Feasibility and impact of prospective DPYD screening in the Irish population

Background Genetic variants of dihydropyrimidine dehydrogenase (DPYD) gene can result in varied enzymatic activity and potential toxicity when receiving 5-FU chemotherapy including treatment related death in up to 1% patients. Current international guidelines suggest an international rate of 3-5% albeit routine prospective pharmacogenomic testing is not currently recommended. However, in a genetically homogenous population such as Ireland, DPYD variant enrichment may support routine testing. Methods All patients receiving 5-FU based chemotherapy in South & South-West region of Ireland were prospectively tested from 01/09/2018 to present. The Viapath DPYD genotyping panel which interrogates for 5 variants was used. Toxicity type and grade for all patients were recorded (CTCAE v5.0). Results To date, 139 patients have been tested,50.4% male and 49.6% female, median age 63 years. The majority(59%) were being treated for colorectal cancer. Sixteen patients were found to be heterozygous carriers of a DYPD variant with one compound heterozygous variant identified i.e. an overall prevalence of 12 %. No homozygous carriers were identified. Grade ≥3 was observed in 33% DPYD variant carriers compared to 19% in DPYD wild type patients i.e. relative risk of grade ≥3 toxicity is 1.7, p = 0.17. Table . 648P DPYD Variants Prevalence % n = 139 % Rate of ≥ G3 toxicity 7(5.0%) 42% c. 2846A>T 1(0.7%) n/a* c. 1905 + 1G>A 3(2.2%) 100% c. 1679T>G 0 (0%) n/a* c. 1601GA 5 (3.6%) 0% c. 1905 + 1G>A+c;1236G>A/Hapb3 compound heterozygous 1(0.7%) n/a* TOTAL:17 (12.2%) Conclusions The study shows a higher than expected prevalence of DPYD variants of 12.2% compared to internationally reported 3-5%. Patients with DPYD variants c.1236G>A and c.1905+1G>A were particularly likely to develop Grade ≥ 3 toxicity. Prospective testing continues to assess the clinical relevance of individual variants in our population. Legal entity responsible for the study: The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.