Page 263 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

A
Endogenous uracil levels B 200 NS 40
150 30 100 20 50 10 00
Endogenous DHU/U ratio
NS
Assay
Endogenous DHU/U ratio
N of Median patients (IQR)
Cut-off for DPD deficiency
≤4.31b
≥13.9 ng/ml20
Sensitivity Specificity (%) (%)
NPV PPV F1-scorea (%) (%) (%)
955
9.0 (6.8-11.6)
6 95 77 21 82 77
26 10 27 24
Endogenous 794
uracil levels (7.8-12.9)
10.0
ng/ml
a The F1-score represents the harmonic mean of sensitivity and PPV;
Phenotyping assays for predicting DPD deficiency
uracil level (ng/m l)
DHU/U ratio
No severe toxicity (N=607)
Severe toxicity (N=187)
No severe toxicity (N=737)
Severe toxicity (N=218)
Figure 2. Results of phenotyping assays separated by the occurrence of severe fluoropyrimidine- induced toxicity
Dots represent individual results. Black lines represent the median and 25th and 75th percentile of the data. All DPYD variant allele carriers were excluded from the analysis as they received initial dose reductions based on their genotype result. For the endogenous uracil levels, 161 wild-type patients were excluded due to divergent phenotyping assay results of the centre in which these patients were recruited.
Abbreviations: U: uracil; DHU: dihydrouracil; NS: not significant p-value.
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Table 3. Comparison of phenotyping assays in performance for prediction of severe fluoropyrimidine- induced toxicity
Clinical validity parameters for the prediction of severe (grade ≥3) fluoropyrimidine-induced toxicity are shown for the endogenous DHU/U ratio and endogenous uracil levels. DPYD variant allele carriers were excluded, since DPYD variant allele carriers received an initial dose reduction based on their genotype, and therefore bias could exist in the onset of severe fluoropyrimidine-induced toxicity. For the endogenous uracil levels, 161 wild-type patients were excluded due to divergent phenotyping assay results of the centre in which these patients were recruited.
b This cut-off value is determined by calculating the 6% lower limit of the data, as was described by Meulendijks et al. 20
Abbreviations: IQR: interquartile range; DPD: dihydropyrimidine dehydrogenase; NPV: negative predictive value; PPV: positive predictive value; DHU: dihydrouracil; U: uracil.
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