Clinical implications of polymorphisms in UDP-glucuronosyl transferase (UGT) in patients with metastatic colorectal cancer (mCRC) who were treated with oxaliplatin, irinotecan, and S-1.

Abstract

503 Background: The three-drug regimen with oxaliplatin, irinotecan and fluoropyrimidine is an effective therapeutic option for patients with mCRC, but is associated with high rate of toxicity. Pharmacogenetic profile might be helpful for selection of proper patients for this intensive regimen. Methods: Forty-two patients were enrolled to our phase II trial and were given irinotecan 150mg/m2 plus oxaliplatin 85mg/m2 on D1 and S-1 80mg/m2/day on D1-14 every 21 days as their front-line therapy for mCRC. Genomic DNA was extracted from peripheral blood, where the presence of germline polymorphisms of UGT including UGT1A1*6, UGT1A1*28, UGT1A1*60, UGT1A6*2, and UGT1A7*3 were tested. Results: Patients with UGT1A1*6 allele had a tendency of more frequent grade 2-3 vomiting (p = 0.06) compared to those without UGT1A1*6. The presence of a haplotype containing UGT1A6*2 and UGT1A7*3 was associated with grade 2-3 vomiting (p = 0.014) and grade 2-3 diarrhea (p = 0.063). Higher objective response rate (18/20, 90%) was noted in patients without UGT1A*60 compared to those with UGT1A1*60 (11/22, 50%; p = 0.008). The absence of UGT1A1*60 was also associated with marginally improved progression-free survival (10.3 mo v 7.7 mo, p = 0.081) and overall survival (26.8 mo v 15.1 mo, p= 0.044) compared to the presence of the variant allele. Conclusions: UGT1A1*6 and a haplotype containing UGT1A6*2 and UGT1A7*3 may be associated with irinotecan-related gastrointestinal toxicities. Phenotypic association of UGT1A1*60 and efficacy of the three-drug regimen requires further investigation.