The Relationship Between UGT1A1 Gene Polymorphisms And Toxicity And Efficacy Of Irinotecan In Patients With Metastatic Colorectal Cancer:a Retrospective Study

Objective:This retrospective study aimed to investigate the associations between UGT1A1 polymorphisms and toxicities and clinical response in Chinese patients with metastatic colorectal cancer(mCRC)receiving irinotecan-based regimens.Methods:A total of eighty-seven patients with metastatic colorectal cancer,who were tested for UGT1A1 genotyping and could not cured by surgery,were included into the study between June 2011 and October 2016.Two irinotecan-based regimens,FOLFIRI and SIR were given until disease progression or the occurrence of intolerable toxicities.The primary endpoint was the incidence of main adverse drug reaction and the secondary endpoint was clinical response,progression free time(PFS)and overall survival(OS).The effects of UGT1A1 polymorphisms on clinical outcome were assessed according to the NCI-CTC criteria and RECIST 1.1.SPSS 17.0 was used to analyze the data statistically.Results:Eighty-seven patients were included and their age ranged from 20 to 79.Different genotypes showed no significance in age,gender,ECOG performance status,disease,treatment line,regimen,prior treatment and treatment cycles.1.The frequencies of UGT1A1*6 homozygous wild-type GG,heterozygous mutant-type GA and homozygous mutant-type AA were 66.7%(n=5 8),31.0%(n=27),and 2.2%(n=2),respectively;UGT1A1*28 wild-type TA6/6 85.1%(n=74)and mutant-type TA6/7 14.9(n=13).2.The incidences of severe delayed diarrhea and neutropenia in the first cycle were both 8.0%,and in the whole treatment duration were 13.8%and 12.6%,respectively.No obvious relationship was observed between severe diarrhea or neutropenia and UGT1A1*6.Patients with UGT1A1*28 mutant allele(s)tended to develop neutropenia in shorter treatment duration(P=0.047).Besides,in the whole treatment duration,the UGT1A1 genotype,the dosage of irinotecan and the absolute account of neutrophil were significantly related to severe neutropenia.3.There was no significant difference in the association between clinical response(response rate and disease control rate)and UGT1A1*6(P=0.415 and P=0.459)or UGT1A1*28(P=0.436 and P=0.401)polymorphisms.PFS and OS seemed to show no association with either UGT1A1*6 or UGT1A1*28,though slightly longer OS were found in patients with UGT1A1 mutant allele(s).Other factors,including gender,ECOG performance,regimen,dosage,were not significantly associated with prognosis.Conclusion:1.The frequency of UGT1A1*6 and UGT1A1*28 in Chinese metastatic colorectal patients is unique,while compared to other ethnic populations.2.UGT1A1*28 was capable of predicting irinotecan-induced severe delayed diarrhea in the first cycle,and there was a increasing trend of severe delayed diarrhea in patients with UGT1A11*28 mutant allele(s).Nevertheless,the result of this study indicated that UGT1A1*6 had no association with severe diarrhea.3.The incidence of neutropenia significantly decreased in UGT1A1 wild-type patients.UGT1A1 genotyping,dose of irinotecan and the absolute count of neutrophil were significant risk factors for severe neutropenia.4.Moreover,no associations were found between UGT1A1 polymorphisms and clinical outcome.Multi-variable logistic regression analysis showed that age was significantly related to response rate.Although patients with UGT1A1 mutant allele(s)had longer OS than those with wild genotype,yet PFS and OS seemed to show no connection with UGT1A1 gene.