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Nat Med. 2018 May;24(5):628-637. doi: 10.1038/s41591-018-0009-7. Epub 2018 Apr 30.

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

Author information

1
Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK. andrew.tutt@icr.ac.uk.
2
Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK. andrew.tutt@icr.ac.uk.
3
Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK.
4
Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, Guy's Hospital, London, UK.
5
King's Health Partners Cancer Biobank, King's College London, London, UK.
6
Velindre Cancer Centre, Cardiff, UK.
7
Beatson West of Scotland Cancer Centre, Glasgow, UK.
8
Department of Surgery and Cancer, Imperial College London, London, UK.
9
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
10
Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK.
11
Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK.
12
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK.
13
Myriad Genetics, Inc., Salt Lake City, UT, USA.
14
Kent Oncology Centre, Maidstone and Tunbridge Wells NHS Trust, Kent, UK.
15
Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK.
16
Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
17
Department of Radiology, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK.
18
School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Medical School Campus, London, UK.
19
Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK.
20
Department of Oncology, University College London Hospitals NHS Foundation Trust and NIHR University College London Hospitals Biomedical Research Centre, London, UK.
21
Department of Medical and Molecular Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
22
Breast Unit, The Royal Marsden NHS Foundation Trust, London, UK.
23
NIHR Manchester Clinical Research Facility at The Christie and Division of Cancer Sciences and University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
24
The Christie NHS Foundation Trust, Manchester, UK.
25
Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London, UK.
26
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA.
27
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
28
Cancer Genetics Unit, The Royal Marsden NHS Foundation Trust, London, UK.
29
Department of Medical Oncology, Guy's and St Thomas Foundation Trust, London, UK.

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.

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