Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Murgioni S, Rossini D, Marmorino F, Mennitto A, Ning Y, Okazaki S, Berger M D, Miyamoto Y, Gopez R, Barzi A, Yamaguchi T, Loupakis F, Lenz H-J
Department of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
Ann Oncol. 2017 May 1;28(5):1015-1022. doi: 10.1093/annonc/mdx035.
Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102.
We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib. Single nucleotide polymorphisms of genes involved in HR (ATM, BRCA1, BRCA2, XRCC3, FANCD2, H2AX, RAD51) and cell cycle checkpoint (ATR, CHEK1, CHEK2, CDKN1A, TP53, CHE1, PIN1, PCNA) were analyzed by PCR-based direct sequencing.
In univariate analysis for the evaluation cohort, patients with any G allele in ATM rs609429 had longer overall survival (OS) than those with the C/C variant (8.7 vs. 4.4 months, HR 0.37, 95% CI: 0.14-0.99, P = 0.022). Patients carrying any A allele in XRCC3 rs861539 had significantly longer progression-free survival (PFS) (3.8 vs. 2.3 months, HR 0.44, 95% CI: 0.21-0.92, P = 0.024) and OS (15.6 vs. 6.3 months, HR 0.25, 95% CI: 0.08-0.79, P = 0.012) than those with the G/G variant. In multivariable analysis, ATM rs609429 remained significant for OS (P = 0.020). In the validation cohort, patients having ATM rs609429 with any G allele showed longer OS and PFS; the G/A variant in XRCC3 rs861539 showed longer OS, though without statistical significance.
Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.
三磷酸曲氟尿苷（FTD）掺入DNA是TAS-102的主要抗肿瘤作用。我们测试了DNA修复的同源重组（HR）和细胞周期检查点途径中的基因多态性是否与接受TAS-102治疗的难治性转移性结直肠癌（mCRC）患者的预后相关。
我们分析了从三个队列的233个样本中提取的基因组DNA：一个由52例接受TAS-102治疗的患者组成的评估队列、一个由129例接受TAS-102治疗的患者组成的验证队列以及一个由52例接受瑞戈非尼治疗的患者组成的对照队列。通过基于聚合酶链反应的直接测序分析了参与HR（ATM、BRCA1、BRCA2、XRCC3、FANCD2、H2AX、RAD51）和细胞周期检查点（ATR、CHEK1、CHEK2、CDKN1A、TP53、CHE1、PIN1、PCNA）的基因的单核苷酸多态性。
在评估队列的单变量分析中，ATM rs609429位点携带任何G等位基因的患者总生存期（OS）长于携带C/C变体的患者（8.7个月对4.4个月，风险比0.37，95%置信区间：0.14-0.99，P = 0.022）。XRCC3 rs861539位点携带任何A等位基因的患者无进展生存期（PFS）显著更长（3.8个月对2.3个月，风险比0.44，95%置信区间：0.21-0.92，P = 0.024），OS也更长（15.6个月对6.3个月，风险比0.25，95%置信区间：0.08-0.79，P = 0.012），而携带G/G变体的患者则不然。在多变量分析中，ATM rs609429位点对OS仍具有显著意义（P = 0.020）。在验证队列中，携带ATM rs609429位点任何G等位基因的患者OS和PFS更长；XRCC3 rs861539位点的G/A变体患者OS更长，尽管无统计学意义。
HR途径中的基因变异可能预测接受TAS-102治疗的mCRC患者的临床结局。
