Implementing pharmacogenetic testing in fluoropyrimidine-treated cancer patients: DPYD genotyping to guide chemotherapy dosing in Greece

Abstract

<b>Introduction:</b> Dihydropyrimidine dehydrogenase (DPD), encoded by <i>DPYD</i> gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. <i>DPYD</i> gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. <i>DPYD</i> variants rs3918290, rs55886062, rs67376798, and rs75017182 are currently included in FP genetic-based dosing guidelines and are recommended for genotyping by the European Medicines Agency (EMA) before treatment initiation. In Greece, however, no data exist on <i>DPYD</i> genotyping. The aim of the present study was to analyze prevalence of <i>DPYD</i> rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients. <b>Methods:</b> Study group consisted of 313 FP-treated cancer patients. <i>DPYD</i> genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan^® assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160). <b>Results:</b> Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. <i>DPYD</i> EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity (<i>p</i> = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, <i>p</i> = 0.004, 97.9% specificity). <i>DPYD</i> deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, <i>p</i> = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, <i>p</i> = 0.014), neurological (OR: 4.134, <i>p</i> = 0.040) and nutrition/metabolism (OR: 4.821, <i>p</i> = 0.035) toxicities. FP dose intensity was significantly reduced in <i>DPYD</i> deficient patients (<i>β</i> = -0.060, <i>p</i> <0.001). <i>DPYD</i> rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of <i>DPYD</i>*<i>TYMS</i>*<i>MTHFR</i> was associated with grade 3-4 toxicity (OR: 3.725, <i>p</i> = 0.007). <b>Conclusion:</b> Our findings confirm the clinical validity of <i>DPYD</i> reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment <i>DPYD</i> genotyping should be implemented in clinical practice and guide FP dosing. <i>DPYD</i>*gene interactions merit further investigation as to their potential to increase the prognostic value of <i>DPYD</i> genotyping and improve safety of FP-based chemotherapy.