The impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX.

Shirasu H1, Todaka A1, Omae K2, Fujii H3, Mizuno N4, Ozaka M5, Ueno H6, Kobayashi S7, Uesugi K8, Kobayashi N9, Hayashi H10, Sudo K11, Okano N12, Horita Y13, Kamei K14, Yukisawa S15, Kobayashi M16, Fukutomi A1.

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Abstract

Studies have demonstrated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We conducted this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients administered with FOLFIRINOX in the JASPAC06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (Oxaliplatin85mg/m2 , Irinotecan180mg/m2 , Leucovorin200mg/m2 , bolus5-FU400mg/m2 , and continuous5-FU2,400mg/m2 ) or a modified FOLFIRINOX (Oxaliplatin85mg/m2 , Irinotecan150mg/m2 , Leucovorin200mg/m2 , and continuous5-FU2,400mg/m2 ) as first-line chemotherapy were included. Of 199patients eligible for this analysis, 79patients were administered the original FOLFIRINOX regimen and 120patients were administered the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 wild type, and 25 were UGT1A1 heterozygous type (-/*6, 12patients; -/*28, 13patients). In the modified FOLFIRINOX group, 64 were UGT1A1 wild type, and 56 were UGT1A1 heterozygous type (-/*6, 33patients; -/*28, 23patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 wild type, and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 -/*6 than among those with UGT1A1 -/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 -/*6 tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. On the other hand, for patients administered the modified FOLFIRINOX, there was no difference in frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with wild type UGT1A1. This article is protected by copyright. All rights reserved.