Results: Patient with oesophageal cancer and a constitutional (germline) DPYD variant

A 59-year-old man is diagnosed with metastatic oesophageal adenocarcinoma and referred for consideration of palliative chemotherapy. Routine DPYD testing is performed and demonstrates that the patient is heterozygous for a toxicity-associated DPYD variant.

• Constitutional (germline) testing of the DPYD gene should be performed in all patients being considered for fluoropyrimidine-based chemotherapy regimens.
• DPYD encodes the enzyme dihydropyrimidine dehydrogenase (DPD), which is required for effective metabolism of fluoropyrimidines.
• DPYD testing screens for four common genomic variants that have been associated with DPD deficiency in the European population.
• Standard dosing of fluoropyrimidine-based chemotherapy in individuals with such variants could lead to severe toxicity, with neutropenia, diarrhoea, mucositis and palmoplantar-erythema, and could be life threatening.

• The dosage adjustments required depend on the particular variant(s) detected and whether the patient has one or two variant alleles (homozygous, compound heterozygous or heterozygous).
• Patients who are heterozygous for a toxicity-associated DPYD variant should be started at a reduced dose of the fluoropyrimidine chemotherapy, according to the UK Chemotherapy Board guidelines.
• An alternative choice of chemotherapy should be considered in patients with biallelic variants in the DPYD gene (for example, they are homozygous for a single DPYD variant or are compound heterozygous, which means they have two different DPYD variants in trans). In specialist centres with careful therapeutic drug monitoring, a low starting dose with upward titration may be considered in individuals with certain homozygous or compound heterozygous genotypes. Dosing recommendations for specific genotypes are provided in the UK Chemotherapy Board guidelines.

For clinicians

• European Medicines Agency: EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine
• Gov.uk Drug Safety Update: 5-fluorouracil (intravenous), capecitabine, tegafur: DPD testing recommended before initiation to identify patients at increased risk of severe and fatal toxicity
• UK Chemotherapy Board: Personalised medicine approach for fluoropyrimidine-based therapies (PDF, eight pages)

For patients

• Cancer Research UK: DPD deficiency
• Macmillan Cancer Support: Fluorouracil (5FU)