Abstract
BackgroundPretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD-deficient patients remains elusive.MethodsAmong a nationwide cohort of 5886 phenotyped patients with cancer who were screened for DPD deficiency over a 3 years period, we assessed the characteristics of both DPD phenotypes and DPYD genotypes in a subgroup of 3680 patients who had completed the two tests. The extent to which defective allelic variants of DPYD predict DPD activity as estimated by the plasma concentrations of uracil [U] and its product dihydrouracil [UH2] was evaluated.ResultsWhen [U] was used to monitor DPD activity, 6.8% of the patients were classified as having DPD deficiency ([U] > 16 ng/ml), while the [UH2]:[U] ratio identified 11.5% of the patients as having DPD deficiency (UH2]:[U] < 10). [U] classified two patients (0.05%) with complete DPD deficiency (> 150 ng/ml), and [UH2]:[U] < 1 identified three patients (0.08%) with a complete DPD deficiency. A defective DPYD variant was present in 4.5% of the patients, and two patients (0.05%) carrying 2 defective variants of DPYD were predicted to have low metabolism. The mutation status of DPYD displayed a very low positive predictive value in identifying individuals with DPD deficiency, although a higher predictive value was observed when [UH2]:[U] was used to measure DPD activity. Whole exon sequencing of the DPYD gene in 111 patients with DPD deficiency and a “wild-type” genotype (based on the four most common variants) identified seven heterozygous carriers of a defective allelic variant.ConclusionsFrequent genetic DPYD variants have low performances in predicting partial DPD deficiency when evaluated by [U] alone, and [UH2]:[U] might better reflect the impact of genetic variants on DPD activity. A clinical trial comparing toxicity rates after dose adjustment according to the results of genotyping or phenotyping testing to detect DPD deficiency will provide critical information on the best strategy to identify DPD deficiency.
Highlights
Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy
Pre-treatment screening for the most clinically relevant defective variants, c.1679T>G, c.1905 + 1G>A, c.2846A>T, and Haplotype B3 (c.1236G>A or c.1129–5923C>G), and a dose adjustment according to the DPYD genotype improves the safety of chemotherapy regimens based on fluorouracil.[10,11]
DPD phenotyping by measuring plasma U and UH2 concentrations Mean patients age was 64.5 ± 13 years, and the sex ratio (M/F) was 41%
Summary
Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended or required prior to the administration of fluoropyrimidine-based chemotherapy. Genetic polymorphisms in DPYD, the gene encoding DPD, predict fluoropyrimidine-associated toxicity.[1,6,7,8,9] Pre-treatment screening for the most clinically relevant defective variants, c.1679T>G, c.1905 + 1G>A, c.2846A>T, and Haplotype B3 (c.1236G>A or c.1129–5923C>G), and a dose adjustment according to the DPYD genotype improves the safety of chemotherapy regimens based on fluorouracil.[10,11] International recommendations provide indications for drug-related genetic tests and DPYD genotype-guided dosing to improve their integration in routine clinical practice.[6,12] The U.S Food and Drug Administration and the Health Candida Santé Canada have added statements to the drug labels for fluorouracil and capecitabine that warn against use in patients with DPD deficiency, and genotype-guided prescribing recommendations for fluorouracil, capecitabine, and tegafur are Received: 17 February 2020 Revised: 2 June 2020 Accepted: 11 June 2020 Published online: 29 June 2020
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