Conducted in 74 hospitals throughout the United Kingdom, TNT (NCT00532727) was a phase 3, parallel group, open-label, randomized controlled trial with preplanned biomarker subgroup analyses. The results published on April 30, 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 trial provide 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 the 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 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, 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 the 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 the carboplatin group vs 34.0% in the docetaxel group. In contrast, in patients with germline-mutated BRCA1/2 breast cancer, carboplatin had double the ORR of docetaxel, 68% vs 33%, respectively. Such benefit was not observed for patients 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 non-basal subgroup.

The authors concluded 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 perspective of these findings is that many countries now perform inexpensive local BRCA1/2 germline testing and patients with TNBC could benefit from the biologically targeted use of a highly active and inexpensive platinum chemotherapy.