Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial
File(s)TNT manuscript_Nat Med_14 February 2018.pdf (202.37 KB)
Accepted version
Author(s)
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.
Date Issued
2018-05-01
Date Acceptance
2018-03-02
Citation
Nature Medicine, 2018, 24 (5), pp.628-637
ISSN
1078-8956
Publisher
Nature Publishing Group
Start Page
628
End Page
637
Journal / Book Title
Nature Medicine
Volume
24
Issue
5
Copyright Statement
© 2018 Nature America Inc., part of Springer Nature. All rights reserved
Sponsor
Cancer Research UK
Grant Number
13086
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
HOMOLOGOUS RECOMBINATION DEFICIENCY
CONTAINING NEOADJUVANT CHEMOTHERAPY
PROMOTER METHYLATION
OVARIAN-CARCINOMA
1ST-LINE THERAPY
PLUS GEMCITABINE
FANCONI-ANEMIA
DNA-REPAIR
OPEN-LABEL
PHASE-III
BRCA1 Protein
BRCA2 Protein
Carboplatin
Female
Homologous Recombination
Humans
Mutation
Progression-Free Survival
Treatment Outcome
Triple Negative Breast Neoplasms
Humans
Carboplatin
BRCA1 Protein
BRCA2 Protein
Treatment Outcome
Mutation
Female
Homologous Recombination
Triple Negative Breast Neoplasms
Progression-Free Survival
Immunology
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2018-04-30