Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in non-small cell lung cancer patients treated with irinotecan and cisplatin

Abstract

13121 Purpose: To determine whether UGT1A1, UGT1A7, and UGT1A9 polymorphisms affect 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 and cisplatin chemotherapy. 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. 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 AUCSN-38G/AUCSN-38 ratio (P = 0.002, 0.009and 0.001, respectively). In linkage disequilibrium (LD) analysis, the UGT1A7 variants were highly linked with UGT1A1*6 (D` = 0.85, r2 = 0.63) and UGT1A9*22 (D` = 0.95, r2 = 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 = 0.001) and overall survival (P = 0.017). Conclusions: These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associated 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. (Supported in part by NCC Grant 0210130 and 0510080 from National Cancer Center, Korea). No significant financial relationships to disclose.