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Clinical features

Fluoropyrimidine-based chemotherapies are a large class of chemotherapeutics which are widely used in the treatment of solid tumours, such as breast, colorectal and gastric cancers. Between 5% and 10% of patients receiving this treatment develop life-threatening toxicities, which may include neutropenia, severe diarrhoea, mucositis and hand-foot syndrome.

A significant proportion of adverse reactions are likely to be the result of genetic variants in DPYD: the gene that encodes for dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for metabolism.

Genetics

Pharmacogenetics and fluoropyrimidine drugs

  • There is substantial evidence linking DPYD genotype with variability in DPD enzyme activity, 5-fluorouracil clearance, and 5-fluorouracil toxicity.
  • Severe fluoropyrimidine-related toxicity is associated with four major DPYD variants:
    • 1905+ 1G>A (rs3918290) DPYD*2A
    • 2846A>T (rs67376798)
    • 1679T>G (rs55886062) DYPD*13
    • 1236G>A/HapB3DPYD (rs56038477)
  • A recent study showed that the strongest impact on DPD activity was observed for c.1905+1G>A and c.1679T>G, with a 50% and 68% reduction in heterozygous carriers, respectively.
  • The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published recommendations and a detailed evidence summary linking various DPYD genotypes with DPD phenotype and associated toxicity.

Genomic testing for DPYD variants

  • Many different approaches can be used in the laboratory to test for four gene variants in DPYD. These approaches usually test only for these four variants and do not detect other changes in the DPYD gene.
  • An EDTA blood sample is collected and sent to the local Genomic Laboratory Hub for testing.
  • A combined test for these four DPYD variants is estimated to predict 20–30% of early-onset life-threatening 5-fluorouracil toxicities. It is also estimated to predict severe (grade ≥3) fluoropyrimidine toxicities.
  • The absence of these four genetic variants does not eliminate the risk of toxicity. Individual patient factors and drug-drug interactions must also be considered when selecting appropriate regimens and dosing, using a shared decision-making approach.
  • Information on the test and appropriate genomic testing technology is updated within the National Genomic Test Directory.

Referring patients for genomic testing

  • The Medicines and Healthcare Products Regulatory Agency (MHRA) recommends that all patients should be tested for partial or complete DPD deficiency before initiation of 5-fluorouracil (intravenous), capecitabine or tegafur.
  • Patients only require this test to be carried out once, at the start of their first fluoropyrimidine treatment, as the results remain applicable to subsequent fluoropyrimidine cycles and future treatment regimens containing a fluoropyrimidine.
  • Chemotherapy team members must ensure that each patient due to receive fluoropyrimidine has a DPYD genetic test prior to starting treatment. Entrusted members should be able to explain the test to the patient, order the test and then follow up with the outcome.
  • Prescribing action based on DPD activity score, as follows:
    • DPYD normal metabolizer (activity score 2) implies normal DPD activity, and hence no indication for change in dose or therapy.
    • DPYD intermediate metabolizer (activity score 1.5 and activity score 1) implies decreased DPD activity (30-70% that of normal population) due to one normal and one variant gene copy, which leads to increased risk of severe or even fatal drug toxicity. The dose must be reduced by 50% for activity score 1 and by 25% to 50% for activity score 1.5.
    • DPYD poor metabolizer indicates complete DPD deficiency (activity score 0 and 0.5) due to two variant copies of the DPYD gene, and hence an increased risk of severe or even fatal drug toxicity when treated with fluoropyrimidine drugs. The recommendation would be to avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens. If no fluoropyrimidine-free regimens are considered a suitable therapeutic option, however, 5-fluorouracil administration at a strongly reduced dose combined with early therapeutic drug monitoring may be considered.

Tagged: Colorectal cancer, Breast cancer, Gastric cancer, Therapies

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  • Last reviewed: 09/05/2022
  • Next review due: 09/05/2023
  • Authors: Dr Nicola Campbell, Dr Spoorthy Kulkarni
  • Reviewers: Dr Ellen Copson, Professor Bill Newman