Clinical Implementation of DPYD Pharmacogenetic Testing to Prevent Early-Onset Fluoropyrimidine-Related Toxicity in Cancer Patients in Switzerland

Abstract

The implementation of pharmacogenetic testing into clinical practice has been a slow process so far. Here, we review the implementation of pre-treatment testing of dihydropyrimidine dehydrogenase gene (DPYD) risk variants to prevent early-onset fluoropyrimidine (FP)-related toxicity in cancer patients in Switzerland based on data of a large Swiss diagnostic center. In January 2017, the Swiss Federal Office of Public Health introduced the reimbursement of DPYD testing by the compulsory health insurance in Switzerland based on evidence for the clinical relevance of DPYD-risk variants and the cost-effectiveness of pre-treatment testing, and on the availability of international guidelines. However, we did not observe a strong increase in DPYD testing at our diagnostic center from 2017 to 2019. Only a low number of DPYD-testing requests (28–42 per year), concerning mostly retrospective investigations of suspected FP-toxicity, were received. In contrast, we observed a 14-fold increase in DPYD testing together with a strong shift from retrospective to pre-treatment test requests upon the release of recommendations for DPYD testing prior to FP-treatment in April 2020 by the European Medicines Agency. This increase was mainly driven by three geographic regions of Switzerland, where partner institutions of previous research collaborations regarding FP-related toxicity are located and who acted as early-adopting institutions of DPYD testing. Our data suggest the important role of early adopters as accelerators of clinical implementation of pharmacogenetic testing by introducing these policies to their working environment and educating health workers from their own and nearby institutions.

Implementation of dihydropyrimidine dehydrogenase deficiency testing in Europe

“… 35 A study by Begré et al. 36 noticed that oncologists who were part of research collaborations related to DPD deficiency testing were ‘early adopters’ of DPD deficiency testing in clinical practice. This highlights how knowledge about clinical relevance impacts implementation of the test.…”

Implementation of upfront DPYD genotyping with a low-cost and high-throughput assay to guide fluoropyrimidine treatment in cancer patients

“…Pretreatment DPYD variant screening can present a significant impact on the number of genotyping tests, constituting a challenge in terms of health care resources. Nonetheless, several studies have demonstrated that upfront genotyping of DPYD variants is feasible and cost-saving while preventing severe toxicity [20,26,28,29,38,43,44]. In this work, we describe a genotyping assay using KASP methodology for the four DPYD variants associated with fluoropyrimidine toxicity that current guidelines recommend testing for.…”

“…Several authors suggested that upfront genotyping of DPYD variants followed by individualized dose adjustment would improve the safety of fluoropyrimidine therapy for patients and reduce overall treatment costs [17,20,[24][25][26][27][28][29]. On 13 March 2020, the European Medicines Agency's (EMA's) Pharmacovigilance Risk Assessment Committee has recommended that patients receiving fluorouracil given by injection or infusion and the related medicines capecitabine and tegafur should be tested for the lack of DPD enzyme, either by measuring the level of uracil in the blood or DPYD gene variant analysis, before starting treatment.…”

Pharmacogenomics in the era of personalised medicine

“… 6 Early prospective data and health economic modelling illustrate the cost‐effectiveness of upfront DPYD genotyping across various health systems internationally, and upfront DPYD genotyping has become part of the standard of care in the Netherlands, France, Switzerland, Germany, and the United Kingdom. 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Although there is limited information on the international uptake of testing, for pharmacogenomics generally and DPYD specifically, increases in uptake of DPYD genotyping rose by 14% following endorsement of pre‐emptive screening by the European Medicines Agency in 2020, showing the impact of both clinical champions and early adopters on the implementation of health practices. 26 , 27 To date, pre‐emptive DPYD screening has not been adopted systematically in Australia.…”

“… 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Although there is limited information on the international uptake of testing, for pharmacogenomics generally and DPYD specifically, increases in uptake of DPYD genotyping rose by 14% following endorsement of pre‐emptive screening by the European Medicines Agency in 2020, showing the impact of both clinical champions and early adopters on the implementation of health practices. 26 , 27 To date, pre‐emptive DPYD screening has not been adopted systematically in Australia.…”