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|Title:||Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group|
|Citation:||Journal of Clinical Oncology, 2008; 26(13):2131-2138|
|Publisher:||Amer Soc Clinical Oncology|
|Matthias Schwab, Ulrich M. Zanger, Claudia Marx, Elke Schaeffeler, Kathrin Klein, Jürgen Dippon, Reinhold Kerb, Julia Blievernicht, Joachim Fischer, Ute Hofmann, Carsten Bokemeyer, Michel Eichelbaum|
|Abstract:||PURPOSE: To assess the predictive value of polymorphisms in dihydropyrimidine dehydrogenase (DPYD ), thymidylate synthase (TYMS ), and methylene tetrahydrofolate reductase (MTHFR ) and of nongenetic factors for severe leukopenia, diarrhea, and mucositis related to fluorouracil (FU) treatment. PATIENTS AND METHODS: A multicenter prospective clinical trial included 683 patients with cancer treated with FU monotherapy. Toxicity was documented according to World Health Organization grades. DPYD, TYMS, and MTHFR genotypes were determined, and DPYD was resequenced in patients with severe toxicity. RESULTS: Grade 3 to 4 toxicity occurred in 16.1% of patients. The sensitivity of DPYD*2A genotyping for overall toxicity was 5.5% (95%CI, 0.02 to 0.11), with a positive predictive value of 0.46 (95% CI, 0.19 to 0.75; P = .01). Inclusion of additional DPYD variants improved prediction only marginally. Analysis according to toxicity type revealed significant association of DPYD with mucositis and leukopenia, whereas TYMS was associated with diarrhea. Genotype, female sex, mode of FU administration, and modulation by folinic acid were identified as independent risk factors by multivariable analysis. A previously unrecognized significant interaction was found between sex and DPYD, which resulted in an odds ratio for toxicity of 41.8 for male patients (95% CI, 9.2 to 190; P < .0001) but only 1.33 (95% CI, 0.34 to 5.2) in female patients. Homozygosity for the TYMS enhancer region double repeat allele increased risk for toxicity 1.6-fold (95% CI, 1.08 to 2.22; P = .02). CONCLUSION: DPYD, TYMS, and MTHFR play a limited role for FU related toxicity but a pronounced DPYD gene/sex-interaction increases prediction rate for male patients. Toxicity risk assessment should include sex, mode of administration, and folinic acid as additional predictive factors.|
|Keywords:||German 5-FU Toxicity Study Group; Humans; Leukopenia; Genetic Predisposition to Disease; Diarrhea; Fluorouracil; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Dihydrouracil Dehydrogenase (NADP); Thymidylate Synthase; Vitamin B Complex; Antimetabolites, Antineoplastic; Severity of Illness Index; Logistic Models; Odds Ratio; Risk Assessment; Risk Factors; Prospective Studies; Predictive Value of Tests; DNA Methylation; Gene Frequency; Homozygote; Polymorphism, Genetic; Patient Selection; Germany; Female; Male; Mucositis; Promoter Regions, Genetic; Genetic Testing|
|Appears in Collections:||Pharmacology publications|
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