Impact of gene promoter polymorphism of the UGT1A1-gene on the occurrance of irinotecan-induced side effects and drug effiacy

Abstract

3570 Background: Irinotecan is an effective agent in the treatment of advanced colorectal cancer (CRC). The most common side effects of irinotecan are myelotoxicity, nausea and delayed diarrhea. The active metabolite of irinotecan (SN 38) is inactivated by uridine diphosphate glucuronosyl transferase (UGT1A1), the enzyme by wich also bilirubin is conjugated. In this study, we investigated the correlation between the gene promoter polymorphism of the UGT1A1 gene and the occurrence of irinotecan-induced side effects as well as the parameters of drug efficacy. Methods: Genotypes were identified by gene scan analysis on the ABI 310 sequencer of the TATA box in the promoter region of the UGT1A1-gene in blood samples from 81 patients (pts) with advanced CRC receiving 1st-line therapy with irinotecan-based chemotherapy. Results: The wildtype allele (6/6) had a frequency of 40.7%, whereas the heterozygous allele (6/7) was observed in 49.4%, and the homozygous allele (7/7) in 9.9% of the pts. The most frequent adverse events were nausea (69.1%), anemia (69.1%), and delayed diarrhea (58.0%). There was no significant difference in nausea (69.7% vs. 68.9%) and anemia (67.1% vs. 71.2%) between pts with wildtype and mutant homozygous or heterozygous genotypes. However, the incidence of delayed diarrhea CTC-NCI grades II, III and IV was higher among pts with the mutant genotype 6/7 (17.0%, 5.4%, 2.7%) and the genotype 7/7 (20.0%, 20.0%, 0%) as compared to the wildtype genotype (6/6) (13.2%, 3.9%, 1.3%). Toxicity-related treatment stop was observed at a rate of 18.6% in mutant genotype pts, but not in wildtype pts (p=0.019). The overall response rate was lower in the 6/7 (45.5%) and 7/7 genotypes (33.3%) as compared to the wildtype genotype (57.1%) (p=0.316). Moreover, no sign. differences were observed between patient groups with regard to TTP (p=0.652) and OS (p=0.626). Conclusions: This study demonstrates that the incidence of delayed diarrhea was higher in pts with a homozygous or heterozygous mutant genotype as compared to the wild-type genotype. Toxicity related treatment stop only occurred in mutant genotype pts. The genetic polymorphism did not appear to have a significant impact on treatment efficacy. No significant financial relationships to disclose.