Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the key enzyme regulating the breakdown of fluoropyrimidines (FPs). Variants in DPYD substantially alter DPD function and are firmly established predictors of FP-related adverse reactions. Four specific DPYD polymorphisms—rs3918290, rs55886062, rs67376798, and rs75017182—are incorporated into genotype-guided FP dosing recommendations and are advised by the European Medicines Agency (EMA) for testing prior to therapy. In Greece, however, information on DPYD screening remains unavailable. This work aimed to determine the occurrence of rs3918290, rs55886062, rs67376798, rs75017182, and additionally rs1801160, and to examine whether these variants correlate with FP-associated toxicities in Greek oncology patients. The cohort included 313 individuals receiving FP-based regimens. Genotyping of DPYD was performed with the QuantStudio™ 12K Flex Real-Time PCR instrument (ThermoFisher Scientific) using TaqMan® assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182), and C__11372171_10 (rs1801160).
Toxic effects of any grade (1–4) were observed in 208 participants (66.5%), and 25 of them (12%) showed grade 3–4 complications. EMA-listed DPYD variants appeared in 9 subjects (2.9%), all of whom developed toxicity (p = 0.031, specificity 100%). Their frequency was higher in those with grade 3–4 events (12%, p = 0.004, specificity 97.9%). Reduced DPYD function increased the likelihood of severe reactions (OR: 6.493, p = 0.014) and of grade 1–4 gastrointestinal (OR: 13.990, p = 0.014), neurologic (OR: 4.134, p = 0.040), and metabolic/nutritional (OR: 4.821, p = 0.035) toxicities. Dose intensity of FP treatment was notably lower in DPD-impaired patients (β = −0.060, p < 0.001). The rs1801160 variant showed no meaningful association with toxicity or dosing. A combined DPYD–TYMS–MTHFR effect was linked to high-grade toxicity (OR: 3.725, p = 0.007). These results reinforce that DPYD reduced-activity alleles serve as significant indicators of FP-related toxicities in the Greek population. Incorporating DPYD genotyping prior to FP therapy is advisable for safer dose selection. Interactions between DPYD and other relevant genes warrant additional study to evaluate whether they enhance predictive power for toxicity in FP-treated patients.
