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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The authors would like to thank all subjects and the families of those who took part in the trial and all involved staff at the participating centers. In addition, we acknowledge R. Buus and B. Haynes for laboratory support for NanoString assays, S. Ferree of NanoString for provision of Prosigna reagents and manuscript review and R. Seitz of Insight Genetics for assistance in TNBC type analysis and manuscript review. The authors also acknowledge past and present colleagues on the TNT Trial Management Group, the Independent Data Monitoring Committee and Trial Steering Committee who oversaw the trial, the Response Evaluation Committee who conducted the independent radiology review and Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer) who funded the study (Cancer Research UK grant number CRUK/07/012) as well as the National Institute for Health Research Cancer Research Networks in England and their equivalent NHS research and development (R&D)–funded networks in Scotland, Wales, and Northern Ireland for ‘in-kind’ support. Funding was provided from Myriad Genetics, Inc., to cover costs of nucleic extraction from tumor blocks appropriate for next-generation sequencing, and Prosigna reagent kits were provided by NanoString Technologies, Inc.
A.T., H.T., M.C.U.C., S.K., L.K., P.G., J.O., R.B., M.D., L.F., A.G., P.P., V.S., C.G., N.R., S.E.P. and J.M.B. report that their institutional departments have received grants from Breast Cancer Now and/or Cancer Research UK and other support for costs or consumables in this research from Myriad Genetics, Inc. and NanoString Technologies, Inc. during the conduct of the study. M.C.U.C. has a patent: US Patent No. 9,631,239 with royalties paid. M.D. reports receiving personal fees from Myriad Genetics, Inc. outside of the submitted work. A.Gu. reports receiving salary compensation and stock/options from Myriad Genetics, Inc. during conduct of the study and has patent rights assigned to Myriad Genetics. C.M.P. reports receiving personal fees from Bioclassifier LLC, consulting fees from Nanostring Technologies outside the submitted work. In addition, C.M.P. has a patent: U.S. Patent No. 9,631,239 with royalties paid. K.M.T. reports receiving personal fees from Myriad Genetics, Inc. during the conduct of the study and personal fees from Myriad Genetics, Inc. outside the submitted work. In addition, K.T. has the following patents pending: 13/164,499; 14/554,715; 15/010,721; 15/192,497; 14/245,576; 62/000,000; 62/311,231; 62/332,526; 14/962,588; 2802882; 11796544.2; 15189527.3; 2,839,210; 12801070.9; 2014-516031; 2012358244; 2,860,312; 201280070358.0; 12860530.0; 2014-548965; 2014248007; 2,908,745; 14779403.6; 2016-506657; 712,663; PCT/US15/045561; PCT/US15/064473; and the following patents issued to Myriad Genetics, Inc.: 9,279,156; 9,388,427 and 625468. J.S.L. reports salary compensation and stock/options from Myriad Genetics Inc. received during conduct of the study. The other authors declare no competing interests.
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Tutt, A., Tovey, H., Cheang, M.C.U. et al. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med 24, 628–637 (2018). https://doi.org/10.1038/s41591-018-0009-7
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