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

A 68-year-old female with metastatic oestrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer that has been treated with a first-line cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor and endocrine therapy now has progressive metastatic liver disease. Tumour biopsy testing for a PIK3CA variant was negative. Treatment with capecitabine is discussed and constitutional (germline) DPYD testing is performed, which shows a pathogenic variant.

• DPYD encodes the enzyme dihydropyrimidine dehydrogenase (DPD), which is required for effective metabolism of fluoropyrimidine-based chemotherapies.
• 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.

Management of the current cancer

• Capecitabine is a fluoropyrimidine that is used in the treatment of metastatic breast cancer in all subtypes.
• Depending on the DPYD variants identified and the associated reduction in DPYD activity, either:
  • the fluoropyrimidine chemotherapy (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 treatment is used.
• Full details of recommended dosing adjustments are described by the UK Chemotherapy Board.
• 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), which can manifest any time from birth.
• Cascade testing of the patient’s family members 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 of their diagnosis, however, particularly in the context of inherited cancer susceptibility syndromes.

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‘. Oncology Practice 2020: volume 16, issue 12, pages 793–798. DOI: 10.1200/OP.20.00553

For patients

• Cancer Research UK: DPD deficiency