Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

Abstract

Abstract5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe

“…Specifically, hurdles included lack of reimbursement, poor knowledge and consideration by oncologists, and absence of clear guidelines. For the latter, the EMA recommendations supported the development and implementation of several national, regional, and institutional guidelines in many European countries including Belgium, 26 Denmark, 27 England, 28 Finland, 29 Italy, 30 Spain, 31 and Switzerland, 32 and a joint guideline for Switzerland, Germany, and Austria 33 ( Supplementary Appendix 3 , available at https://doi.org/10.1016/j.esmoop.2023.101197 ).…”

Clinical Relevance of Novel Polymorphisms in the Dihydropyrimidine Dehydrogenase (DPYD) Gene in Patients with Severe Fluoropyrimidine Toxicity: A Spanish Case-Control Study

“…Clinical pharmacogenetics is one strategy to reduce these toxicities by avoiding prescribing fluoropyrimidines to patients who cannot metabolize them correctly. In this line, the evidence that pre-emptive genotyping leads to a reduction in the incidence of adverse reactions is indisputable, as several institutions, such as the CPIC, SEFF or the Dutch Pharmacogenetics Working Group (DPWG), already recommend it [10,14,21]. Furthermore, since 2020, the AEMPS recommends pre-emptive genotyping of DPYD *HapB3, *2A, *13 and c.2846A > T (D949V) [9].…”

“…Other factors may be responsible for toxicity, such as a patient's age, general condition, co-morbidities, as well as polymorphism of other genes, among others [13]. In fact, the Spanish Society of Pharmacogenetics and Pharmacogenomics (SEFF) will soon publish their Guideline on DPYD genotyping and prescription of fluoropyrimidines, where genotyping of the four core variants is con-sidered mandatory and the genotyping of six additional variants is recommended [14]. Ultimately, the functional impact of several additional DPYD SNPs remains unknown to date or, further, several variants may have not been described yet.…”

Allelic Frequency of DPYD Genetic Variants in Patients With Cancer in Spain: The PhotoDPYD Study

“…In May 2020, the Spanish Agency for Medicines and Health Products (AEMPS) published an informative note in this regard, recommending carrying out genotyping tests in patients who are candidates for treatment with fluoropyrimidines, which is also suggested in the data sheet of these drugs. 6 …”