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

Abstract

BACKGROUND

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

AIM

To assess the prevalence of DPYD 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 DPYD testing; and (2) 151 patients treated without DPYD testing. Among the patients in cohort A, 15% tested only the DPYD2A polymorphism, 19% tested four polymorphisms (DPYD2A, HapB3, c.2846A>T, and DPYD13), and 66% tested five polymorphisms including DPYD6.

RESULTS

Overall, 14.8% of patients were found to be carriers of a DPYD variant, the most common being DPYD6 (12.1%). Patients in cohort A reported ≥ G3 toxicities (P = 0.00098), particularly fewer nonhematological toxicities (P = 0.0028) compared with cohort B, whereas there was no statistically significant difference between the two cohorts in hematological toxicities (P = 0.6944). Significantly fewer chemotherapy dose reductions (P = 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 DPYD polymorphisms in the Italian population and highlights the role of pharmacogenetic testing to prevent severe toxicity.

Keywords: Dihydropyrimidine dehydrogenase; DPYD polymorphisms; Fluoropyrimidine; Caucasian population; Gastrointestinal cancers

Core Tip: In this retrospective study, we report the prevalence of DPYD polymorphisms in a real-world population of patients treated for gastrointestinal malignancies and their impact on fluoropyrimidine tolerability. Furthermore, we demonstrate that the presence of polymorphisms in the DPYD gene, which encodes dihydropyrimidine dehydrogenase, leads to an increased risk of G3/G4 nonhematologic toxicity and more frequent dose reductions. We did not find a significant difference in chemotherapy delay.