Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer
Genetic variants of DNA repair-related genes predict efficacy of TAS-102 in patients with refractory metastatic colorectal cancer
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DOI：
10.1093/annonc/mdx035
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发表时间：
2017-05-01
影响因子：
50.5
通讯作者：
Lenz, H. -J.
中科院分区：
文献类型：
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作者：
Suenaga, M.;Schirripa, M.;Lenz, H. -J.
背景：三磷酸化三氟啶（FTD）结合DNA是TAS-102的主要抗肿瘤作用。我们测试了同源重组（HR）和DNA修复细胞周期检查点通路的遗传多态性是否与接受TAS-102治疗的难治性转移性结直肠癌（mCRC）患者的预后相关。患者和方法：我们分析了从三个队列的233个样本中提取的基因组DNA: 52名接受TAS-102的患者的评估队列，129名接受TAS-102的验证队列和52名接受瑞非尼的对照队列。通过pcr直接测序分析HR （ATM、BRCA1、BRCA2、XRCC3、FANCD2、H2AX、RAD51）和细胞周期检查点（ATR、CHEK1、CHEK2、CDKN1A、TP53、CHE1、PIN1、PCNA）相关基因的单核苷酸多态性。结果：在评估队列的单因素分析中，携带ATM rs609429中任意G等位基因的患者比携带C/C变异的患者总生存期（OS）更长（8.7个月vs 4.4个月，HR 0.37, 95% CI: 0.14-0.99, P = 0.022）。携带XRCC3 rs861539中任何A等位基因的患者比携带G/G变异的患者具有更长的无进展生存期（PFS） （3.8 vs 2.3个月，HR 0.44, 95% CI: 0.21-0.92, P = 0.024）和OS （15.6 vs 6.3个月，HR 0.25, 95% CI: 0.08-0.79, P = 0.012）。在多变量分析中，ATM rs609429对OS仍然具有显著性（P = 0.020）。在验证队列中，携带任意G等位基因的ATM rs609429患者表现出更长的OS和PFS；XRCC3 rs861539的G/A变异OS更长，但无统计学意义。结论：HR通路的遗传变异可能预测接受TAS-102治疗的mCRC患者的临床预后。
Background: 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.Patients and methods: 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.Results: 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.Conclusion: Genetic variants in the HR pathway may predict clinical outcome in mCRC patients receiving TAS-102.