Optimizing fluoropyrimidine therapy through dihydropyrimidine dehydrogenase polymorphism testing

Abstract

Fluoropyrimidines (FP), including 5-fluorouracil and its prodrug capecitabine, are commonly employed in treating various solid tumors. Nonetheless, their use is frequently constrained by severe toxicities in 20%–30% of patients. Pharmacogenetic testing for dihydropyrimidine dehydrogenase (DPYD) deficiency, based on DPYD polymorphisms, has notably decreased severe adverse events, improving the safety of FP therapy. A recent D'Amato et al study evaluated the prevalence of DPYD polymorphisms and their effect on FP tolerability among Italian patients with gastrointestinal cancers. Although this study provided important insights into the significance of DPYD testing, its retrospective nature, inconsistency in testing DPYD variants, and lack of consideration for socioeconomic and confounding factors showed considerable limitations. Expanding the screening to include DPYD variants, addressing confounding biases through robust statistical analyses, and implementing prospective studies are critical next steps to strengthen the clinical evidence. Furthermore, the absence of a comprehensive cost-effectiveness analysis highlights the need for further financial assessments to advocate for broader implementation. We emphasized integrating DPYD-guided dosing, pre-treatment genetic counseling, and standardized testing procedures into clinical practice to improve patient outcomes and minimize treatment-related toxicities.

Key Words: Dihydropyrimidine dehydrogenase; Polymorphisms; Fluoropyrimidine; Drug adverse reactions; Drug toxicity; Economic evaluation; Genetic testing; Gastrointestinal cancers

Core Tip: Dihydropyrimidine dehydrogenase (DPYD) polymorphism testing is important for minimizing severe fluoropyrimidine (FP)-related toxicities in cancer patients. This pharmacogenetic strategy promotes personalized dosing, improving patient safety and tolerability. A study by D’Amato et al assessed the prevalence of DPYD polymorphisms and their impact on FP tolerability in patients with gastrointestinal malignancies. However, it is important to tackle study limitations such as retrospective designs, variability in testing, and confounding factors and assess the cost-effectiveness of including DPYD testing in standard clinical practice. Future studies should broaden genetic screening, provide pre-treatment counseling, and establish standardized methodologies to improve clinical relevance.

TO THE EDITOR

We read the dihydropyrimidine-dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine (FP) tolerability[1]. This study contributed important data to understanding how genetic polymorphisms in the dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) gene can influence the tolerability of FP-based chemotherapy in patients with gastrointestinal malignancies. Based on real-world data, the findings underscore the importance of implementing pharmacogenetic testing to mitigate treatment-related toxicities. Although the results are encouraging, several limitations deserve attention.

Importance of DPYD testing

FP, particularly 5-fluorouracil and its prodrug capecitabine, remain widely used in treating several solid tumors[2]. Although FP is often well tolerated by patients; however, severe toxicity is encountered in approximately 20%-30% of the patients. Tailoring doses for these individuals can reduce the incidence of severe FP-related toxicity[3]. Studies indicate that DPYD-guided personalized dose significantly decreases the incidence of severe toxicity and is suitable for routine clinical practice[3]. FP primarily leads to several adverse events: Hematological manifestation, such as leukopenia, anemia, and thrombocytopenia; gastrointestinal symptoms, including mucositis, diarrhea, stomatitis, nausea, and vomiting; and dermatological effects like dry skin, hair loss, and hand-foot syndrome. Most of these events are mild, reversible, and manageable with supportive care[3]. Moreover, measuring DPD enzyme activity can effectively identify patients with DPD deficiency. However, this assay is resource-intensive and time-consuming; hence, it is not routinely applied in clinical care[4].

Study limitations and future directions

In this article, there are some limitations and potential biases worth discussing. First, the study's retrospective nature limits the ability to determine causal relationships. Prospective studies provide more robust evidence to confirm these findings. Additionally, while the authors explored the four most common DPYD variants, including DPYD2A, DPYD13, HapB3, and c.2846A>T, other less common variants may also play a role in altering FP metabolism[5]. Hence, expanding the screening to include a broader panel of polymorphisms could provide a better understanding of the prevalence and impact of DPYD polymorphisms in this population.

Patients were divided into two cohorts based on whether they received DPYD testing. Still, it is worth considering external factors like socioeconomic status or regional variations in access to testing. In addition, there was variability in the types and number of DPYD polymorphisms tested in Cohort A, with some patients tested for only one polymorphism. In contrast, others were tested for up to five, which introduces inconsistency and detection bias, as patients with fewer polymorphisms tested may have unidentified variants that could affect treatment outcomes[6].

The study failed to address confounding bias that could directly affect the incidence of adverse events and dose adjustments. While the analysis adjusted for age, comorbidities, and renal function, patients' baseline performance status, prior treatments, and use of concurrent medications were not considered. These factors could affect patients' tolerance to FP, leading to biased conclusions about the association between DPYD polymorphisms and adverse events[7]. Additionally, socioeconomic factors influencing access to testing warrant further exploration. Hence, a well-planned statistical approach, such as multivariable regression analysis, could have better controlled for these confounding variables and provided more robust conclusions.

Economic implications

The study required to address the cost-effectiveness of universal DPYD testing. While studies have shown that dose adjustment based on DPYD genotyping can reduce the incidence of severe toxicities and lower the costs associated with managing adverse events[8,9], the authors did not provide a detailed analysis of the financial implications of implementing such testing in routine clinical practice. A comprehensive financial analysis incorporating these metrics strengthens the argument for routine testing.

CONCLUSION

In conclusion, the study highlights the importance of DPYD polymorphism testing in reducing adverse events in patients treated with FP. Addressing these limitations could improve the accuracy of future research and allow DPYD testing to be reliably implemented in clinical practice. Furthermore, future studies should prioritize genetic counseling for high-risk patients based on their DPYD status, conduct Mendelian randomization analyses, and work on standardizing testing procedures to improve clinical application.