Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.

2.50
Hdl Handle:
http://hdl.handle.net/10541/621029
Title:
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.
Authors:
Tutt, A; Tovey, H; Cheang, M; Kernaghan, S; Kilburn, L; Gazinska, P; Owen, J; Abraham, J; Barrett, S; Barrett-Lee, P; Brown, R; Chan, S; Dowsett, M; Flanagan, J; Fox, L; Grigoriadis, A; Gutin, A; Harper-Wynne, C; Hatton, M; Hoadley, K; Parikh, J; Parker, P; Perou, C; Roylance, R; Shah, V; Shaw, A; Smith, I; Timms, K; Wardley, Andrew M ( 0000-0002-9639-0888 ) ; Wilson, Gregory; Gillett, C; Lanchbury, J; Ashworth, A; Rahman, N; Harries, M; Ellis, P; Pinder, S; Bliss, J
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.
Affiliation:
Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK
Citation:
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. 2018, 24 (5):628-637 Nat Med
Journal:
Nature Medicine
Issue Date:
May-2018
URI:
http://hdl.handle.net/10541/621029
DOI:
10.1038/s41591-018-0009-7
PubMed ID:
29713086
Type:
Article
Language:
en
ISSN:
1546-170X
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorTutt, Aen
dc.contributor.authorTovey, Hen
dc.contributor.authorCheang, Men
dc.contributor.authorKernaghan, Sen
dc.contributor.authorKilburn, Len
dc.contributor.authorGazinska, Pen
dc.contributor.authorOwen, Jen
dc.contributor.authorAbraham, Jen
dc.contributor.authorBarrett, Sen
dc.contributor.authorBarrett-Lee, Pen
dc.contributor.authorBrown, Ren
dc.contributor.authorChan, Sen
dc.contributor.authorDowsett, Men
dc.contributor.authorFlanagan, Jen
dc.contributor.authorFox, Len
dc.contributor.authorGrigoriadis, Aen
dc.contributor.authorGutin, Aen
dc.contributor.authorHarper-Wynne, Cen
dc.contributor.authorHatton, Men
dc.contributor.authorHoadley, Ken
dc.contributor.authorParikh, Jen
dc.contributor.authorParker, Pen
dc.contributor.authorPerou, Cen
dc.contributor.authorRoylance, Ren
dc.contributor.authorShah, Ven
dc.contributor.authorShaw, Aen
dc.contributor.authorSmith, Ien
dc.contributor.authorTimms, Ken
dc.contributor.authorWardley, Andrew Men
dc.contributor.authorWilson, Gregoryen
dc.contributor.authorGillett, Cen
dc.contributor.authorLanchbury, Jen
dc.contributor.authorAshworth, Aen
dc.contributor.authorRahman, Nen
dc.contributor.authorHarries, Men
dc.contributor.authorEllis, Pen
dc.contributor.authorPinder, Sen
dc.contributor.authorBliss, Jen
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.en
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

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.