title: UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma.
abstract: BACKGROUND
  It is known that the uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC).
  
  
  METHODS
  In total, 128 patients with metastatic CRC who had received previous treatment with irinotecan plus 5-fluorouracil/leucovorin were analyzed retrospectively. Genomic DNA samples were obtained from patients' leukocytes, and genotypes were determined by analyzing the sequence of TATA boxes in the UGT1A1 gene. The influence of the UGT1A1*28 polymorphism on toxicity and treatment outcome was analyzed.
  
  
  RESULTS
  Approximately 20% of patients were identified with the UGT1A1*28 polymorphism, including 15.6% (n = 20 patients) with the thymine-adenine (TA)6/TA7 genotype and 4.7% (n = 6 patients) with the TA7/TA7 genotype. The remaining 79.7% of patients (n = 102) had wild type TA6/TA6. Marked increases in grade 3 or 4 neutropenia (53.8% vs 4.9%; P < .01), neutropenic fever (38.5% vs 3.9%; P < .01), diarrhea (26.9% vs 5.9%; P < .01), and pretreatment bilirubin level (23.1% vs 8.8%; P = .04) were observed in patients who had the TA6/TA7 or TA7/TA7 genotypes. Patients' pretreatment bilirubin levels correlated well with irinotecan-induced neutropenia (P < .01). It was noted that, although the requirement for irinotecan dose reduction was significantly greater in patients who had this genetic variant (42.3% vs 12.7%; P < .01), it did not affect the response rate to irinotecan-based chemotherapy (42.3% vs 45.1%; P = .80), and it did not significantly affect progression-free survival (10 months vs 11 months; P = .94) or overall survival (19 months vs 18 months; P = .84).
  
  
  CONCLUSIONS
  The current data suggested that the UGT1A1*28 polymorphism may be a key determinant for predicting irinotecan-induced severe toxicities without affecting treatment outcome for patients with metastatic CRC. Further prospective studies are warranted for using this polymorphism to optimize irinotecan-based chemotherapy.
authors.affiliation: National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Po-Min
authors.initials: PM
authors.lastname: Chen
authors.forename: Tzeon-Jye
authors.initials: TJ
authors.lastname: Chiou
authors.forename: Jin-Hwang
authors.initials: JH
authors.lastname: Liu
authors.forename: Jen-Kou
authors.initials: JK
authors.lastname: Lin
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Lin
authors.forename: Wei-Shone
authors.initials: WS
authors.lastname: Chen
authors.forename: Jeng-Kae
authors.initials: JK
authors.lastname: Jiang
authors.forename: Huann-Sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: Wei-Shu
authors.initials: WS
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D001663:Bilirubin / Q000097:blood; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001663:Bilirubin; D002166:Camptothecin; D042943:Dihydrouracil Dehydrogenase (NADP); D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme