Should dermatologists screen for DPD deficiency before prescribing 5-FU?

The Dihydropyrimidine Dehydrogenase (DPYD) gene directly encodes the dihydropyrimidine dehydrogenase (DPD) enzyme which is responsible for 5-FU catabolism.

It's estimated that 5%–7% of patients carry a polymorphism in the DPYD gene, while ~0.4% of patients carry 2 DPYD variants. Because of the potential for toxicity in these patients, genetic testing is often performed prior to administering systemic 5-FU (for GI and other non-dermatological cancers). However, routine genetic testing is not typically performed prior to prescribing topical 5-FU.

A 2023 study by the American Society of Clinical Oncology (ASCO) sought to determine whether patients carrying DPYD variant alleles have increased risk of severe toxicity from topical 5-FU treatment, and to determine whether testing and dosing recommendations should also apply to topical 5-FU administration.

Results indicated that the risk of severe toxicity from topical 5-FU treatment is extremely low, even in patients with partial DPD deficiency. Their findings suggest there may limited potential clinical benefit of DPYD or DPD testing prior to topical 5-FU treatment.

Despite over 1,000 deaths per year being reported as having resulted from toxicity to systemic 5-FU, to date there has only been one case report of a fatality due to its topical application.

Although the ASCO's findings would not support routine genetic testing prior to topical 5-FU treatment, we should remain aware of its significance should any of our patients self-report polymorphism in the DPYD gene or DPD deficiency.

Likewise, we should avoid being quick to dismiss the occasional patient who reports "not feeling well" while undergoing treatment with topical 5-FU. Although unlikely, we simply cannot rule out that their symptoms aren't providing the first clue of impending systemic toxicity.