title: UGT1A1*6, 1A7*3, and 1A9*22 genotypes predict severe neutropenia in FOLFIRI-treated metastatic colorectal cancer in two prospective studies in Japan.
abstract: Retrospective studies have suggested that UDP-glucuronosyltransferase (UGT)1A1, UGT1A7, and UGT1A9 predict severe toxicity and efficacy of irinotecan-containing regimens. We prospectively evaluated the impact of UGT1A genotypes and haplotypes on severe toxicity and efficacy in patients treated with fluorouracil, leucovorin, and irinotecan combination chemotherapy (FOLFIRI) for metastatic colorectal cancer (mCRC) from the two prospective multicenter phase II studies in Japan. The FLIGHT1 study was a first-line FOLFIRI trial, and FLIGHT2 was a FOLFOX-refractory, second-line FOLFIRI trial. A total of 73 patients agreed to additional analysis, and were genotyped for UGT1A polymorphisms, UGT1A1*28 (TA6>TA7), UGT1A1*6 (211G>A), UGT1A1*27 (686C>A), UGT1A1*60 (-3279T>G), UGT1A1*93 (-3156G>A), UGT1A7 (-57T>G), UGT1A7*3 (387T>G, 622T>C), and UGT1A9*22 (T9>T10). Of 73 patients, 34 developed G3/4 severe hematological toxicities. The toxicities were significantly more frequent in patients with UGT1A1*6 (211A), UGT1A7 (387G), and UGT1A9*22 reference alleles (T9). Haplotype I, which consists of all favorable alleles, was associated with a significant reduction in hematologic toxicity (P = 0.031). In contrast, haplotype II, which contains four high-risk alleles, showed significantly higher hematologic toxicity than the other haplotypes (P = 0.010). Six out of seven patients who were homozygous for UGT1A1*28 or *6 experienced severe hematological toxicity despite the fact that their response rate was not impaired (42.9%). We concluded that UGT1A polymorphisms, especially UGT1A1*6, are important for the prediction of severe toxicity of FOLFIRI in northeast Asian populations. In this regard, haplotype analyses should substantially impact the prediction of severe hematological toxicities of FOLFIRI. (
  
  
  BACKGROUND
  UMIN000002388 and UMIN000002476).
authors.affiliation: Department of Digestive Surgery and Surgical Oncology (Surgery II), Yamaguchi University Graduate School of Medicine, Ube, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mishima
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Tsunedomi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kato
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nozawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ando
authors.forename: Michiya
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Takemoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Nagata
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kanekiyo
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hamamoto
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hinoda
authors.forename: Naoko
authors.initials: N
authors.lastname: Okayama
authors.forename: Koji
authors.initials: K
authors.lastname: Oba
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sakamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C524630:UGT1A7 protein, human
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