DPYD genotyping and DPD phenotyping before fluoropyrimidines

What it measures. Fluorouracil and its oral prodrug capecitabine are cleared by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. About three to eight per cent of Europeans carry one of four well-characterised variants (DPYD*2A, *13, c.2846A>T, HapB3) that halve enzyme activity; very rare people carry two and have no enzyme at all. Genotyping reads these variants from blood or saliva. France and some other countries instead or additionally measure plasma uracil, the enzyme's natural substrate, which rises when DPD is deficient whatever the genetic cause (phenotyping).

Evidence and guidelines. A prospective Dutch study of 1,103 patients (Lancet Oncology 2018) showed that reducing the starting dose in carriers cut severe toxicity to the level seen in non-carriers, and pharmacokinetic work showed exposure matched a normal dose. The Clinical Pharmacogenetics Implementation Consortium publishes the dose table: a 50 per cent starting dose reduction for heterozygous carriers and avoidance for homozygous or compound heterozygous patients, with the option to escalate on tolerance. In 2020 the European Medicines Agency recommended DPD testing before all fluoropyrimidine treatment; NHS England commissioned genotyping the same year, and most European countries followed. In the United States testing is recommended by several bodies and the drug labels warn of the risk, but it is not yet universal.

Who should have it and what changes. Everyone about to start fluorouracil, capecitabine or tegafur, whatever the cancer. A normal result changes nothing. A carrier result lowers the starting dose, with careful escalation if tolerated; a complete deficiency means choosing a different drug. The test costs tens of pounds, comes back in a few days to a week, and needs doing once in a lifetime. The main gaps are variants common in non-European populations that the standard four-variant panel misses, and delays when the result is not back before cycle one.