A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab.
A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab.
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DOI：
10.1158/1078-0432.ccr-17-1663
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发表时间：
2018-02-15
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影响因子：
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通讯作者：
Lenz HJ
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文献类型：
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作者：
Berger MD;Stintzing S;Heinemann V;Cao S;Yang D;Sunakawa Y;Matsusaka S;Ning Y;Okazaki S;Miyamoto Y;Suenaga M;Schirripa M;Hanna DL;Soni S;Puccini A;Zhang W;Cremolini C;Falcone A;Loupakis F;Lenz HJ
维生素D通过抑制Wnt信号和血管生成来抑制结肠癌的生长。我们假设，参与维生素D转运、代谢和信号传导的基因snp与接受一线FOLFIRI和贝伐单抗治疗的转移性结直肠癌（mCRC）患者的预后相关。本研究纳入了522名参加了使用FOLFIRI/贝伐单抗治疗的FIRE-3（发现队列）和TRIBE（验证组）试验的mCRC患者。278名接受FOLFIRI和西妥昔单抗（FIRE-3）治疗的患者作为对照队列。分析6个基因（GC、CYP24A1、CYP27B1、VDR、DKK1、CST5）的6个snp。在发现队列中，在单变量分析（P = 0.001）和多变量分析（P = 0.047）中，携带编码维生素d结合蛋白的GC rs4588 SNP的AA携带者，接受FOLFIRI/贝伐单抗治疗的总生存期（OS）均短于携带任何C等位基因的患者（15.9个月vs 25.1个月）。在多变量分析的验证队列中证实了这种关联（OS 18.1 vs. 26.2个月，HR, 1.83; P = 0.037）。有趣的是，对照组AA携带者表现出更长的OS（48.0比25.2个月，HR, 0.50; P = 0.021）。在第二个验证队列中，在单变量分析（P = 0.033）和多变量分析（P = 0.046）中，该关联进一步得到证实，该队列包括接受西妥昔单抗±伊立替康治疗的难治性mCRC患者（PFS 8.7 vs 3.7个月）。GC rs4588 SNP可能作为使用FOLFIRI/贝伐单抗或FOLFIRI/西妥昔单抗治疗的mCRC患者的预测标志物。尽管AA携带者使用FOLFIRI/西妥昔单抗可获得生存获益，但使用FOLFIRI/贝伐单抗治疗的预后较差。
Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab. 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed. In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D–binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046). GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome.