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

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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Fig. 1: Diagram of study.
Fig. 2: Response rates documented in the overall population and within BRCA subgroups.
Fig. 3: PFS in the entire population and in subgroups stratified according to BRCA status.
Fig. 4: Response rates in groups stratified according to HRD status.
Fig. 5: Response rates in groups stratified according to basal-like status.
Fig. 6: PFS for groups stratified according to basal-like status.

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Acknowledgements

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.

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A.T., H.T., S.K., L.K., P.B.-L., L.F., C.H.-W, P.P., R.R., I.E.S., A.M.W., C.G., A.A., N.R., M.H., P.E., S.E.P. and J.M.B. are members of the Trial Management Group (TMG), and M.C.U.C, A.Gr., C.M.P., A.S. and R.B. are in the Biological Subcommittee of the TMG. J.P. is a Response Evaluation Committee member. A.T. was the Chief Investigator and chair of the Biological Subcommittee of the TMG and performed trial design and protocol development, including writing of the translational subsection of the protocol at trial outset to test the BRCAness hypotheses. A.T. also performed participant recruitment, data collection, data interpretation and writing of the manuscript. H.T. performed statistical analysis, data interpretation and writing of the manuscript. M.C.U.C. was the lead biostatistician for the translational substudies and performed data analysis of biological data generated from the biomarker assays, including basal-like subtype by NanoString (Prosigna) and IHC, BRCA1 methylation, BRCA1/2 mutation status, HRD score and total RNA-seq, data interpretation and writing of the manuscript. S.K. performed trial management, data collection and data management. L.K. performed trial design, protocol development, statistical analysis, data interpretation and writing of the manuscript. P.G., J.O. and V.S. performed TNT tissues resource preparation. J.A., S.B.,P.B.-L., S.C., C.H.-W., M.Q.H, R.R., I.E.S., A.M.W. and G.W.  performed participant recruitment and data collection. R.B. and J.M.F. performed data analysis of BRCA1 methylation and writing of the manuscript. M.D. performed the NanoString (Prosigna) experiment. L.F. performed trial management and data collection. A.Gr. and A.Gu. performed HRD analysis. K.A.H. and C.M.P. performed total RNA-seq from which BRCA1 mRNA was derived. J.P. performed independent radiology review. A.S. served as a germline genetics advisor for biological analyses and data interpretation, supported the germline BRCA1/2 mutation analysis and performed protocol development and writing of the manuscript. K.M.T. and J.S.L. performed tumor BRCA1/2 mutation analysis, BRCA1 methylation analysis and HRD analysis. C.G. served as the TNT tissue bank lead and performed TNT tissues resource preparation, ER/PgR and HER2 central testing, basal breast cancer subtyping by IHC and gene expression analysis. N.R. served as a germline genetics advisor for biological analyses and data interpretation, led the germline BRCA1/2 mutation analysis and performed protocol development and writing of the manuscript. M.H. and P.E. performed trial design, protocol development, participant recruitment and data collection. S.E.P. served as the study’s lead pathologist and performed ER/PgR, HER2 central testing, and basal breast cancer subtyping by IHC. J.M.B. performed trial design, protocol development, study conduct oversight, statistical analysis, data interpretation and writing of the manuscript. All authors reviewed the manuscript prior to submission.

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Correspondence to Andrew Tutt.

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Competing interests

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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Biological data used for subgroup analyses

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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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