Fluoropyrimidines (FP) are the cornerstone of chemotherapy of several, mainly gastrointestinal, solid tumors. FP includes 5-fluorouracil, capecitabine, and tegafur, all metabolized by dihydropyrimidine dehydrogenase (DPD) enzyme. Patients with decreased DPD-activity have a higher risk of getting severe toxicity if treated with standard FP doses. The DPD-activity is currently a standard test in Denmark with a DPYD-genotype-test and/or a measurement of the endogenous compound uracil (DPD-phenotype test). In Denmark, the recommended FP starting dose for patients diagnosed with partial DPD-deficiency is 50%. FP treatment is contraindicated in patients with complete DPD-deficiency due to a high risk of life-threatening adverse effects. Patients with one variant SNP and/or uracil concentrations above 16 ng/ml are categorized as having partial DPD deficiency. However, patients are categorized as having complete DPD deficiency if they are homozygous for one variant SNP or compound heterozygous (patients with≥ 2 different variant SNPs) and/or have uracil concentrations above 150 ng/ml. In France and the Netherlands, the prevalence of clinically relevant DPYD variants was 4.7% and 7.7% respectively. No studies have reported data on the prevalence of DPYD variants or P-uracil in Danish cancer patients. We collected data from all Danish public hospital laboratories performing DPYD-genotype and DPD-phenotype analysis from the 1st of July 2020 to the 31st of December 2021. Patients were genotyped for the four clinically relevant DPYD-variants: rs3918290, rs67376798, rs55886062, and rs56038477/rs75018182. Most of the samples were genotyped using the LAMP (loop-mediated isothermal amplification) technology (Lc-Dpd4mut-Lp-24-Lacar Mdx Technologies). Plasma uracil concentrations were measured using liquid chromatography-mass spectrometry (LC-MS). In total 4228 Danish cancer patients were tested. 1985 of the patients were only tested using one method (P-uracil=17, DPYD-genotype=1968). 2243 patients were tested using P-uracil and DPYD-genotyping. Of the 4215 DPYD-genotyped patients, 3895 (92.4%) was wild type and 316 (7.5%) was heterozygous for one of the tested variants (SNP'S). rs3918290 (1%, n=43), rs67376798 (1.4%, n=57), rs55886062 (0.2%, n=8) and rs56038477/rs75018182 (4.9%, n=208). Four patients (0.1%) were compound heterozygous. Among 2260 patients tested, 2132 (94.3%) had an uracil concentration below 16 ng/ml. The remaining 128 (5.7%) patients had uracil concentrations ≥ 16 ng/mL and < 150 ng/ml. No values above 150 ng/ml was found. Median uracil concentration was 8 ng/ml (range 5-82 ng/ml). Both geno- and phenotype were available for 2243 of the patients. Uracil concentrations among wild type patients were lower (mean 8.6 ng/ml) compared to patients with DPYD-variants (mean 11.2 ng/ml), mean difference of 2.7 ng/ml. (95% CI; 1.9-3.4 ng/ml). In 4.8% (n=99) of wild type patients, the uracil concentration was ≥ 16 ng/ml compared to 16.8% (n=29) in the group with DPYD-mutations. The prevalence of clinically relevant DPYD-mutations in Danish cancer patients is 7.6% and is in line with results from similar studies of other European populations. 5.7% of phenotyped patients had uracil concentrations ≥ 16 ng/ml. Patients with DPYD-variants had higher mean uracil concentrations compared to wild type, but the uracil concentrations varied substantially in both groups. Data regarding adverse events are needed to conclude on the clinical implications.
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