Journal Article

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

Harper-Wynne, Catherine, Lanchbury, Jerry S., Wardley, Andrew M., Barrett-Lee, Peter, Fox, Lisa, Abraham, Jacinta, Chan, Stephen, Ellis, Paul, Grigoriadis, Anita, Gazinska, Patrycja, Owen, Julie, Timms, Kirsten M., Flanagan, James M, Parikh, Jyoti, Hoadley, Katherine A., Gillett, Cheryl, Ashworth, Alan, Smith, Ian E., Tutt, Andrew, Kilburn, Lucy, Dowsett, Mitchell, Bliss, Judith M., Shaw, Adam, Brown, Robert, Gutin, Alexander, Cheang, Maggie Chon U., Barrett, Sophie, Shah, Vandna, Roylance, Rebecca, Parker, Peter, Rahman, Nazneen, Harries, Mark, Pinder, Sarah E., Perou, Charles M., Tovey, Holly, Kernaghan, Sarah, Wilson, Gregory, Hatton, Matthew Q.

2018

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059 / 631/67/1347 / 631/67/68 / 692/308/575 / 692/53/2423 / Antineoplastic agents / Biomarkers / Biomedical and Life Sciences / Biomedicine / Biotechnology / BRCA mutations / BRCA1 protein / BRCA1 Protein - genetics / BRCA2 Protein - genetics / Breast cancer / Cancer / Cancer Research / Cancer therapies / Carboplatin / Carboplatin - therapeutic use / Chemotherapy / Clinical trials / Deoxyribonucleic acid / DNA / Dosage and administration / Drug therapy / Female / Gene expression / Gene mutation / Genes / Genetic aspects / Genetic research / Genomic instability / Health aspects / Homologous recombination / Homologous Recombination - genetics / Homology / Humans / Infectious Diseases / Lesions / Maintenance / Messenger RNA / Metabolic Diseases / Methylation / Molecular Medicine / Mutation / Mutation - genetics / Neurosciences / Phenotypes / Platinum / Poly(ADP-ribose) polymerase / Progression-Free Survival / RNA / Stability / Subgroups / Subpopulations / Treatment Outcome / Triple negative breast cancer / Triple Negative Breast Neoplasms - drug therapy / Triple Negative Breast Neoplasms - genetics / Tumors