Comprehensive Analysis of UGT1A Polymorphisms Predictive for Pharmacokinetics and Treatment Outcome in Patients With Non–Small-Cell Lung Cancer Treated With Irinotecan and Cisplatin

Abstract

Purpose: To determine whether uridine diphosphate-glucuronosyltransferase 1A1, UGT1A7, and UGT1A9 polymorphisms affect the pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non–small-cell lung cancer (NSCLC). Methods: Eighty-one patients with advanced NSCLC were treated with irinotecan (80 mg/m 2) on day 1 and 8 and cisplatin (60 mg/m 2) on day 1 intravenously of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. All statistical tests were two-sided. Results: In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6), and UGT1A9-118(dT)9/9(n = 11) were associated with significantly lower area under the time-concentration curve (AUC) SN-38G to SN-38 (AUC SN-38G/AUC SN-38) ratio (P = .002, P = .009, and P = .001, respectively). In linkage disequilibrium analysis, the UGT1A7 variants were highly linked with the UGT1A1*6 (D′ = 0.85, r 2= 0.63) and UGT1A9*22 (D′ = 0.95, r 2= 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9-118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = .001) and overall survival (P = .017). Conclusion: These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associate with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy.