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

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Title: Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial
Authors: Tutt, A
Tovey, H
Cheang, MCU
Kernaghan, S
Kilburn, L
Gazinska, P
Owen, J
Abraham, J
Barrett, S
Barrett-Lee, P
Brown, R
Chan, S
Dowsett, M
Flanagan, JM
Fox, L
Grigoriadis, A
Gutin, A
Harper-Wynne, C
Hatton, MQ
Hoadley, KA
Parikh, J
Parker, P
Perou, CM
Roylance, R
Shah, V
Shaw, A
Smith, IE
Timms, KM
Wardley, AM
Wilson, G
Gillett, C
Lanchbury, JS
Ashworth, A
Rahman, N
Harries, M
Ellis, P
Pinder, SE
Bliss, JM
Item Type: Journal Article
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.
Issue Date: 30-Apr-2018
Date of Acceptance: 2-Mar-2018
URI: http://hdl.handle.net/10044/1/58825
DOI: https://dx.doi.org/10.1038/s41591-018-0009-7
ISSN: 1078-8956
Publisher: Nature Publishing Group
Journal / Book Title: Nature Medicine
Copyright Statement: © 2018 Nature America Inc., part of Springer Nature. All rights reserved
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: C536/A13086
Keywords: 11 Medical And Health Sciences
Immunology
Publication Status: Published online
Online Publication Date: 2018-04-30
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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