Association of ABCC2 genotype with efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer

Abstract

  This exploratory retrospective study examined the effects of polymorphisms in transporter genes related to irinotecan pharmacokinetics and those in genes related to irinotecan pharmacodynamics on the efficacy of first-line combination chemotherapy with irinotecan, 5-fluorouracil, and folinic acid (leucovorin) (FOLFIRI) in Japanese patients with advanced colorectal cancer. All patients harbored UDP-glucuronosyltransferase (UGT) 1A1*1/*1, *1/*6, or *1/*28 genotypes, which are associated with similar irinotecan pharmacokinetics and responses to FOLFIRI. Genetic polymorphisms were analyzed by direct sequencing. Overall response rate and median progression-free survival in total 61 patients were 43% and 7.5 months, respectively. The overall response rate was higher in patients with CC genotype at −24 in ATP-binding cassette, subfamily C, and member 2 (ABCC2) than in the others (P=0.0313). Median progression-free survival was the longest in patients with CC at −24 in ABCC2, followed by those with CT and TT (P=0.00910). A clear gene-dose effect was seen between −24C>T and median progression-free survival. All other polymorphisms tested were not related to the efficacy of FOLFIRI. The efficacy of first-line FOLFIRI is related to −24C>T in ABCC2 in Japanese patients with advanced colorectal cancer. We thus found that −24C>T polymorphism in ABCC2 gene was significantly associated with the efficacy of first-line FOLFIRI.