AUTHOR=Ragia Georgia , Maslarinou Anthi , Atzemian Natalia , Biziota Eirini , Koukaki Triantafyllia , Ioannou Charalampia , Balgkouranidou Ioanna , Kolios George , Kakolyris Stylianos , Xenidis Nikolaos , Amarantidis Kyriakos , Manolopoulos Vangelis G. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1248898

DOI=10.3389/fphar.2023.1248898

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Dihydropyrimidine dehydrogenase (DPD), encoded by <italic>DPYD</italic> gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. <italic>DPYD</italic> gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. <italic>DPYD</italic> 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 <italic>DPYD</italic> genotyping. The aim of the present study was to analyze prevalence of <italic>DPYD</italic> rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients.</p><p><bold>Methods:</bold> Study group consisted of 313 FP-treated cancer patients. <italic>DPYD</italic> genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan<sup>®</sup> assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160).</p><p><bold>Results:</bold> Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. <italic>DPYD</italic> EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity (<italic>p</italic> = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, <italic>p</italic> = 0.004, 97.9% specificity). <italic>DPYD</italic> deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, <italic>p</italic> = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, <italic>p</italic> = 0.014), neurological (OR: 4.134, <italic>p</italic> = 0.040) and nutrition/metabolism (OR: 4.821, <italic>p</italic> = 0.035) toxicities. FP dose intensity was significantly reduced in <italic>DPYD</italic> deficient patients (<italic>β</italic> = −0.060, <italic>p</italic> &lt;0.001). <italic>DPYD</italic> rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of <italic>DPYD</italic>*<italic>TYMS</italic>*<italic>MTHFR</italic> was associated with grade 3-4 toxicity (OR: 3.725, <italic>p</italic> = 0.007).</p><p><bold>Conclusion:</bold> Our findings confirm the clinical validity of <italic>DPYD</italic> reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment <italic>DPYD</italic> genotyping should be implemented in clinical practice and guide FP dosing. <italic>DPYD</italic>*gene interactions merit further investigation as to their potential to increase the prognostic value of <italic>DPYD</italic> genotyping and improve safety of FP-based chemotherapy.</p>