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Therapies

Fluoropyrimidine-based chemotherapies

Genetic variants in the DPYD gene can make individuals susceptible to severe adverse (and sometimes life-threatening) reactions to fluoropyrimidine-based chemotherapy.

Overview

Genetic variants in the DPYD gene can cause complete or partial deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme. DPD deficiency makes individuals prone to severe adverse reactions to fluoropyrimidine-based chemotherapies (such as 5-fluorouracil, capecitabine and tegafur). The associated effects can be life-threatening in some cases.

Clinical context

Fluoropyrimidine-based chemotherapies are a large class of chemotherapeutics that 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, severe diarrhoea and vomiting, mucositis and hand-foot syndrome (palmar-plantar erythrodysesthesia syndrome).

A significant proportion of adverse drug reactions are likely to be the result of inter-individual genetic variation in the DPYD gene. This gene encodes DPD, the rate-limiting enzyme responsible for the inactivation of the active metabolite of fluoropyrimidine-based chemotherapy.

Fluoropyrimidine-based chemotherapies and pharmacogenomics

  • There is substantial evidence linking DPYD genotypes with variability in DPD enzyme activity, which affects 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).
  • A recent study showed that the strongest impact on DPD activity was observed in c.1905+1G>A and c.1679T>G, with a 50% and 68% reduction in people with heterozygous variants respectively.
  • Overall, combined testing for these four DPYD variants predicts an estimated 20%–30% of early onset life-threatening 5-fluorouracil toxicities.

Genomic testing for DPYD variants

  • The Medicines and Healthcare products Regulatory Agency recommends that all patients should be tested for partial or complete DPD deficiency before initiation of intravenous 5-fluorouracil, capecitabine or tegafur.
  • Information about the approved test for DPD deficiency is updated regularly within the National Genomic Test Directory.
  • This test only needs to be carried out once, prior to a patient’s first fluoropyrimidine treatment, because the results remain valid for all future fluoropyrimidine-containing treatment regimens.
  • Chemotherapy team members must ensure that each patient due to receive fluoropyrimidine has had a DPYD test prior to starting treatment. Trained team members should be able to explain the test to the patient, order the test and then follow up on the outcome.
  • Detailed guidelines on which patients should receive a DPYD test and the clinical interpretation and management of the test results has been published by the UK Systemic Anti-Cancer Therapy (SACT) Board (previously known as the UK Chemotherapy Board). These recommendations are summarised below in table 1 (please refer to the SATC Board website to check the latest recommendations when interpreting results for your own patients).

Table 1: Summary of dose adjustment recommendations according to DPD genotype (adapted from UK SACT Board)

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 the genotypes. Use alternate therapy 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 therapy. In some centres with the expertise and therapeutic drug monitoring, a starting dose of 10% of the target dose can be considered. If the patient is tolerant after the first cycle, the dose can be titrated, based on toxicity noted 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 therapy. In some centres with the expertise and therapeutic drug monitoring, a starting dose of 10% of the target dose can be considered. If the patient is tolerant after the first cycle, the dose can be titrated upwards, based on toxicities noted 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% 50% dose reduction or alternative therapy. If tolerant after the first cycle, dose increment to a dose of 75% of the target dose over subsequent cycles.
c.2846A>T (p.D949V) heterozygous or c.1236G>A/HapB3DPYD heterozygous 50%–75% 50% dose reduction or alternative therapy. If the patient is tolerant after the first cycle, the dose can be increased to a maximum of 75% of the target 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 but caution is advised.
  • An absence of the relevant genetic variants does not eliminate the risk of toxicity, and patients 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.
  • Clinical Pharmacogenetics Implementation Consortium recommendations and a detailed evidence summary linking various DPYD genotypes with DPD phenotype and associated toxicity are available (see the resources section below).
  • For more information about genomic testing for DPYD variants and how the identification of variants affects patient management, see Presentation: Patient requiring fluoropyrimidine-based chemotherapy and Results: Patient with known DPYD variants requiring fluoropyrimidine-based chemotherapy.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 15/08/2023
  • Next review due: 15/08/2025
  • Authors: Dr Azara Janmohamed, Dr Spoorthy Kulkarni
  • Reviewers: Charlotte Barker