Prevalence of Dihydropyrimidine Dehydrogenase Deficiency in Breast Cancer Patients

ABSTRACT & COMMENTARY

Synopsis: 5-Fluorouracil is commonly used in breast cancer patients, and its metabolism depends on dihydropyrimidine dehydrogenase (DPD). In the absence of the enzyme, serious toxicities may develop. In a survey of 360 patients with breast cancer, 21 (5.8%) were found to have DPD deficiency.

Source: Lu Z, Clin Cancer Res 1998;4:325-329.

Among the top three most frequently prescribed anticancer drugs is 5-fluorouracil. It is active in a variety of tumors but is used chiefly in the treatment of gastrointestinal tract and breast primaries. The major site of its action is the inhibition of denovo thymidine synthesis by blocking the action of thymidylate synthase. 5-Flurouracil is degraded to dihydrofluorouracil by DPD, which is widely distributed throughout the body but is present in the greatest amount in the liver. DPD is the initial step in degradation and is the rate-limiting step in the catabolic pathway.

Deficiency of DPD has been demonstrated to be associated with severe toxicity from 5-fluorouracil.1,2 Furthermore, circadian variations in 5-fluorouracil levels during continuous infusion regimens have been documented to be related to circadian variation in DPD activity in peripheral blood mononuclear cells.3 Thus, the pharmacokinetics and metabolism of 5-fluorouracil are correlated with DPD activity.

Lu and colleagues examined DPD activity in peripheral blood mononuclear cells in 360 women with breast cancer. The mean DPD levels were 0.26 ± 0.01 nmol/min/mg protein, which were significantly lower than female controls (0.44 ± 0.02 nmol/min/mg protein). When individual values in the population of patients and controls were plotted on a frequency distribution, a large fraction of patients fell into groups representing the lowest quartile of normal activity or lower. Frank DPD deficiency was noted in 21 patients (5.8%), a frequency considerably higher than would have been anticipated based upon surveys of normal populations.

COMMENTARY

Why do women with breast cancer have such a high incidence of DPD deficiency? The number of women sampled in this study is so sufficiently large that the credibility of the result seems substantial. However, I cannot recall more than a couple of patients who had unexpected levels of toxicity from standard 5-fluorouracil regimens. Does the low level of DPD in the peripheral blood mononuclear cells reflect hepatic levels of the enzyme? If there were, in the case of breast cancer, a dissociation between DPD levels in the peripheral blood and liver, one might not see enhanced 5-fluorouracil toxicity. Should we routinely screen women with breast cancer for DPD deficiency? The decrease appears to be disease-related. Women without breast cancer and both men and women with colon cancer did not have significantly decreased enzyme levels. At the moment, this result is a puzzling potential explanation for a clinical phenomenon that has not been observed. However, if you see a patient with toxicity from adjuvant chemotherapy that is out of proportion to the drug doses, it might be well to consider the possibility of DPD deficiency.

References

    1. Tuchman M, N Engl J Med 1985;313:245.

    2. Diasio RB, J Clin Invest 1988;81:47.

    3. Harris BE, Cancer Res 1990;50:197.