title: Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients.
abstract: BACKGROUND
  Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase-I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.
  
  
  METHODS
  The study included 329 colorectal cancer patients from the Israeli population-based Molecular Epidemiology of Colorectal Cancer study who were treated with a chemotherapy regimen that included irinotecan. Patients with metastases or disease recurrence were followed up for a median period of 2 years after occurrence of the event. Study end points were appearance of grade 3-4 hematological and gastroenterological toxicity, hospitalization due to toxic events (mostly neutropenia, fever, diarrhea, or vomiting), length of hospitalization, and overall survival. UGT1A1*28 was genotyped from peripheral blood DNA by fragment analysis and reported as number of TATA sequence repeats in the promoter of the gene.
  
  
  RESULTS
  The 7/7 variant of UGT1A1*28 was detected in 11.9% of the 329 participants. Grade 3-4 hematological toxicity was significantly higher in 7/7 carriers compared with 6/7 and 6/6 carriers (48.0%,10.2%, and 7.7% respectively; P < .001), as was the risk of toxicity-related hospitalization (45.8%, 25.3%, and 14.4% respectively; P = .001). Both short-term death within 2 months of treatment start (12.8%, 5.2%, and 2.9%, respectively) and median overall survival (1.6, 2.0, and 2.4 years, respectively; P = .01) were significantly worse in the 7/7 carriers. The age/stage-adjusted hazard ratio for patients with the 7/7 genotype compared with 6/6 was 1.7 (95% confidence interval, 1.1-2.3).
  
  
  CONCLUSIONS
  The UGT1A1*28 7/7 genotype is strongly associated with severe hematological toxicity and higher hospitalization rate and predicts lower survival of colorectal cancer in users of irinotecan.
authors.affiliation: CHS National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Katerina
authors.initials: K
authors.lastname: Shulman
authors.forename: Ilana
authors.initials: I
authors.lastname: Cohen
authors.forename: Ofra
authors.initials: O
authors.lastname: Barnett-Griness
authors.forename: Abraham
authors.initials: A
authors.lastname: Kuten
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Flavio
authors.initials: F
authors.lastname: Lejbkowicz
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D007970:Leukopenia / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme