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DNA double helix

Despite decades of use, cancer chemotherapy treatments remain a tight balance between maximising effectiveness while minimising the toxicity burden for the patient. Fluoropyrimidines, for instance, are chemotherapy drugs which are used to treat various cancers (including breast, colorectal and oesophago-gastric cancers) but cause severe or life-threatening adverse effects for around 10-40% of treated patients. These effects include nausea, vomiting, diarrhoea, inflammation of the mouth and gut, low white blood cells (neutropenia), and death.

Patients with rare gene variants in the dihydropyrimidine dehydrogenase (DPYD) enzyme are significantly more likely to experience these adverse effects because they metabolise fluoropyrimidine-based chemotherapy drugs more slowly. Pre-emptively testing for the presence of these DPYD gene variants before patients start fluoropyrimidine-based chemotherapy could enable clinicians to reduce the dose or select alternative therapies for these patients.

Several European countries, besides the European Medicines Agency, recommend upfront DPYD genetic testing, however its adoption into clinical practice has been slow so far. A key concern is the lack of evidence that the benefits of universal testing would outweigh the costs.

To investigate this, researchers from the Health Economics Research Centre (HERC) at Oxford Population Health led a toxicity and cost evaluation of the ToxNav test, which can detect 18 different DPYD gene variants. The study used hospital records of all cancer patients in Oxford University Hospitals (OUH) NHS Trust who received fluoropyrimidine-based chemotherapy from June 2017 to September 2020. The team compared 466 patients who underwent ToxNav testing before starting treatment with 1,556 patients who did not to assess the impact of upfront DPYD testing on adverse effects and associated hospital costs.

The results of the analysis are published today in BMC Cancer.

Key results

  • Among the tested participants, 16 (3%) were identified as having critical/high risk DPYD gene variants. Of these participants, 73% had the dose of their first cycle of fluoropyrimidine-based chemotherapy reduced.
  • Overall, participants in the ToxNav group had a reduced likelihood of experiencing moderate or severe anaemia (41% and 45% less respectively), and of experiencing pain for more than 4 days a week (50% less). However, the likelihood of mild neutropenia (low white blood cell count) increased by 73% in this group.
  • Driven by patients with critical/high risk DPYD variants, the average reduction in hospital costs was over £20,000 for participants in the ToxNav group. These savings were mainly due to the costs of chemotherapy treatment reducing by 12% (£9,765), the costs of non-elective hospital admissions reducing by 23% (£2,331), and the costs of critical care reducing by 21% (£1,219) per patient.

According to the research team, since a ToxNav test is expected to cost between £100 and £300 per patient, these results demonstrate that introducing mandatory DPYD testing would be highly cost-effective. In England alone, 38,000 patients start fluoropyrimidine-based chemotherapy each year (Public Health England, 2020), indicating that universal testing could bring significant cost savings to the NHS.

Associate Professor Apostolos Tsiachristas, who led the study, said: ‘This study provides evidence from a real-world setting that upfront screening for DPYD variants can enable the provision of personalised chemotherapy treatment to effectively avert toxic side effects for high risk patients. Overall, this leads to substantial hospital cost savings per cancer patient treated with fluoropyrimidine-based chemotherapy. However, these savings are only captured if the dose management of these drugs in response to detecting these variants is standardised and regulated.’