DPYD (DPD) activity score calculator. Genotype guided fluoropyrimidine dosing tool. CPIC guidelines.
The enzyme dihydropyrimidine dehydrogensase encoded by the gene DPYD (DPD) is the rate limiting enzyme in the metabolism of fluoropyrimidine drugs (5-fluorouracil, capecitabine, tegafur).
Individuals with pathogenic germline variants in the DPYD gene have reduced ability to metabolise fluoropyrimidine chemotherapy. This can result in severe toxicity when exposed to standard doses of fluoropyrimidine chemotherapy.
Genetic testing for common pathogenic DPYD variants has been proposed as a means of identifying individuals at risk of severe fluoropyrimidine toxicity. The
Clinical Pharmogenetics Implementation Consortium (CPIC) created guidelines on DPYD genotype guided fluoropyrimidine dosing.
The CPIC guidelines were developed after detailed literature review of prospective(2-4) and retrospective(5) studies demonstrating genotype guided fluoropyrimidine dosing resulting in reduced toxicity.
Four decreased function DPYD variants have been identified as most relevant due to their population frequency and known impact on enzyme activity. Most DPYD genotype tests focus on these four variants:
*In a European population.
Approximately 7% of individuals of European ancestry are carriers of at least one of the four variants above.
In individuals of African ancestry the decreased function variant c. 557A>G is observed in approximately 3-5% of individuals.
The CPIC guidelines include other less common DPYD variants. For rare variants clinical validation data is often lacking and only in-vitro data are available. CPIC guidelines therefore include the strength of evidence supporting recommendations for each variant.
In 2020 the European Medicines Agency recommended DPYD testing before commencing fluoroypyrimidine chemotherapy(6). The ESMO localised colon cancer guidelines recommend DPYD genotyping before initiating fluoropyrimidine chemotherapy(7).
Evidence supporting genotype guided fluoropyrimidine dosing not impairing treatment efficacy has been shown in case control and retrospective studies(5,8). A prospective case control study found that DPYD genotype guided dose reduction resulted in similar overall and progression free survival in 40 DPYD*2A carriers versus matched controls.
References:
- Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103(2):210-216. doi:10.1002/cpt.911
- Deenen MJ, Meulendijks D, Cats A, et al. Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(3):227-234. doi:10.1200/JCO.2015.63.1325
- Lunenburg CA, van Staveren MC, Gelderblom H, Guchelaar H-J, Swen JJ. Evaluation of clinical implementation of prospective DPYD genotyping in 5-fluorouracil- or capecitabine-treated patients. Pharmacogenomics. 2016;17(7):721-729. doi:10.2217/pgs-2016-0013
- Boisdron-Celle M, Capitain O, Faroux R, et al. Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach. Semin Oncol. 2017;44(1):13-23. doi:10.1053/j.seminoncol.2017.02.008
- Deenen MJ, Tol J, Burylo AM, et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin cancer Res an Off J Am Assoc Cancer Res. 2011;17(10):3455-3468. doi:10.1158/1078-0432.CCR-10-2209
- EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine. Published 2020. https://www.ema.europa.eu/en/news/ema-recommendations-dpd-testing-prior-treatment-fluorouracil-capecitabine-tegafur-flucytosine
- Argilés G, Tabernero J, Labianca R, et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol. 2020;31(10):1291-1305. doi:10.1016/j.annonc.2020.06.022
- Henricks LM, van Merendonk LN, Meulendijks D, et al. Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: A matched pair analysis. Int J cancer. 2019;144(9):2347-2354. doi:10.1002/ijc.32022