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Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group.
J Clin Oncol 2008; 26(13):2131-8JC

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.

Authors+Show Affiliations

Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Stuttgart, Stuttgart, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18299612

Citation

Schwab, Matthias, et al. "Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-related Severe Toxicity: a Prospective Clinical Trial By the German 5-FU Toxicity Study Group." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 26, no. 13, 2008, pp. 2131-8.
Schwab M, Zanger UM, Marx C, et al. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol. 2008;26(13):2131-8.
Schwab, M., Zanger, U. M., Marx, C., Schaeffeler, E., Klein, K., Dippon, J., ... Eichelbaum, M. (2008). Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 26(13), pp. 2131-8. doi:10.1200/JCO.2006.10.4182.
Schwab M, et al. Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-related Severe Toxicity: a Prospective Clinical Trial By the German 5-FU Toxicity Study Group. J Clin Oncol. 2008 May 1;26(13):2131-8. PubMed PMID: 18299612.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. AU - Schwab,Matthias, AU - Zanger,Ulrich M, AU - Marx,Claudia, AU - Schaeffeler,Elke, AU - Klein,Kathrin, AU - Dippon,Jürgen, AU - Kerb,Reinhold, AU - Blievernicht,Julia, AU - Fischer,Joachim, AU - Hofmann,Ute, AU - Bokemeyer,Carsten, AU - Eichelbaum,Michel, AU - ,, Y1 - 2008/02/25/ PY - 2008/2/27/pubmed PY - 2008/5/21/medline PY - 2008/2/27/entrez SP - 2131 EP - 8 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J. Clin. Oncol. VL - 26 IS - 13 N2 - 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. SN - 1527-7755 UR - https://www.unboundmedicine.com/medline/citation/18299612/Role_of_genetic_and_nongenetic_factors_for_fluorouracil_treatment_related_severe_toxicity:_a_prospective_clinical_trial_by_the_German_5_FU_Toxicity_Study_Group_ L2 - http://ascopubs.org/doi/full/10.1200/JCO.2006.10.4182?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -