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.

中文翻译：

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BRCA1/2 突变和三阴性乳腺癌 BRCAness 亚组中的卡铂：TNT 试验。

BRCA1/2 中的种系突变通过损害同源重组 (HR) 并导致基因组不稳定，使个体易患乳腺癌（称为种系突变的 BRCA1/2 乳腺癌，gBRCA-BC）。HR 还修复由铂类药物和 PARP 抑制剂引起的 DNA 损伤。三阴性乳腺癌 (TNBCs) 包含具有 BRCA1/2 突变的亚群，假设对铂特别敏感。推定的“BRCAness”亚组中的癌症——具有 BRCA1 甲基化的肿瘤；BRCA1 mRNA 水平低（BRCA1 mRNA-low）；HR缺陷或具有基础表型的突变特征也可能对铂敏感。我们在未选择的晚期 TNBC 受试者的 3 期试验中评估了卡铂和另一种机制不同的疗法多西他赛的疗效。预先指定的方案能够在 gBRCA-BC 和 BRCAness 亚组中进行生物标志物-治疗相互作用分析。主要终点是客观反应率（ORR）。在未选择的人群（376 名受试者；188 名卡铂，188 名多西他赛）中，卡铂的活性并不比多西他赛高（ORR，分别为 31.4% 和 34.0%；P = 0.66）。相比之下，在 gBRCA-BC 受试者中，卡铂的 ORR 是多西紫杉醇的两倍（分别为 68% 和 33%；生物标志物，治疗相互作用 P = 0.01）。对于 BRCA1 甲基化、BRCA1 mRNA 低肿瘤或 Myriad HRD 测定中得分高的受试者，未观察到这种益处。治疗与基底样亚型之间的显着相互作用是由非基底亚组中多西紫杉醇的高反应驱动的。我们得出结论，晚期 TNBC 患者受益于 BRCA1/2 突变的表征，但不是 BRCA1 甲基化或 Myriad HRD 分析，以告知基于铂的化学疗法的选择。此外，基底样癌症的基因表达分析也可能影响治疗选择。