Clinical Study Of The Correlation Between UGT1A1*28/*6Polymorphism And The Adverse Events And Efficacy Of Irinotecan

Objective: As an inhibitor of DNA topoisomerase I, irinotecan (CPT-11) is asemisynthetic derivative of camptothecin and is used for treatment of advanced colorectalcancer. However, CPT-11often causes severe adverse events such as diarrhea andneutropenia. Uridine diphosphate glucuronosyltransferase (UGT)1A is one of the mainenzymes involved in the metabolism of CPT-11, and it converts the active metabolite ofCPT-11(SN-38) to an inactive glucuronide (SN-38G). It is known that toxicities areassociated with UGT1A enzyme activities. The gene polymorphism significantly affectedthe activity of UGT1A enzyme. This study aims to investigate the association betweenUGT1A1*28/*6gene polymorphism and irinotecan related adverse events and efficacy.Methods: A total of66advanced colorectal cancer patients were enrolled from July2011to December2012in Shandong Cancer Hospital. All patients received standarddosage of FOLFIRI regimen (irinotecan180mg/m2d1, CF400mg/m2d1,5-FU400mg/m2d1, followed by continuous infusion of5-FU2400mg/m2for48h d1-d2, every2weeks). Gene polymorphisms of UGT1A1*28and UGT1A1*6were detected bypyrosequencing of DNA extracted from peripheral blood. The influence of the UGT1A1gene polymorphisms on the adverse events and short-term efficacy of irinotecan wasanalyzed.Results: The distribution of the genotypes in66advanced colorectal cancer patientswas as follows: UGT1A1*28wild type (WT) genotype TA6/6in52patients (78.8%),heterozygous genotype TA6/7in13patients (19.7%), and homozygous genotype TA7/7in1patient (1.5%); UGT1A1*6WT genotype G/G in46patients (69.7%), heterozygousgenotype G/A in17patients (25.8%), and homozygous genotype A/A in3patients (4.5%);UGT1A1*28/*6double wild type (DW, meaning*1/*1) in34patients (51.5%), singlevariant type (SV, including*1/*28and*1/*6) in26patients (39.4%), double variant type(DV, including*28/*28,*6/*6and*28/*6) in6patients (9.1%). There was no definite relation between UGT1A1*28,*6polymorphisms and adverse events (P>0.05).Univariate analysis showed that the incidence of grade3and4neutropenia in the patientscarrying DV type of UGT1A1*28/*6was higher than that in the DW type (83.3%vs.29.4%, P=0.04). Multivariate analysis identified the DV type of UGT1A1*28/*6was anindependent factor for the occurrence of grade3and4neutropenia (OR3.95,95%CI1.02-8.53, P=0.03). No significant difference of chemotherapeutic effect was observedbetween different genotypes (P>0.05)．Conclusion:1. There was no definite relation between UGT1A1*28,*6polymorphisms and adverse events of irinotecan.2. The DV type of UGT1A1*28/*6increase the risk of irinotecan-induced grade3and4neutropenia.3. No significantdifference of chemotherapeutic effect was observed between different genotypes.