Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer

BACKGROUND. The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polyrnorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS. Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB] (1236C > T, 2677G > T/ A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS. Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CLSN-38G. When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38)G (P =.006), whereas 2677GG/3435CC ('atriers showed significantly higher AUC(SN-38) (P -.039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P =.031 and.046, respectively) and longer progress ion- free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS. Specific polymorphisms of ABCB] and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan- based chemotherapy in patients with advanced NSCI,C.