Last April 30th, the European Medicines Agency (EMA) published recommendations on accessing DPYD gene mutations prior to cancer treatment with fluoropyrimidines (5-fluorouracil, capecitabine, tegafur).

Fluoropyrimidines are among the most widely used cytotoxic drugs for treatment of solid tumours such as colorectal cancer, breast cancer, lung cancer and melanoma.

The reduction or absence of fluorouracil metabolism in certain patients can lead to severe and life-threatening side effects such as neutropenia, neurotoxicity, severe diarrhoea and stomatitis (10-40% of treated patients). In 1% of cases, fluorouracil toxicity becomes lethal.

A partial or complete deficiency of the key enzyme (DPD) for fluorouracil metabolism, resulting in the above side effects, is linked to DPYD gene mutations that can be found in 3-5% of European people.

The EMA underlines the importance of assessing the presence of DPYD mutations, which are predictive of toxicity, before starting cancer treatment with fluoropyrimidines given by injection or infusion in order to determine the right drug dose. These same recommendations have been published by other scientific associations, such as CPIC and DPWG.

DPYD variants recommended to be analysed are:

  • DPYD*2A (IVS14+1G>A, c.1905+1G>A)
  • DPYD*13 (c.1679T>G)
  • DPYD c.2846A>T
  • DPYD c.1236G>A (HapB3)
  • DPYD c.2194G>A

Approximately 7% of Europeans have at least one allele of the first four variants in the DPYD gene.

Patients with homozygous and compound heterozygous mutations have complete or near complete absence of DPD enzymatic activity and should avoid treatments with fluoropyrimidines. Patients with heterozygous DPYD variants, and therefore a partial DPD enzyme deficiency, should be treated with a lower initial dose of fluoropyrimidines.

The pharmacogenetic analysis of D