A randomised phase III trial of carboplatin compared with docetaxel in BRCA1/2 mutated and pre-specified triple negative breast cancer “BRCAness” subgroups: the TNT Trial

By Andrew Tutt, H. Tovey, M. Cheang, S. Kernaghan, L. Kilburn, P. Gazinska, J. Owen, J. Abraham, S. Barrett, P. Barrett-Lee and 28 more. Nature Medicine, 2018

811 citations recorded by the source corpus.

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. The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2-mutated tumors and a greater response to taxanes in the nonbasal subtype.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/5457bcbdd2c1bc05f8d99a669676e40ec31b40fd

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Citations in the corpus

• Molecular profiling for precision cancer therapies (2020, background): “However, one study found that germline mutations in BRCA1 and BRCA2 responded to carboplatin, whereas those with a BRCA mutational signature and no germline variant did not respond [109].”
• Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment (2019, background): “In the metastatic setting, carboplatin and docetaxel achieved comparable objective response rates (ORR) in basal-like tumors in the TNT trial (32.5% vs. 31.0%, respectively; P = 0.87; ref.”
• Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge (2019, background): “Indeed, platinum-based chemotherapy significantly increased the pCR rates of TNBC patients that harbor germ-line BRCA mutations [204].”
• Recent advances in therapeutic strategies for triple-negative breast cancer (2022, background): “another phase III trial, unselected advanced BRCA1/2 mutated and BRCAness TNBC subgroups were treated with a platinum agent or docetaxel [24].”
• ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. (2021, methodology): “73 There are no studies directly comparing PARP inhibitors with a platinum agent (either alone or in combination with other ChT agents or ICIs).”