| UGT1A1*28
polymorphism is a predictor of neutropenia in irinotecan chemotherapy.
Authors: F. Innocenti, S. D. Undevia, L. Iyer, S. Das, T. Karrison, L. Janish, J. Ramirez, C. M. Rudin, E. E. Vokes, M. J. Ratain; University of Chicago, Chicago, IL Abstract: The hepatic uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) enzyme is responsible for the glucuronidation of the active irinotecan metabolite SN-38 to the inactive SN-38G. The UGT1A1*28 polymorphism is characterized by an additional TA repeat in the TATA sequence of the UGT1A1 promoter (denoted 7 vs. 6) and was hypothesized to be associated with lower glucuronidation rates and greater irinotecan toxicity. We performed a prospective clinical trial in which patients received 350 mg/m2 of irinotecan as a 90 min intravenous infusion every 21 days and underwent UGT1A1 genotyping. The study was originally designed to enroll 60 patients to investigate the relationship between UGT1A1 genotype and grade 3+ diarrhea. However, the incidence of grade 3+ diarrhea was only 5% on this treatment schedule. Sixty-one of 66 enrolled patients were evaluable for myelosuppression, and the overall incidence of grade 4 neutropenia was 8%. UGT1A1 genotype was significantly associated (p<0.001) with grade 4 neutropenia (%): 6/6 － 0 of 28 patients (0%), 6/7 － 2 of 24 patients (8%), 7/7 － 3 of 6 patients (50%) (3 patients with one allele 5 or 8 were excluded from analysis). Screening for the 6/6 genotype as a predictive test for grade 0-3 neutropenia had 53% sensitivity, 100% specificity, and 100% positive predictive value. Screening for the 7/7 genotype as a predictive test for grade 4 neutropenia had 60% sensitivity, 94% specificity, and 96% negative predictive value. Multivariate analysis demonstrated that ln(nadir ANC) was significantly correlated with 7/7 genotype (p<0.001) and SN-38 AUC (p<0.001)(r2=0.52). UGT1A1 genotype is an important determinant of irinotecan-induced neutropenia. Pharmacogenetic testing may improve the therapeutic index of irinotecan.
|