Background and Importance Dihydropyrimidine dehydrogenase (DPYD) is a key enzyme in the metabolism of fluoropyrimidines. Patients with deficiency in DPYD are at great risk of severe adverse events when treated with fluoropyrimidines (5-fluorouracil, capecitabine). It is recommended that patients are screened for the most common variants in this gene before initiating chemotherapy. However, some patients still develop early serious toxicities.

Aim and Objectives We report the result of a clinical pharmacogenomics programme targeted to patients who developed toxicity with fluoropyrimidines. The aim was to identify rare variants in the DPYD gene associated with severe toxicity, and to provide patients and clinicians with pharmacogenomic counselling.

Material and Methods Patients who suffered severe toxicities (grade≥3) during their first three cycles of treatment with fluoropyrimidines were identified by their oncologist or oncology pharmacist. They were all negative for the four recommended variants (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A). A methodology for sequencing the 23 exons of DPYD was developed by the Pharmacogenomics Unit, integrated in the Hospital Pharmacy Department. The study was approved by the local Ethics Committee. Patients were informed and gave consent to participate in the programme.

Results Since 2017, 91 patients have been included in the programme and 32 variants in DPYD were identified. Nine of these 32 variants were associated with the development of severe toxicity in these patients (c.257C>T, c.704G>A, c.775A>G, c.851G>T, c.1977–1984-CTCCAGAA>C, c.2197insA, c.2242+1G>T, c.2324T>G and c.2087G>A). As a result of the programme, the cause for toxicity was found in 10% (9/91) of patients. The results of the test together with a dose adjustment recommendation were communicated to patients and included in their electronic medical record to make the information available for the oncologist and the rest of the clinical team.

Conclusion and Relevance This programme helped us to identify uncommon variants in the DPYD gene that were associated with toxicity to fluoropyrimidines in a clinical practice setting. These variants will be included in a new test that is currently under development. We believe that performing this extended test before initiating treatment can improve patient safety.

Conflict of Interest No conflict of interest.