dc.contributor.authorBrown, R
dc.contributor.authorChan, S
dc.contributor.authorDowsett, M
dc.contributor.authorFlanagan, J
dc.contributor.authorFox, L
dc.contributor.authorGrigoriadis, A
dc.contributor.authorGutin, A
dc.contributor.authorHarper-Wynne, C
dc.contributor.authorHatton, M
dc.contributor.authorHoadley, K
dc.contributor.authorParikh, J
dc.contributor.authorParker, P
dc.contributor.authorPerou, C
dc.contributor.authorRoylance, R
dc.contributor.authorShah, V
dc.contributor.authorShaw, A
dc.contributor.authorSmith, I
dc.contributor.authorTimms, K
dc.contributor.authorWardley, Andrew M
dc.contributor.authorWilson, Gregory
dc.contributor.authorGillett, C
dc.contributor.authorLanchbury, J
dc.contributor.authorAshworth, A
dc.contributor.authorRahman, N
dc.contributor.authorHarries, M
dc.contributor.authorEllis, P
dc.contributor.authorPinder, S
dc.contributor.authorBliss, J
dc.date.accessioned2018-06-04T09:47:04Z
dc.date.available2018-06-04T09:47:04Z
dc.date.issued2018-05
dc.identifier.citationCarboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. 2018, 24 (5):628-637 Nat Meden
dc.identifier.issn1546-170X
dc.identifier.pmid29713086
dc.identifier.doi10.1038/s41591-018-0009-7
dc.identifier.urihttp://hdl.handle.net/10541/621029
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.
dc.language.isoenen
dc.rightsArchived with thanks to Nature medicineen
dc.titleCarboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.en
dc.typeArticleen
dc.contributor.departmentBreast Cancer Now Research Centre, The Institute of Cancer Research, London, UKen
dc.identifier.journalNature Medicineen
html.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.


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