title: Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin.
abstract: OBJECTIVE
  To determine whether uridine diphosphate-glucuronosyltransferase 1A1, UGT1A7, and UGT1A9 polymorphisms affect the pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Eighty-one patients with advanced NSCLC were treated with irinotecan (80 mg/m2) on day 1 and 8 and cisplatin (60 mg/m2) on day 1 intravenously of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using direct sequencing. We analyzed the association of UGT1A genotypes with irinotecan PK and clinical outcomes. All statistical tests were two-sided.
  
  
  RESULTS
  In genotype-PK association analysis, UGT1A1*6/*6 (n = 6), UGT1A7*3/*3 (n = 6), and UGT1A9-118(dT)9/9 (n = 11) were associated with significantly lower area under the time-concentration curve (AUC) SN-38G to SN-38 (AUC(SN-38G)/AUC(SN-38)) ratio (P = .002, P = .009, and P = .001, respectively). In linkage disequilibrium analysis, the UGT1A7 variants were highly linked with the UGT1A1*6 (D' = 0.85, r2 = 0.63) and UGT1A9*22 (D' = 0.95, r2 = 0.88), which was substantiated in haplotype analysis. Patients with UGT1A1*6/*6 had lower tumor response and higher incidence of severe neutropenia. UGT1A9-118(dT)9/9 also showed a trend for high incidence of severe diarrhea, but not tumor response. In survival analysis, patients with UGT1A1*6/*6 had significantly shorter progression-free survival (P = .001) and overall survival (P = .017).
  
  
  CONCLUSIONS
  These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associate with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy.
authors.affiliation: Research Institute and Hospital, National Cancer Center, Goyang, Korea.
authors.forename: Ji-Youn
authors.initials: JY
authors.lastname: Han
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.forename: Eun Soon
authors.initials: ES
authors.lastname: Shin
authors.forename: Yeon-Kyeong
authors.initials: YK
authors.lastname: Yoo
authors.forename: Yong Hoon
authors.initials: YH
authors.lastname: Park
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Dae Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D007723:Korea; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D016019:Survival Analysis; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D002945:Cisplatin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme