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Example clinical scenario

A 64-year-old man has been diagnosed with colon cancer and was due to start adjuvant chemotherapy containing 5-fluorouracil. Prior to commencing treatment, however, pharmacogenomic testing identified the c.1905+1G>A variant, which predisposes him to fluoropyrimidine-associated toxicity.

What do you need to know?

  • Fluoropyrimidine-based chemotherapies include 5-fluorouracil, capecitabine and tegafur. They are widely used in the treatment of solid tumours such as breast, head and neck, colorectal and oesophago-gastric cancers. Between 5%–10% of patients receiving this treatment develop severe toxicity, which may include neutropenia, diarrhoea, mucositis and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome). These reactions can sometimes be life-threatening.
  • A significant proportion of adverse drug reactions are likely to be the result of genetic variation in the DPYD gene. This gene encodes DPD, the rate-limiting enzyme responsible for inactivation of the active metabolite.
  • There is substantial evidence linking the DPYD genotype with variability in DPD enzyme activity, affecting 5-fluorouracil clearance and 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; and
    • 1236G>A/HapB3DPYD (rs56038477).
  • Overall, a combined test for these four DPYD variants is estimated to predict 20%–30% of early onset life-threatening 5-fluorouracil toxicities.

What do you need to do?

Table 1: UK SACT Board recommendations for adjusting prescription of fluoropyrimidine therapy based on genotype

Genotype and alleles % DPD activity Recommended dose adjustment
c.1905+ 1G>A/c.1905+ 1G>A homozygous; c.1679T>G/ c.1679T>G homozygous; or c.1905+ 1G>A/ c.1679T>G compound heterozygous. 0% Complete DPD deficiency: fluoropyrimidine therapy not to be used for any of these genotypes. Use alternate therapies only.
c.1679T>G/c.2846A>T compound heterozygous; c.1905+ 1G>A/HapB3DPYD compound heterozygous; c.1679T>G/HapB3DPYD compound heterozygous; c.1236G>A/HapB3/c.1905+1G>A compound heterozygous; or  c.1905+ 1G>A/ c.2846A>T compound heterozygous. 10%–25% Consider alternate therapies. However, if your service has appropriate expertise and only with the use of therapeutic drug monitoring (TDM), use a starting dose of 10% of the standard dose. If the patient is tolerant after the first cycle, the dose can be titrated, based on toxicity, to a maximum of 25% of the target dose.
HapB3DPYD/HapB3DPYD homozygous; c.2846A>T/HapB3DPYD compound heterozygous; c.1236G>A/HapB3/c.2846A>T compound heterozygous; or  c.2846A>T/c.2846A>T homozygous. 10%–50% Consider alternate therapies. However, if your service has appropriate expertise and only with the use of therapeutic drug monitoring (TDM), use a starting dose of 10% of the standard dose. If the patient is tolerant after the first cycle, the dose can be titrated, based on toxicity, to a maximum of 50% of the target dose.
c.1905+ 1G>A (IVS14+1G>A) heterozygous or c.1679T>G (p.I560S) heterozygous 50% Use 50% of the standard dose or alternative therapy. If the patient is tolerant after the first cycle of 50% of the standard dose, increase the dose to a maximum of 75% of the standard dose over subsequent cycles.
c.2846A>T (p.D949V) heterozygous or c.1236G>A/HapB3DPYD heterozygous 50%–75% Use 50% of the standard dose or alternative therapy. If the patient is tolerant after the first cycle of 50% of the standard dose, increase the dose to a maximum of 75% of the standard dose over subsequent cycles. If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% may be possible, though caution is advised.
  • For any dose adjustments in practice, please refer to the UK SACT Board website to ensure that you are using the latest version of these recommendations.
  • Note that if a patient tests negative for DPYD variants, their absence does not eliminate the risk of toxicity, and the patient should be counselled accordingly. Individual patient factors and drug-drug interactions must also be considered when selecting appropriate regimens and dosing, using a shared decision-making approach.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
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  • Last reviewed: 02/07/2024
  • Next review due: 02/07/2025
  • Authors: Dr Azara Janmohamed, Dr Spoorthy Kulkarni
  • Reviewers: Dr Charlotte Barker, Professor Bill Newman