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Correspondence re: Raida, M. et al., Prevalence of a Common Point Mutation in the Dihydropyrimidine Dehydrogenase (DPD) Gene within the 5'-Splice Donor Site of Intron 14 in Patients with Severe 5-Fluorouracil (5-FU)-related Toxicity Compared with Controls. Clin. Cancer Res., 7: 2832–2839, 2001.

Committee on Clinical Pharmacology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637

Mark J. Ratain¹

Committee on Clinical Pharmacology, Department of Medicine, Cancer Research Center, The University of Chicago, Chicago, Illinois 60637

Raida et al. (1) , in the September 2001 issue of Clinical Cancer Research, investigated the genetic basis of dihydropyrimidine dehydrogenase deficiency in cancer patients who developed grade 3–4 toxicity after 5-FU² -containing regimens. Twenty-five patients were genotyped for the exon 14-skipping GA mutation in the DPYD gene (DPYD*2A). This mutation was found in 6 of 25 cancer patients with severe toxicities. The high frequency (24%) of DPYD*2A allele in this selected group of patients compared with normal individuals led the authors to the conclusion that patients should be screened for DPYD*2A allele before undergoing 5-FU.

The findings of Raida et al. (1) increase our knowledge regarding the molecular basis of dihydropyrimidine dehydrogenase genetic deficiency, but the identification of patients at risk for severe toxicity is still an unattained goal. We believe that the use of DPYD*2A genotyping for routine screening is not indicated.

The clinical use of a diagnostic test derives from its sensitivity (percentage of true positives) and specificity (percentage of true negatives; Refs. 2 , 3 ). Raida et al. (1) demonstrate that DPYD*2A test has low sensitivity and unknown specificity for predicting toxicity. The sensitivity is 24%, with a 95% confidence interval of 7–41% (3) . Concerning the specificity of the test, the percentage of positive patients that will eventually develop severe toxicity has never been estimated, making the specificity unknown. Even assuming 100% specificity (all of the positive patients will develop severe toxicity after 5-FU), this test will not be able to enlarge the therapeutic window of 5-FU because of its low sensitivity.

Frequency of DPYD*2A heterozygotes is 1.8% in Caucasians (4) . The "best case" scenario based on the available data would be a specificity of 100% and a sensitivity of 41%. All of the patients with at least one DPYD*2A allele (1.8%) would be at risk for severe toxicity, and this would represent 41% of all such individuals (1.8%/0.41 or 4.4%). In this scenario, the reduction in the percentage of patients with severe toxicity would be only 1.8%, leaving 2.6% of patients who would not be detected before treatment.

Clinical application of genotyping procedures as a tool for individualized therapy has to be validated and benefit estimated. Misinterpretation and misapplication of pharmacogenetic findings should alert investigators in the field that recommended procedures for diagnostic use of genetic tests should be outlined and decision analysis applied. Tests for detection of DPYD mutations are still of investigational use and should not be used outside of clinical trials.

FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom requests for reprints should be addressed, at The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, IL 60637. Phone: (773) 702-4400; Fax: (773) 702-3969; E-mail: mratain{at}medicine.bsd.uchicago.edu

² The abbreviations used are: 5-FU, 5-fluorouracil.

Received 11/ 5/01; accepted 2/13/02.

REFERENCES

1. Raida M., Schwabe W., Hausler P., Van Kuilenburg A. B., Van Gennip A. H., Behnke D., Hoffken K. Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-related toxicity compared with controls. Clin. Cancer Res., 7: 2832-2839, 2001.[Abstract/Free Full Text]
2. Holtzman N. A. Benefits and risks of emerging genetic technologies: the need for regulation. Clin. Chem., 40: 1652-1657, 1994.[Abstract/Free Full Text]
3. Empson M. B. Statistics in the pathology laboratory: characteristics of diagnostic tests. Pathology, 33: 93-95, 2001.[Medline]
4. van Kuilenburg A. B., Muller E. W., Haasjes J., Meinsma R., Zoetekouw L., Waterham H. R., Baas F., Richel D. J., van Gennip A. H. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin. Cancer Res., 7: 1149-1153, 2001.[Abstract/Free Full Text]

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