title: UGT1A1*28 genotype predicts gastrointestinal toxicity in patients treated with intermediate-dose irinotecan.
abstract: OBJECTIVE
  Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting.
  
  
  METHODS
  Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m(2), twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects.
  
  
  RESULTS
  No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carrying two copies of UGT1A1*28 (p = 0.04; OR: 14; 95% CI: 1.1-185) or c.-3156G>A (p = 0.03) had a significantly increased risk of diarrhea over all cycles.
  
  
  CONCLUSIONS
  Our findings indicate that UGT1A1 genotyping is not a good predictor of hematological toxicity in patients treated with intermediate irinotecan doses. However, it may be useful in the identification of patients at risk of severe diarrhea.
authors.affiliation: Department of Medical Genetics, St Mary's Hospital, Manchester, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferraldeschi
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Minchell
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Roberts
authors.forename: Simon
authors.initials: S
authors.lastname: Tobi
authors.forename: Kristen D
authors.initials: KD
authors.lastname: Hadfield
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Blackhall
authors.forename: Saifee
authors.initials: S
authors.lastname: Mullamitha
authors.forename: Gregory
authors.initials: G
authors.lastname: Wilson
authors.forename: Juan
authors.initials: J
authors.lastname: Valle
authors.forename: Mark
authors.initials: M
authors.lastname: Saunders
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000633:toxicity; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D003967:Diarrhea / Q000139:chemically induced; D005006:Ethnicity; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011446:Prospective Studies; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D004247:DNA; D004273:DNA, Neoplasm; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme