Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution.

Background: Fluoropyrimidines are metabolized in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the gene. About 7% of the European population is a carrier of gene polymorphisms associated with reduced DPD enzyme activity.

Aim: To assess the prevalence of polymorphisms and their impact on fluoropyrimidine tolerability in Italian patients with gastrointestinal malignancies.

Methods: A total of 300 consecutive patients with a diagnosis of gastrointestinal malignancy and treated with a fluoropyrimidine-based regimen were included in the analysis and divided into two cohorts: (1) 149 patients who started fluoropyrimidines after testing; and (2) 151 patients treated without testing. Among the patients in cohort A, 15% tested only the polymorphism, 19% tested four polymorphisms (2A, HapB3, c.2846A>T, and 13), and 66% tested five polymorphisms including 6.

Results: Overall, 14.8% of patients were found to be carriers of a variant, the most common being 6 (12.1%). Patients in cohort A reported ≥ G3 toxicities ( = 0.00098), particularly fewer nonhematological toxicities ( = 0.0028) compared with cohort B, whereas there was no statistically significant difference between the two cohorts in hematological toxicities ( = 0.6944). Significantly fewer chemotherapy dose reductions ( = 0.00002) were observed in cohort A compared to cohort B, whereas there was no statistically significant differences in chemotherapy delay.

Conclusion: Although this study had a limited sample size, it provides additional information on the prevalence of polymorphisms in the Italian population and highlights the role of pharmacogenetic testing to prevent severe toxicity.