Page 254 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 10
Abstract
Fluoropyrimidines are widely used anticancer drugs. Prospective DPYD (encoding dihydropyrimidine dehydrogenase, DPD, the key metabolic enzyme for degradation of fluoropyrimidines) genotyping followed by dose adjustments in DPYD variant allele carriers reduces severe fluoropyrimidine-induced toxicity. However, when using this approach still ~20% of patients experience severe toxicity. We evaluated four DPD phenotyping assays, aiming to determine which is most suitable for identifying patients at risk for severe fluoropyrimidine-induced toxicity, and identifying DPD deficient patients.
Study participants underwent testing of two, three or four DPD phenotyping assays before starting fluoropyrimidine-based therapy; the endogenous dihydrouracil/uracil (DHU/U) ratio, endogenous uracil levels, the oral uracil loading dose, and the 2-13C-uracil breath test. Phenotyping results were associated with the onset of severe toxicity and DPD deficiency according to the DPD enzyme activity measurement in peripheral blood mononuclear cells. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and F1-score (harmonic mean of sensitivity and PPV) were calculated per phenotyping assay as predictive measures for severe (grade ≥3) fluoropyrimidine-induced toxicity and DPD deficiency.
In total, 1,037 patients participated in this study. Of these, 1,037, 92 and 82 patients underwent two, three or four DPD phenotyping assays, respectively. Two phenotyping assays were analysed on their performance for the prediction of severe fluoropyrimidine- induced toxicity. No differences were identified between wild-type patients who did or did not experience severe toxicity in the mean endogenous DHU/U ratio or mean endogenous uracil levels. The F1-scores of both assays were 10 and 24%, respectively. In the comparison of phenotyping assays in performance for prediction of DPD deficiency, four phenotyping assays were analysed in both wild-type patients and DPYD variant allele carriers. The highest F1-score of the phenotyping assays in predicting DPD deficiency was 40% for the oral uracil loading dose.
All four investigated DPD phenotyping assays in this study have been favourably evaluated as predictive test for the occurrence of severe fluoropyrimidine-induced toxicity in previous studies. However, in a first-time prospective head-to-head comparison study we could not show associations with the onset of severe fluoropyrimidine-induced toxicity or DPD deficiency. In order to determine the true clinical value of DPD phenotyping assays, additional research is required.
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