AUTHOR=Wu Angela , Anderson Helen , Hughesman Curtis , Young Sean , Lohrisch Caroline , Ross Colin J. D. , Carleton Bruce C. 

TITLE=Implementation of pharmacogenetic testing in oncology: DPYD-guided dosing to prevent fluoropyrimidine toxicity in British Columbia

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1257745

DOI=10.3389/fphar.2023.1257745

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Fluoropyrimidine toxicity is often due to variations in the gene (<italic>DPYD</italic>) encoding dihydropyrimidine dehydrogenase (DPD). <italic>DPYD</italic> genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels.</p><p><bold>Methods:</bold> A multiplex QPCR assay was locally developed to allow genotyping for six <italic>DPYD</italic> variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between <italic>DPYD</italic> variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide.</p><p><bold>Results:</bold> In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in <italic>DPYD</italic> variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after <italic>DPYD</italic>-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, <italic>DPYD</italic> testing likely prevented lethal toxicity. In <italic>DPYD</italic> variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%.</p><p><bold>Conclusion:</bold><italic>DPYD</italic>-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in <italic>DPYD</italic> variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, <italic>DPYD</italic> genotyping was made available province-wide in British Columbia.</p>