Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX

Hiromichi Shirasu, Akiko Todaka, Katsuhiro Omae, Hirofumi Fujii, Nobumasa Mizuno, Masato Ozaka, Hideki Ueno, Satoshi Kobayashi, Kazuhiro Uesugi, Noritoshi Kobayashi, Hideyuki Hayashi, Kentaro Sudo, Naohiro Okano, Yosuke Horita, Keiko Kamei, Seigo Yukisawa, Marina Kobayashi, Akira Fukutomi

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 , bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 , leucovorin 200 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT 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. However, for patients who received the modified FOLFIRINOX, there was no difference in the 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 WT UGT1A1.

Original languageEnglish
Pages (from-to)707-716
Number of pages10
JournalCancer Science
Volume110
Issue number2
DOIs
Publication statusPublished - 2019 Feb 1
Externally publishedYes

Fingerprint

Genetic Polymorphisms
Pancreatic Neoplasms
irinotecan
oxaliplatin
Fluorouracil
Leucovorin
UGT1A1 enzyme
Diarrhea
Incidence
Drug Therapy
Leukopenia

Keywords

  • chemotherapy
  • FOLFIRINOX
  • pancreatic cancer
  • toxicity
  • UGT1A1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shirasu, H., Todaka, A., Omae, K., Fujii, H., Mizuno, N., Ozaka, M., ... Fukutomi, A. (2019). Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX. Cancer Science, 110(2), 707-716. https://doi.org/10.1111/cas.13883

Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX. / Shirasu, Hiromichi; Todaka, Akiko; Omae, Katsuhiro; Fujii, Hirofumi; Mizuno, Nobumasa; Ozaka, Masato; Ueno, Hideki; Kobayashi, Satoshi; Uesugi, Kazuhiro; Kobayashi, Noritoshi; Hayashi, Hideyuki; Sudo, Kentaro; Okano, Naohiro; Horita, Yosuke; Kamei, Keiko; Yukisawa, Seigo; Kobayashi, Marina; Fukutomi, Akira.

In: Cancer Science, Vol. 110, No. 2, 01.02.2019, p. 707-716.

Research output: Contribution to journalArticle

Shirasu, H, Todaka, A, Omae, K, Fujii, H, Mizuno, N, Ozaka, M, Ueno, H, Kobayashi, S, Uesugi, K, Kobayashi, N, Hayashi, H, Sudo, K, Okano, N, Horita, Y, Kamei, K, Yukisawa, S, Kobayashi, M & Fukutomi, A 2019, 'Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX', Cancer Science, vol. 110, no. 2, pp. 707-716. https://doi.org/10.1111/cas.13883
Shirasu, Hiromichi ; Todaka, Akiko ; Omae, Katsuhiro ; Fujii, Hirofumi ; Mizuno, Nobumasa ; Ozaka, Masato ; Ueno, Hideki ; Kobayashi, Satoshi ; Uesugi, Kazuhiro ; Kobayashi, Noritoshi ; Hayashi, Hideyuki ; Sudo, Kentaro ; Okano, Naohiro ; Horita, Yosuke ; Kamei, Keiko ; Yukisawa, Seigo ; Kobayashi, Marina ; Fukutomi, Akira. / Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX. In: Cancer Science. 2019 ; Vol. 110, No. 2. pp. 707-716.
@article{943ecfc1257945bc869d4bdcf615fcc2,
title = "Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX",
abstract = "Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 , bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 , leucovorin 200 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT 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. However, for patients who received the modified FOLFIRINOX, there was no difference in the 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 WT UGT1A1.",
keywords = "chemotherapy, FOLFIRINOX, pancreatic cancer, toxicity, UGT1A1",
author = "Hiromichi Shirasu and Akiko Todaka and Katsuhiro Omae and Hirofumi Fujii and Nobumasa Mizuno and Masato Ozaka and Hideki Ueno and Satoshi Kobayashi and Kazuhiro Uesugi and Noritoshi Kobayashi and Hideyuki Hayashi and Kentaro Sudo and Naohiro Okano and Yosuke Horita and Keiko Kamei and Seigo Yukisawa and Marina Kobayashi and Akira Fukutomi",
year = "2019",
month = "2",
day = "1",
doi = "10.1111/cas.13883",
language = "English",
volume = "110",
pages = "707--716",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX

AU - Shirasu, Hiromichi

AU - Todaka, Akiko

AU - Omae, Katsuhiro

AU - Fujii, Hirofumi

AU - Mizuno, Nobumasa

AU - Ozaka, Masato

AU - Ueno, Hideki

AU - Kobayashi, Satoshi

AU - Uesugi, Kazuhiro

AU - Kobayashi, Noritoshi

AU - Hayashi, Hideyuki

AU - Sudo, Kentaro

AU - Okano, Naohiro

AU - Horita, Yosuke

AU - Kamei, Keiko

AU - Yukisawa, Seigo

AU - Kobayashi, Marina

AU - Fukutomi, Akira

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 , bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 , leucovorin 200 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT 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. However, for patients who received the modified FOLFIRINOX, there was no difference in the 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 WT UGT1A1.

AB - Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 200 mg/m 2 , bolus 5-fluorouracil [5-FU] 400 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , irinotecan 150 mg/m 2 , leucovorin 200 mg/m 2 , and continuous 5-FU 2400 mg/m 2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (−/*6, 12 patients; −/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (−/*6, 33 patients; −/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT 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. However, for patients who received the modified FOLFIRINOX, there was no difference in the 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 WT UGT1A1.

KW - chemotherapy

KW - FOLFIRINOX

KW - pancreatic cancer

KW - toxicity

KW - UGT1A1

UR - http://www.scopus.com/inward/record.url?scp=85058238012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058238012&partnerID=8YFLogxK

U2 - 10.1111/cas.13883

DO - 10.1111/cas.13883

M3 - Article

C2 - 30447099

AN - SCOPUS:85058238012

VL - 110

SP - 707

EP - 716

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 2

ER -