Genetic variation in the cytochrome P450 2C9 enzyme and dose of Celecoxib in the prevention of colorectal adenoma

B32

Background: In a randomized trial, the cyclooxygenase-2 inhibitor celecoxib reduced, in a dose-dependent manner, the occurrence of newly detected colorectal adenomas but was associated with an increase in cardiovascular events. Genetic variants in the cytochrome P450 2C9 (CYP2C9) enzyme, particularly the I359L allele, are associated with impaired metabolism of celecoxib and may influence dose-related response or toxicity.
 Methods: In the Adenoma Prevention with Celecoxib trial, 2,035 participants with a history of prior adenoma were randomized to placebo, 200 mg, or 400 mg of celecoxib twice daily. We genotyped 1660 participants for the I359L as well as R144C variant alleles of CYP2C9; 1497 patients underwent evaluation with at least one follow-up colonoscopy at 1 and 3 years for the occurrence of newly detected adenomas.
 Results: Compared with placebo, celecoxib treatment at either the twice-daily 200 mg and 400 mg dose was associated with an overall lower three-year cumulative incidence of adenoma among participants with either wild-type or variant genotypes (≥ one R144C or I359L allele). However, the additional benefit of the higher dose was observed primarily among those with I359 genotypes. Among 183 participants with I359L genotypes, treatment with the 400 mg dose was significantly associated with reduced adenoma incidence compared with the 200 mg dose (RR 0.54; 95% CI, 0.31-0.92; p=0.02). In contrast, treatment with the 400 mg dose was not associated with a significantly greater reduction in adenoma incidence compared with the 200 mg dose among the 318 participants with R144C genotypes (RR 0.93; 95% CI, 0.64-1.36; p=0.72) or the 996 participants with wild-type genotypes (RR 0.88; 95% CI, 0.71-1.11; p=0.28). Among participants with I359L genotypes, the three-year cumulative incidence of investigator-reported, treatment-emergent, cardiovascular events was 4.4% for placebo, 3.4% for 200 mg, and 13.3% for 400 mg. The cumulative incidence of cardiovascular events was 3.9% for placebo, 2.8% for 200 mg, and 9.4% for 400 mg among participants with R144C genotypes and 5.7% for placebo, 9.6% for 200 mg, and 8.1% for 400 mg among participants with wild-type genotypes.
 Conclusions: Chemoprevention with celecoxib appears to be modified by genetic variation in its metabolism. Individuals with CYP2C9 variant I359L genotypes may benefit differentially according to celecoxib dose.