Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance

Purpose: Although single nucleotide polymorphisms (SNP) of the dihydropyrimidine dehydrogenase gene ( DPYD ) have been reported, which affect enzyme activity and the severity of 5-fluorouracil (5-FU) toxicity, no pretherapeutic detection has thus far been developed. We investigated 22 DPYD gene SNPs, their respective incidence, their link with grade 3 to 4 toxic side effects, and their management in practice: 9 were looked for in 487 patients, whereas 13 others were investigated in 171 patients. Patients and Methods: SNPs were detected before 5-FU-based treatment in WBC using a Pyrosequencing method. Close clinical and biological follow-up was done. Results: Five different SNPs were found in 187 patients (IVS14 + 1G>A, 2846A>T, 1679T>G, 85T>C, −1590T>C). Three hundred patients had no SNP. Forty-four patients had grade 3 to 4 toxic side effects in either the first or second cycle. Sixty percent of patients with either IVS14 + 1G>A or 2846A>T SNPs and the only patient with 1679T>G SNP experienced early grade 3 to 4 toxicity, compared with 0%, 5.5%, and 15% of those with either −1590T>C, 85T>C SNP, or no SNP, respectively. In cases with grade 3 to 4 toxicity, treatment either had to be quickly stopped, or could be safely continued with an individual dose adjustment. Sensitivity, specificity, and positive and negative predictive values of the detection of these three major SNPs as toxicity predictive factors were 0.31, 0.98, and 0.62 and 0.94, respectively. Conclusion: Pretreatment detection of three DPYD SNPs could help to avoid severe toxic side effects. This approach is suitable for clinical practice and should be compared or combined with pharmacologic approaches. In the case of dihydropyrimidine dehydrogenase deficiency, 5-FU administration often can be safely continued with an individual dose adjustment. [Mol Cancer Ther 2006;5(11):2895–904]