The Influence of UGT 1A6 Variants and Aspirin Use in a Randomized Trial of Celecoxib for Prevention of Colorectal Adenoma
Cet essai randomisé (1 647 patients) évalue l'influence de variants génétiques de l'enzyme UGT1A6 et de l'usage de l'aspirine sur l'efficacité d'un traitement à base de célécoxib pour prévenir le risque de récidive d'un adénome colorectal
Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200 mg-twice-daily, or 400 mg-twice-daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 (95%CI,0.59-0.79) for 200 mg-twice-daily celecoxib and 0.54 (95%CI,0.46-0.64) for 400 mg-twice-daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95%CI,0.86-1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95%CI,0.81-3.15) after withdrawal of 200 mg-twice-daily and 1.98 (95%CI,1.06-3.70) after withdrawal of 400 mg-twice-daily celecoxib compared to withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals that initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid re-emergence of disease.