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Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.
Tutt, A Tovey, H Cheang, M Kernaghan, S Kilburn, L Gazinska, P Owen, J Abraham, J Barrett, S Barrett-Lee, P
Tutt, A
Tovey, H
Cheang, M
Kernaghan, S
Kilburn, L
Gazinska, P
Owen, J
Abraham, J
Barrett, S
Barrett-Lee, P
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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.
Authors
Tutt, A
Tovey, H
Cheang, M
Kernaghan, S
Kilburn, L
Gazinska, P
Owen, J
Abraham, J
Barrett, S
Barrett-Lee, P
Brown, R
Chan, S
Dowsett, M
Flanagan, J
Fox, L
Grigoriadis, A
Gutin, A
Harper-Wynne, C
Hatton, M
Hoadley, K
Parikh, J
Parker, P
Perou, C
Roylance, R
Shah, V
Shaw, A
Smith, I
Timms, K
Wardley, Andrew M
Wilson, Gregory
Gillett, C
Lanchbury, J
Ashworth, A
Rahman, N
Harries, M
Ellis, P
Pinder, S
Bliss, J
Tovey, H
Cheang, M
Kernaghan, S
Kilburn, L
Gazinska, P
Owen, J
Abraham, J
Barrett, S
Barrett-Lee, P
Brown, R
Chan, S
Dowsett, M
Flanagan, J
Fox, L
Grigoriadis, A
Gutin, A
Harper-Wynne, C
Hatton, M
Hoadley, K
Parikh, J
Parker, P
Perou, C
Roylance, R
Shah, V
Shaw, A
Smith, I
Timms, K
Wardley, Andrew M
Wilson, Gregory
Gillett, C
Lanchbury, J
Ashworth, A
Rahman, N
Harries, M
Ellis, P
Pinder, S
Bliss, J
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Date
2018-05
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Citation
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. 2018, 24 (5):628-637 Nat Med