4CPS-035 Association of dihydropyrimidine dehydrogenase deficiency with capecitabine tolerance

Background and ImportanceDihydropyrimidine dehydrogenase (DPD) is the first of the enzymes in the fluoropyrimidine metabolic pathway. Recently, the Spanish Agency of Medicine and Health Products reported an informative note warning that patients with partial or total deficiency in DPD activity cannot adequately degrade fluoropyrimidines, increasing the risk of serious toxicity. DPD genotyping is recommended as standard practice for predicting the occurrence and severity of capecitabine toxicity.Aim and ObjectivesTo assess the rate of deficiency of the metabolising enzyme DPD in patients treated with capecitabine and to describe the associated toxicity.Material and MethodsA retrospective observational study was conducted during 2022 in a regional hospital. Age, gender, Eastern Cooperative Oncology Group (ECOG) and diagnosis were collected from the electronic clinical history. To determine the variants of DPD, a pharmacogenomics analysis was performed using a real-time polymerase chain reaction technique. The polymorphisms studied were rs3918290, rs55886062, rs67376798 and rs56038477. Regarding the management of patients, the doses reduction, adverse events (AE), and withdrawal treatments were recorded.ResultsThirty-six patients were included with median age 70.9 (50–88) years. ECOG 0–1 was observed in 94% of cases. Capecitabine was used for the following diagnoses: colorectal cancer (n=22, 61%), gastric cancer (n=9, 25%) and breast cancer (n=5, 14%). DPD genotyping was performed on 25 patients (69%). A mutated allele heterozygote was detected in 3 (8.3%) patients: rs56038477 (n=2, 5.5%) and rs67376798 (n=1, 2.8%). A 50% dose reduction was prescribed initially according to pharmacogenetics recommendations in DPD deficiency and this dose was maintained throughout the entire treatment. In patients without mutation a dose reduction was required in 8 (32%). All patients with DPD mutation and 20 (80%) without DPD mutation presented AE. The most common AE in this population were weakness (n=18, 50%), diarrhoea (n=17, 47.2%), gastrointestinal such as nausea (n=10, 27.8%), dactylitis (n=8, 22.2%), mucositis (n=8, 22.2%), paraesthesia (n=8, 22.2%),hyperpigmentation (n=6, 16.7%) and constipation (n=4,11.1%). Six (16.7%) discontinuations of capecitabine due to AE were reported.Conclusion and RelevanceIt is important to know the DPD polymorphism to correctly adjust the capecitabine dose. A considerable percentage of patients without DPD mutation report AE. Determination