Results: Patient with known DPYD variants requiring fluoropyrimidine-based chemotherapy
Genetic variants in the DPYD gene can cause complete or partial deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which can leave affected individuals prone to severe adverse reactions to fluoropyrimidine-based chemotherapy.
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?
- Guidance from the UK Systemic Anti-Cancer Therapy (SACT) Board (previously known as the UK Chemotherapy Board) makes the following recommendations for interpreting DPYD genotype results and adjusting prescriptions accordingly (see table 1).
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.
Resources
For clinicians
- Medicines and Healthcare Products Regulatory Agency: Drug Safety Update: 5-fluorouracil (intravenous), capecitabine, tegafur: DPD testing recommended before initiation to identify patients at increased risk of severe and fatal toxicity
- NHS England: Clinical commissioning urgent policy statement: Pharmacogenomic testing for DPYD polymorphisms with fluoropyrimidine therapies (PDF, 10 pages)
- UK SACT Board: Personalised medicine approach for fluoropyrimidine-based therapies (PDF, eight pages)
References:
- Amstutz U, Henricks LM, Offer SM and others. ‘Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update’. Clinical Pharmacology & Therapeutics 2018: volume 103, issue 2, pages 210–216. DOI: 10.1002/cpt.911