Patients with Advanced TNBC Benefit from Characterisation of BRCA1/2 Mutations to Inform Choices on Platinum-Based Chemotherapy

Results from the TNT study

Conducted in 74 hospitals throughout the United Kingdom, TNT (NCT00532727) was a phase III, parallel group, open-label randomised controlled trial with preplanned biomarker subgroup analyses. The results are published on 30 April 2018 in the Nature Medicine. The authors wrote that the PARP inhibitor olaparib is now approved in advanced germline-mutated BRCA1/2 breast cancer, but this treatment may remain unaffordable to many health care systems and patients for many years. It remains unknown how potent PARP1-trapping inhibitors would compare with platinums in this setting, but the results of the TNT trialprovide evidence that a widely available, affordable off-patent biomarker, which is enriched in the triple-negative breast cancers (TNBCs) prevalent in many developing countries, has utility in selecting a patient population that could benefit during this period from the biologically targeted use of a highly active and inexpensive platinum chemotherapy agent rather than the current licensed standard-of-care chemotherapies for breast cancer. 

The authors wrote in study background that germline mutations in BRCA1/2 predispose individuals to germline-mutated BRCA1/2 breast cancer by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. TNBCs harbour subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative ‘BRCAness’ subgroups (tumours with BRCA1 methylation, low levels of BRCA1 mRNA, or mutational signatures for HR deficiency and those with basal phenotypes) may also be sensitive to platinum. 

The TNT study team assessed the efficacy of carboplatin and docetaxel in patients with unselected advanced TNBC. A prespecified protocol enabled biomarker–treatment interaction analyses in germline-mutated BRCA1/2 breast cancer and BRCAness subgroups. The primary endpoint was objective response rate (ORR). 

Between 2008 and 2014, the study enrolled 376 patients, 188 allocated to carboplatin and 188 to docetaxel arm. All patients were included in the analysis of the primary endpoint. The trial population largely comprised patients with TNBC and no known BRCA1/2 mutation (338 of 376) and with baseline characteristics typical of patients with relapse of TNBC following first-line therapy. 

There was no evidence of a difference between the ORR to carboplatin and to docetaxel in the overall population with ORR 31.4% in carboplatin group versus 34.0% in docetaxel group. In contrast, in patients with germline-mutated BRCA1/2 breast cancer, carboplatin had double the ORR of docetaxel, 68% versus 33%, respectively; biomarker, treatment interaction p= 0.01. Such benefit was not observed for patients with BRCA1 methylation, BRCA1 mRNA-low tumours 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 non-basal subgroup. 

The authors concluded that patients with advanced TNBC benefit from characterisation 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 perspective of these findings is that many countries now perform inexpensive local BRCA1/2 germline testing and patients with TNBCs could benefit from the biologically targeted use of a highly active and inexpensive platinum chemotherapy, if PARP inhibitor is unaffordable to health care system or until its availability. 

The trial was cosponsored by The Institute of Cancer Research and King's College London, UK. The authors acknowledge colleagues on the TNT Trial Management Group, the Independent Data Monitoring Committee and Trial Steering Committee, the Response Evaluation Committee, 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–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 tumour blocks appropriate for next-generation sequencing, and Prosigna reagent kits were provided by NanoString Technologies, Inc. 

Reference 

Tutt A, Tovey H, Cheang MCU, et al. Carboplatin in BRCA1/2-mutated and triple negative breast cancer BRCAness subgroups: the TNT Trial. Nature Medicine; Published online 30 April 2018. doi:10.1038/s41591-018-0009-7.