Significant Correlation between Polymorphisms of UGT1A1 Gene andLow Irinotecan Toxicity in Colorectal Cancer Patients with FOLFIRI

Aim: To investigate the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity in Taiwanese patients with metastatic colorectal cancer (mCRC) receiving irinotecan chemotherapy. Methods: We genotyped the UGT1A1 gene by direct sequencing. All the patients were evaluated to see whether the variant UGT1A1 genotype would correlate to severe toxicity of irinotecan consisting of grade III-IV neutropenia, diarrhea and nausea/vomiting. Genomic DNA was genotyped for UGT1A1, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the promoter region. Results: The results showed that the genotype distribution of UGT1A1 in Taiwanese subjects differed significantly from that in Caucasians. Furthermore, patients with 6/7 or 7/7 genotype were associated with a higher incidence of grade III-IV neutropenia or diarrhea or nausea/vomiting (all p < 0.0001). The less frequencies of 6/7 and 7/7 genotypes may be responsible for the considerably lower occurrence of grade III-IV neutropenia and diarrhea in Taiwanese patients. Indeed, the UGT1A1 genotype was closely related to clinical response (p = 0.018). Conclusion: UGT1A1 genotyping is a potential predictor of severe toxicity for Taiwanese mCRC patients treated with irinotecan chemotherapy, and may be useful to identify patients at-risk of toxicity, and thus could be used as a screening tool prior to therapy.