UGT1A1基因多态性与伊立替康为主方案治疗晚期结直肠癌的毒性和疗效的相关性分析

Correlation between UGT1A1 gene polymorphisms and toxicity and efficacy in patients with metastatic colorectal cancer treated with irinotecan based chemotherapy

目的探讨中国汉族人结直肠癌患者尿苷二磷酸葡糖苷酸转移酶1A1(UGT1A1)基因多态性分布,评价UGT1A1基因多态性与伊立替康(CPT-11)为主方案治疗晚期结直肠癌的毒性和疗效的关系。方法以CPT-11为主的FOL-FIRI方案(CPT-11 180mg/m2)和IFL方案(CPT-11 125mg/m2)治疗晚期结直肠癌,检测患者的UGT1A1*28和UGT1A1*6基因型,分析UGT1A1基因多态性及其与化疗毒性、疗效和预后的相关性。结果共纳入192例患者,189例行UGT1A1*28和UGT1A1*6基因型检测,野生型占37.6%,1个位点变异型占43.9%,2个位点突变异型占18.5%。183例可评价毒副反应,3～4级中性粒细胞减少的发生率为26.6%(51/183);3～4级迟发性腹泻的发生率为15.1%(29/183)。2个位点变异的患者3～4级迟发性腹泻发生率显著高于野生型患者(26.5%vs.9.0%,P=0.021)。UGT1A1*28野生型、杂合突变型、纯合突变型的2～4级迟发性腹泻的发生率分别为29.6%、37.5%和88.9%,差异具有统计学意义(P=0.02)。UGT1A1*28纯合突变者4级中性粒细胞减少的发生率为33.3%,高于UGT1A1*28野生型的9.6%,但差异无统计学意义(P=0.07)。Logistic多因素分析显示UGT1A1*28和UGT1A1*6基因型是2～4级迟发性腹泻的影响因素。CPT-11剂量高者的3～4级中性粒细胞减少(OR=5.666,95%CI:2.088～15.377,P=0.001)和2～4级迟发性腹泻(OR=4.481,95%CI:1.568～12.807,P=0.005)发生率也显著升高。158例可评价疗效,获CR 3例、PR 30例、SD 91例、PD 34例,总有效率为20.9%。2个位点变异患者的有效率为33.3%,高于野生型的15.3%,但差异无统计学意义(P=0.063)。治疗时间在6周以下者疾病进展的风险显著增加(OR=6.106,95%CI:1.680～22.197,P=0.006)。Cox多因素分析显示,ECOG评分、治疗时间及治疗方案是影响患者预后的独立因素,而UGT1A1基因多态性与预后无关。结论 UGT1A1*28和UGT1A1*6基因型2个位点变异的患者应用CPT-11为主方案化疗的不良反应发生率较高,但疗效较好,由不良反应导致的治疗时间缩短可能会影响其获得更好的疗效。

Objective To analyze the distribution of UDP-glucuronosyltransferaselA1 （ UGT1A1 ） gene polymorphisms in Chinese Han patients with metastatic colorectal cancer（ mCRC）, and to evaluate correlations between UGT1A1 gene polymorphisms and toxicity and efficacy of irinotecan（ CPT-11 ） combined with fluorouracil （5-FU） regimen in patients with mCRC. Methods Chi- nese Han patients with mCRC in the multicenter phasⅡ study were treated with FOLFIRI regimen（ CPT-11 180mg/m2 iv）and IFL regimen（CPT-11 125mg/m2 iv）. UGT1A1 ＊ 28 and UGT1A1 ＊ 6 genotypes were determined by direct sequencing. Effect of UGT1A1gene polymorphisms on toxicity, efficacy and survival of chemotherapy were analyzed. Results A total of 192 patients were enrolled, and 189 patients were detected UGT1A1 gene polymorphisms. The rates of wild type, unit point mutation and two points mutation of UGT1A1 were 37.6%, 43.9% and 18.5%. Treatment options included FOLFIRI or IFL regimens. One hundred and eighty-three ca- ses were eligible for toxicity evaluation, incidence of grade 3-4 neutropenia was 26.6% （51/183）, and grade 3-4 late diarrhea rate was 15.1% （29/183）. Patients with two points mutation had significantly higher incidence of grade 3-4 late diarrhea than patients with wild type（26. 5% vs. 9.0%, P = 0. 021 ）. Grade 2-4 late diarrhea rates of UGT1A1 ＊ 28 wide type, UGT1A1 ＊ 28 heterozygote and UGT1 A1 ＊ 28 homozygous were 29. 6%, 37. 5% and 88. 9%, showing significant differences （P 〈 0. 05 ）. Grade 4 neutropenia rate of UGT1A1 ＊ 28 homozygous was higher than that of UGT1A1 ＊ 28 wide type（33.3% vs. 9. 6% ）, with no significant difference（ P = 0. 07 ）. Additionally, poor ECOG status and higher dose intensity of CPT-11 also significantly increased irinotecan-related toxicity. One hundred and fifty-eight patients were evaluatable for efficacy and response rate was 20. 9%. Better response rate was found in patients with two points mutation of UGT1A1 compared with wild type of UGTIA1 （33.3% vs. 15.3% ）, with no significant difference （P = 0. 063）. Multiple regression analysis showed treatment duration has a significant impact on treatment outcomes. Less than 6 weeks treatment had significantly increased risk of disease progression（ OR = 6. 106,95% CI： 1. 680-22. 197, P = 0. 006）. Prognostic factors were ECOG status, treatment duration and regimens, but not UGT1A1 gene polymorphisms. Conclusion Chinese Han mCRC patients with two points mutation of UGT1 A1 were associated with higher incidence of irinotecan-related toxicity and better response, but treat- ment duration shortened due to toxicity might impair the efficacy, and it is worth further investigation.