5PSQ-132 Pharmacogenetic-guided treatment in patients with dyhydropirymidine dehydrogenase deficiency

Background and Importance

Certain polymorphisms in DPYD gene are associated with partial or complete deficiency of dyhydropyrimidine dehydrogenase (DPD) enzyme and are linked to a greater risk of severe toxicities after fluoropyrimidines-based treatment. In 2020, the European Medicines Agency recommended that patients should be tested for the deficiency of DPD prior to treatment with fluorouracil, capecitabine or tegafur.

Aim and Objectives

To assess the prevalence of DPYD variants linked to DPD deficiency in cancer patients who are candidates to treatment with fluoropyrimidines and to evaluate the safety of pharmacogenetic guided treatment in patients with DPD deficiency.

Material and Methods

Prospective, observational study at a third level hospital. Cancer patients who underwent genotyping test for DPD deficiency between 1 November 2021 and 15 September 2022 were included. Demographic and clinical data were collected from electronic medical records. The polymorphisms studied were rs3918290, rs55886062, rs67376798 and rs75017182. DNA was obtained from peripheral blood samples and a pharmacogenetic analysis was performed using a real-time polymerase chain reaction technique. Patients were classified as normal, intermediate, and poor metabolisers according to the result of the test. Severe toxicities (grade 3-4 CTCAE 5.0) in intermediate and poor metabolisers were screened during the first two cycles of treatment.

Results

A total of 345 patients were included, 52.6% male, mean age 68.3 years (SD 11.7). The most frequent diagnoses were colon cancer (43.8%), rectal cancer (18.9%), pancreatic cancer (9.8%), breast cancer (8.0%) and gastric cancer (7.1%). Overall, 14 patients were classified as intermediate metabolisers: 8 patients were heterozygous for rs75017182, 3 patients were heterozygous for rs67376798, 2 patients were heterozygous for rs3918290 and one patient was homozygous for rs75017182. Eleven of the intermediate metabolisers were treated with fluoropyrimidine-based chemotherapy (three patients did not start treatment) with an initial 50% dose reduction and further adjustment based on initial tolerance to treatment. During follow up, these patients underwent treatment without suffering any grade 3-4 adverse event. No further dose reductions or treatment delays were required in this group of patients.

Conclusion and Relevance

Overall, 4.1% of the patients of our cohort had partial DPD deficiency. Treatment individualisation based on DPYD genotyping can help to avoid severe adverse events in patients treated with fluoropyrimidines.

References and/or Acknowledgements

Conflict of Interest

No conflict of interest