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@article{tutt:2018:10.1038/s41591-018-0009-7,
author = {tutt, A and tovey, H and Cheang, MCU and Kernaghan, S and Kilburn, L and Gazinska, P and Owen, J and Abraham, J and Barrett, S and Barrett-Lee, P and Brown, R and Chan, S and Dowsett, M and Flanagan, JM and Fox, L and Grigoriadis, A and Gutin, A and Harper-Wynne, C and Hatton, MQ and Hoadley, KA and Parikh, J and Parker, P and Perou, CM and Roylance, R and Shah, V and Shaw, A and Smith, IE and Timms, KM and Wardley, AM and Wilson, G and Gillett, C and Lanchbury, JS and Ashworth, A and Rahman, N and Harries, M and Ellis, P and Pinder, SE and Bliss, JM},
doi = {10.1038/s41591-018-0009-7},
journal = {Nature Medicine},
pages = {628--637},
title = {Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial},
url = {http://dx.doi.org/10.1038/s41591-018-0009-7},
volume = {24},
year = {2018}
}

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TY  - JOUR
AB  - 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.
AU  - tutt,A
AU  - tovey,H
AU  - Cheang,MCU
AU  - Kernaghan,S
AU  - Kilburn,L
AU  - Gazinska,P
AU  - Owen,J
AU  - Abraham,J
AU  - Barrett,S
AU  - Barrett-Lee,P
AU  - Brown,R
AU  - Chan,S
AU  - Dowsett,M
AU  - Flanagan,JM
AU  - Fox,L
AU  - Grigoriadis,A
AU  - Gutin,A
AU  - Harper-Wynne,C
AU  - Hatton,MQ
AU  - Hoadley,KA
AU  - Parikh,J
AU  - Parker,P
AU  - Perou,CM
AU  - Roylance,R
AU  - Shah,V
AU  - Shaw,A
AU  - Smith,IE
AU  - Timms,KM
AU  - Wardley,AM
AU  - Wilson,G
AU  - Gillett,C
AU  - Lanchbury,JS
AU  - Ashworth,A
AU  - Rahman,N
AU  - Harries,M
AU  - Ellis,P
AU  - Pinder,SE
AU  - Bliss,JM
DO  - 10.1038/s41591-018-0009-7
EP  - 637
PY  - 2018///
SN  - 1078-8956
SP  - 628
TI  - Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial
T2  - Nature Medicine
UR  - http://dx.doi.org/10.1038/s41591-018-0009-7
UR  - http://hdl.handle.net/10044/1/58825
VL  - 24
ER  -

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DR JAMES M. FLANAGAN

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