Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience

Abstract

Background Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life‐threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. Methods We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. Results During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty‐four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine‐based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. Conclusion Upfront genotyping before fluoropyrimidine‐based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. Implications for Practice Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life‐threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine‐based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.

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

“…The joint research with these early adopters enabled the optimization of diagnostic processes. This was actually reflected by our TAT analysis showing that DPYD testing results can be reliably returned in due time, i.e., without causing treatment delays, which is crucial for sustainable implementation ( Henricks et al, 2018 ; Jolivet et al, 2021 ).…”

“…For three cases, it took more than 7 days (five working days) to report the result including an average “time to lab” of 2.0 days (range 0–7 days) and an “internal TAT” of 1.1 day (range 0–6 days). A TAT of 7 days is considered to be adequate to avoid therapy delays ( Henricks et al, 2018 ; Hamzic et al, 2020 ; Varughese et al, 2020 ; Jolivet et al, 2021 ). For the 97 requests indicating a planned therapy start, 77.3% of the reports ( n = 75) were returned to the ordering institution before planned therapy start or on the same day.…”

“…In 2020, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) published a recommendation to screen for DPD deficiency in cancer patients either by DPYD genotyping or DPD phenotyping before the use of FP ( EMA, 2020 ; EMA, 2022 ). To our knowledge, implementation of pre-treatment DPYD testing as standard of care has started in several countries, e.g., France, Germany, Canada, with the Netherlands playing a leading role in this process ( ANSM, 2018 ; Lunenburg et al, 2020 ; Martens et al, 2020 ; Wörmann et al, 2020 ; Jolivet et al, 2021 ). However, a systematic overview on the implementation status is lacking.…”

Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature

“…57 Reported experience of systematic DPYD genotyping in routine practice showed that the administration of 5-FU at a reduced dose in patients heterozygous for DPYD*2A is safe. 58 There are also reported cases of severe toxicity (grade 3/4) induced by capecitabine that were found to be DPD deficient, 59 and DPYD genotyping successfully reduced this risk in a prospective study for breast cancer patients. 60 Variability in the genotype-phenotype relationship can be due to the regulation of DPD at the post-transcriptional level.…”

Reply to H.S. Hochster

“…9 Finally, I agree that turnaround time is critical; real-world data from Quebec, Canada, indicate an average turnaround time of 6 days, with 99% of physicians reporting no significant treatment delays. 10 I also agree with Dr Hochster 1 that practitioners will inevitably encounter patients with complete loss of DPD activity. However, I would argue that the dire consequences are not medicolegal for practitioners but rather severe toxicity and death for those patients who receive full-dose fluoropyrimidine treatment.…”