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

A 76-year-old man is diagnosed with localised colorectal cancer. Right hemicolectomy reveals a stage-three colorectal cancer and adjuvant chemotherapy is discussed. Constitutional (germline) hotspot testing of the DPYD gene reveals a pathogenic variant.

• DPYD encodes the enzyme dihydropyrimidine dehydrogenase (DPD), which is required for effective metabolism of fluoropyrimidines.
• Patients with pathogenic constitutional (germline) DPYD variants will have DPD deficiency, which affects their ability to metabolise fluoropyrimidines.
• This can result in severe and sometimes life-threatening toxicity if fluoropyrimidine-based chemotherapy is prescribed at the standard dose.
• Constitutional (germline) testing of the DPYD gene should be performed in all patients being considered for fluoropyrimidine-based chemotherapy regimens.

Management of the current cancer

• Adjuvant chemotherapy for colorectal cancer usually consists of a fluoropyrimidine doublet (5-fluorouracil with either oxaliplatin or irinotecan, or capecitabine with oxaliplatin).
• Patients with constitutional (germline) pathogenic variants in the DPYD gene have DPD deficiency and cannot metabolise fluoropyrimidine as efficiently as individuals with wild-type DPYD. This results in serious and sometimes life-threatening toxicity including diarrhoea, mucositis and skin reactions if fluoropyrimidine chemotherapy is given at standard doses.
• Depending on the DPYD variant(s) identified, and the associated reduction in DPYD activity, either:
  • the fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) is commenced at a reduced dose (the dose may be increased for the second cycle and subsequent cycles according to tolerance of the first cycle); or
  • an alternative drug, such as trifluridine or tipiracil, may be recommended.
• Detailed recommendations of dosing modifications are provided by the UK Chemotherapy Board.

Management of the family's risk

• DPD deficiency may arise as a consequence of heterozygous (monoallelic) or compound heterozygous or homozygous (biallelic) DPYD pathogenic variants.
  • Individuals with biallelic DPYD variants (autosomal recessive DPD deficiency) are variably affected. Most remain asymptomatic, other than having an increased sensitivity to fluoropyrimidines, but some demonstrate serious problems (including seizures, developmental delay, hypotonia and microcephaly) manifesting any time from birth.
• Cascade testing of the family is not usually required, as all patients being considered for fluoropyrimidine chemotherapy should now undergo DPYD testing prior to commencing treatment. It is good practice for patients to make relatives aware, however, particularly in the context of inherited cancer susceptibility syndromes.

Note that the above management advice is relevant in both the adjuvant and metastatic settings, providing fluoropyrimidine chemotherapy is indicated.

For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.

For clinicians

• European Society for Medical Oncology: EMA provides new testing and treatment recommendations for fluorouracil, capecitabine and tegafur
• NHS England: National Genomic Test Directory
• UK Chemotherapy Board: Personalised medicine approach for fluoropyrimidine-based therapies (PDF, eight pages)

References:

• Innocenti F, Mills SC, Sanoff H and others. ‘All you need to know about DPYD genetic testing for patients treated with fluorouracil and capecitabine: A practitioner-friendly guide‘. Journal of Clinical Oncology: Oncology Practice 2020: volume 16, issue 12, pages 793–798. DOI: 10.1200/OP.20.00553

For patients

• Cancer Research UK: DPD deficiency