UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan
UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan
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DOI：
10.1158/1078-0432.ccr-06-2290
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发表时间：
2007-06-01
影响因子：
11.5
通讯作者：
Ychou, Marc
中科院分区：
文献类型：
--
作者：
Cote, Jean-Francois;Kirzin, Sylvain;Ychou, Marc
目的：伊立替康 (CPT-11) 被批准用于转移性结直肠癌治疗，但可能引起严重毒性。我们研究的主要目的是在一项前瞻性随机试验中评估不同多态性对接受 5-氟尿嘧啶 (5FU) 和 CPT-11 辅助化疗方案的高危 III 期结肠癌患者发生血液学毒性和无病生存的作用。 实验设计：在比较 LV5FU2 与 LV5FU2 + CPT-11 的 III 期试验中，400 名患者被随机分配。提取 184 名患者的 DNA 并进行基因分型，以检测核苷酸多态性：ABCB1 为 3435C > T，CYP3/15 为 6986A > G，UGT1A1*28 和 UGT1A1 -3156G > A。 结果：两个治疗组的基因型频率相似。在测试组中，ABCB1 和 CYP3A5 多态性的毒性或无病生存率没有观察到显着差异。 UGT1A1*28 纯合子患者较 UGT1A1*1 纯合子患者 (16.2%) 更常见严重血液毒性 (50%)，P = 0.06。此外，-3156G > UGT1A1 多态性突变等位基因纯合的患者比野生型等位基因纯合的患者（12.5%）更频繁地出现严重血液毒性（50%），P = 0.01。这种毒性在纯合突变体中发生的时间明显早于野生型纯合子患者（P = 0.043）。在 Cox 模型中，与 G/G 基因型患者相比，A/A 基因型患者发生严重血液毒性的风险比显着更高 [风险比，8.4； 95%置信区间，1.9-37.2； P = 0.005]。结论：本研究支持在 LV5FU2 + CPT-11 治疗前鉴定 UGT1A1 启动子多态性以预测早期血液学毒性的临床实用性。 -3156G > A 多态性似乎是比 UGT1A1 (TA)(6)TAA)(TA)(7)TAA 多态性更好的预测因子。
Purpose: Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial.Experimental Design: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C > T for ABCB1, 6986A > G for CYP3/15, UGT1A1*28 and -3156G > A for UGT1A1.Results: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival forABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G > A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005].Conclusions: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G > A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA)(TA)(7)TAA polymorphism.