The Relationship Between The Toxicity And Efficacy Of Irinotecan And UGT1A1Gene Polymorphisms

Background:Irinotecan (CPT-11) is a DNA topoisomerase I inhibitor, effecting on the S phase of the cell cycle, that interferes with DNA replication and cell division.It is widely used for the treatment of metastatic colorectal cancer and other solid tumors. Because of it’s possible serious adverse reactions, it is restricted in clinical application. However, there is an obvious individual difference in such adverse reactions, and studies showed that uridine-diphosphoglucuronosyltransferase1A1(UGT1A1) gene polymorphism is one of the important causes. UGT1A1gene polymorphisms effect the activity of the main metabolic enzyme of irinotecan, and affect its conversion of activity product of SN-38and inactivation of SN-38GIn addition, the UGT1A1polymorphism has obvious ethnic differences. The UGT1A1gene mutation rate is very low in Chinese Han population, and predictive role of UGT1A1gene polymorphism in patients with irinotecan chemotherapy efficacy and toxicity remain to be further. Whether it is appropriate by detecting UGT1A1gene polymorphism in Chinese patients to guide clinical medication needs further investigation.Objective:To study the differences in efficacy and toxicity among UGT1A1*28and UGT1A1*6gene polymorphisms with irinotecan chemotherapy.Methods:1Subjects:A total of107Han Chinese patients with malignant tumor were enrolled at the First Affiliated Hospital of Soochow University from August,2010to November,2012, and all patients received irinotecan based chemotherapy. Collect the patients’peripheral blood and medical history, record the adverse reactions and recent clinical efficacy,follow up the progression-free survival (PFS);2Genotyping:Genomic DNA was extracted from peripheral blood, application of high resolution melting analysis (HRM or HRMA) technology was used for UGT1A1*6genotyping, and direct sequence was used for UGT1A1*28genotyping;3Compare the differences among different genotypes of serious adverse reactions. And response was assessed in53of the colorectal cancer patients, analysis differences in response and Progression-free survival (PFS) among UGT1A1polymorphisms;4Statistical analysis:using SPSS17.0statistical software for statistical analysis, the chi-square(χ2) test or Fisher’s exact test was used to evaluate the association of UGT1A1genotype with toxicity. Analysis of responce between different genotypes were compared using polytomous Logistic regression analysis, introduced the related factors for correction; PFS was calculated by the Kaplan-Meier method, and the affecting factors were analyzed by COX regression. Correlations were considered statistically significant when the two-tailed P value was less than0.05.Results:In107cases with irinotecan based chemotherapy, homozygous mutation rates of UGT1A1*28and UGT1A1*6were0.9%and2.8%. Severe hematological toxicity occurred in29patients, accounting for27.1%;10patients occurred in grade3/4diarrhea, accounted for9.3%. The incidence of grade3/4thrombocytopenia (P=0.09) and delayed diarrhea (P=0.041) in the patients carrying UGT1A1*28(TA6/7or TA7/7) was higher than that in the wild genotype (TA6/6), while neutropenia showed no significant difference (P>0.05). UGT1A1*6polymorphism was associated with the general toxicity of hematology (P=0.036) and grade3/4neutropenia (P=0.034). It seems that there was no significant effect on hemoglobin and platelet (P>0.05), and does not increase the risk of severe diarrhea (P=0.848). Comprehensive analysis of the two sites indicated that UGT1A1mutations significantly increased the risk of both hematological toxicity and delayed diarrhea.Subgroup analysis of CPT-11dose suggested that there was no significant association between toxicity and UGT1A1polymorphisms in low dose group. In the higher dose group toxicity was significantly associated with UGT1A1polymorphisms.The UGT1A1polymorphism had no effect on the responce rate. Compared with defective allele groups, wild type patients may obtain a better PFS (RR=2.187,P=0.037). Conclusion:The UGT1A1polymorphisms significantly associated with irinotecan induced hematologic toxicity and delayed diarrhea, particularly at higher doses. UGT1A1wild type patients may obtain longer PFS, but there was no significant effect on the response rate.