DPYD Genotyping and Predicting Fluoropyrimidine Toxicity: Where do we Stand?

Abstract

Fluoropyrimidines (FPs) are antineoplastic drugs widely used in the treatment of various solid tumors. Nearly 30% of patients treated with FP chemotherapy experience severe FP-related toxicity, and in some cases, toxicity can be fatal. Patients with reduced activity of DPD, the main enzyme responsible for the breakdown of FP, are at an increased risk of experiencing severe FP-related toxicity. While European regulatory agencies and clinical societies recommend pre-treatment DPD deficiency screening for patients starting treatment with FPs, this is not the case with American ones. Pharmacogenomic guidelines issued by several pharmacogenetic organizations worldwide recommend testing four DPD gene (DPYD) risk variants, but these can predict only a proportion of toxicity cases. New evidence on additional common DPYD polymorphisms, as well as identification and functional characterization of rare DPYD variants, could partially address the missing heritability of DPD deficiency and FP-related toxicity.

Keywords::

• adverse drug reactions
• chemotherapy
• dihydropyrimidine dehydrogenase
• DPYD
• fluoropyrimidines
• fluoropyrimidine toxicity
• fluorouracil
• pharmacogenetics

Author contributions

All co-authors participated sufficiently in the work to take responsibility for the content including substantial contributions to the conception or design of the work; or the acquisition, analysis or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.