title: UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan.
abstract: OBJECTIVE
  Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11 adjuvant chemotherapy regimen in a prospective randomized trial.
  
  
  METHODS
  Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and -3156G>A for UGT1A1.
  
  
  RESULTS
  Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of -3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01. This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9-37.2; P = 0.005].
  
  
  CONCLUSIONS
  This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The -3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA)(6)TAA>(TA)(7)TAA polymorphism.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale UMR-S775, Bases moléculaires de la réponse aux xénobiotiques, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.forename: Sylvain
authors.initials: S
authors.lastname: Kirzin
authors.forename: Andrew
authors.initials: A
authors.lastname: Kramar
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mosnier
authors.forename: Marie-Danièle
authors.initials: MD
authors.lastname: Diebold
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Thirouard
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Marc
authors.initials: M
authors.lastname: Ychou
mesh_terms: D000368:Aged; D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme