Background and Importance Dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, is the rate-limiting enzyme of fluoropyrimidines catabolism.

Among around 450 missense DPYD single-nucleotide polymorphisms, only approximately twenty of them acquire a functional significance. Four of these variants are considered to be of clinical relevance for recognised effects on the protein, their identified higher risk of severe toxicity, and for their population frequency.

Aim and Objectives To analyse DPYD gene mutations in all patients who are candidates for receiving a fluoropyrimidine-based regimens and their influence on the individualisation of cancer treatment.

Material and Methods Retrospective observational study from July/2020-July/2022. All patients who underwent a genotyping test for DYPD were included. Demographic variables were recorded. The loss-of-function variants in the DPYD gene were analysed: c.1905+1G>A that identifies the DPYD*2A haplotype, and c.1679T>G that identifies the DPYD*13 haplotype. It also studies the variants of reduced function: c.1129-5923C>G that identifies the HapB3 haplotype and c.2846A>T. The frequency of each of these variants were determined, and the recommendations of treatment individualisation were collected.

Results We analysed 638 requests for DPYD gene determination, mean age was 62.65 ± 12.58 years, and 52.98% were men. Thirty-two (5,0%) had some mutation in the DPYD gene. Four (0,6%) patients were heterozygous for the loss-of-function variant c.1905 + 1G> A and one (0,16%) patient was heterozygous for the variant c.1679T>G. Twenty-three (3,6%) patients were heterozygous for the decreased function variant c.1129-5923C>G, and four (0,6%) patients were heterozygous for the reduced function variant c.2846A>T.

All of them were intermediate metabolisers, who if they started treatment with fluoropyrimidines, they should start treatment with a dose reduced to approximately 50% and then escalate the dose in later cycles if no toxicity was observed.

The recommendation of individualisation of treatment was: sixteen patients started treatment at 50% of the dose, in seven patients the chemotherapy regimen were changed, in seven patients adjuvant therapy were dismissed, one patient was not treated, and one patient received radiatiotherapy alone.

Conclusion and Relevance The determination of DPYD polymorphisms prior to the start of treatment with fluoropyrimidines, allows to identify DPD-deficient patients, and avoid may experience serious side effects when treated with fluoropyrimidines; and thus clinicians’ decisions are influenced by the results of DYPD genotyping.

Conflict of Interest No conflict of interest