To predict precisely severe toxicity of
irinotecan, we evaluated the association of UGT1A variants, haplotypes and the combination of UGT1A genotypes to severe toxicity of
irinotecan. UGT1A1*6 (211G>A), UGT1A1*28 (TA6>TA7), UGT1A1*60 (-3279T>G), UGT1A7 (387T>G), UGT1A7 (622T>C), and UGT1A9*1b (-118T9>T10, also named *22) were genotyped in 123 patients with metastatic
colorectal cancer who had received
irinotecan-based
chemotherapy. Among the 123 patients, 73 were enrolled in either of two phase II studies of the FOLFIRI (
leucovorin,
5-fluorouracil and
irinotecan) regimen; these patients constituted the training population, which was used to construct the predicting system. The other 50 patients constituted the validation population; these 50 patients either had participated in a phase II study of
irinotecan/5'-deoxy-5-fluorouridine or were among consecutive patients who received FOLFIRI
therapy. This prediction system used sequential forward floating selection based on statistical pattern recognition using UGT1A genotypes, gender and age. Several UGT1A genotypes [UGT1A1*6, UGT1A7 (387T>G), UGT1A7 (622T>C) and UGT1A9*1b] were associated with the
irinotecan toxicity. Among the haplotypes, haplotype-I (UGT1A1: -3279T, TA6, 211G; UGT1A7: 387T, 622T; UGT1A9: T10) and haplotype-II (UGT1A1: -3279T, TA6, 211A; UGT1A7: 387G, 622C; UGT1A9: T9) were also associated with
irinotecan toxicity. Furthermore, our new system for predicting the risk of
irinotecan toxicity was 83.9% accurate with the training population and 72.1% accurate with the validation population. Our novel prediction system using statistical pattern recognition depend on genotypes in UGT1A, age and gender; moreover, it showed high predictive performance even though the treatment regimens differed among the training and validation patients.