Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm?

Abstract

Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.

Phenotype versus genotype to optimize cancer dosing in the clinical setting—focus on 5‐fluorouracil and tyrosine kinase inhibitors

“…28,29 A recent review proposed that a polygenic algorithm may be required. 35 The issue of using only the four variants only for 5FU dose guidance highlights a mortality risk. If the dose is reduced because the screen is positive, the resulting 5FU exposure may be lower than Patients with DPD deficiency do not always have a UH2/U ratio below the "normal" threshold.…”

“…34 This is an additional risk to the introduction of genetics without any phenotype measurements as the relationship between gene expression and drug handling across these groups is currently unknown. 27,35,36 1.1.1 | Tyrosine kinase inhibitors Tyrosine kinase inhibitors (TKIs) are a large group of diversely structured compounds that have activity on a wide group of kinases.…”

“…For example, in the white population, ~3%–7% have a DPD deficiency and 0.01%–0.1% have a complete deficiency 33 ; around 8% of the African American population have a partial DPD deficiency 34 . This is an additional risk to the introduction of genetics without any phenotype measurements as the relationship between gene expression and drug handling across these groups is currently unknown 27,35,36 …”

“…There is accumulating evidence that additional variations in genes are involved in fluoropyrimidine pharmacokinetics and pharmacodynamics which also increase the risk of toxicity 28,29 . A recent review proposed that a polygenic algorithm may be required 35 …”

Implementing pharmacogenetic testing in fluoropyrimidine-treated cancer patients: DPYD genotyping to guide chemotherapy dosing in Greece

“…The fluoropyrimidines (FPs) 5-fluorouracil (5-FU) and its oral prodrug capecitabine (CAP) constitute an efficient treatment of solid tumors. Despite their well-documented efficacy, toxicity is a serious drawback of FP therapy ( Maslarinou et al, 2023 ). Toxicity rate in FP-treated patients has been reported to range between 10%–40%.…”