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Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.

Authors: Innocenti, F  Undevia, SD  Iyer, L  Chen, PX  Das, S  Kocherginsky, M  Karrison, T  Janisch, L  Ramirez, J  Rudin, CM  Vokes, EE  Ratain, MJ 
Citation: Innocenti F, etal., J Clin Oncol. 2004 Apr 15;22(8):1382-8. Epub 2004 Mar 8.
Pubmed: (View Article at PubMed) PMID:15007088
DOI: Full-text: DOI:10.1200/JCO.2004.07.173

PURPOSE: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. PATIENTS AND METHODS: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. RESULTS: The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51). CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

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RGD Object Information
RGD ID: 10768826
Created: 2016-02-09
Species: All species
Last Modified: 2016-02-09
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.