A new meta-analysis published in BMC Cancer on September 23, 2024 provides compelling evidence that genetic variants in the DPYD gene significantly increase the risk of mortality in cancer patients receiving fluoropyrimidine-based chemotherapy. The study, conducted by researchers at several institutions in Brazil, analyzed data from 36 previous studies involving over 16,000 patients to assess the relationship between DPYD variants and treatment-related deaths.
Fluoropyrimidines like 5-fluorouracil (5-FU) and capecitabine are commonly used chemotherapy drugs for various solid tumors, particularly colorectal, breast, and head and neck cancers. These drugs rely on the enzyme dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, for their metabolism. Certain genetic variants in DPYD can cause DPD deficiency, leading to impaired drug metabolism and increased risk of severe toxicity.
The meta-analysis aimed to examine treatment-related mortality in cancer patients undergoing fluoropyrimidine chemotherapy, comparing those with and without DPD deficiency. The researchers systematically searched multiple databases, including PubMed, Cochrane, Embase, and Web of Science, ultimately selecting 36 prospective and retrospective studies that met their inclusion criteria. To be included, studies had to assess at least one of the main DPYD variants of interest: DPYD*2A (rs3918290), DPYD p.D949V (rs67376798), DPYD*13 (rs55886062), and DPYD HapB3 (rs75017182).
The analysis encompassed a total of 16,005 patients, with the vast majority (86.49%) having colorectal cancer. Other cancer types represented included gastrointestinal (3.09%), breast (2.55%), pancreatic (1.76%), and head and neck (0.35%). The study population was predominantly European (78.38%), with smaller proportions from Asia (18.92%), the Americas (2.7%), and Oceania (2.7%).
Among the study participants, 587 (3.62%) were found to carry at least one of the DPYD variants of interest. The researchers identified 27 deaths attributed to fluoropyrimidine toxicity across all studies. Strikingly, 13 of these deaths occurred in carriers of DPYD variants, while 14 occurred in non-carriers. Statistical analysis revealed that carriers of DPYD variants had a significantly higher risk of treatment-related mortality, with an odds ratio of 34.86 (95% CI: 13.96-87.05, p < 0.05).
The study's findings reinforce the critical importance of DPYD genotyping in predicting severe toxicity risk for patients undergoing fluoropyrimidine-based chemotherapy. The authors suggest that identifying mutations associated with DPD deficiency could help clinicians adjust medication doses before initiating treatment, potentially reducing the occurrence of severe side effects and fatalities.
While the meta-analysis provides robust evidence for the association between DPYD variants and treatment-related mortality, it does have some limitations. The majority of included studies focused on colorectal cancer patients, which may limit the generalizability of results to other cancer types. Additionally, the predominance of European study populations restricts the understanding of how DPYD variants may impact patients of different ethnicities.
Despite these limitations, the study's conclusions have significant potential clinical impacts. The authors emphasize the importance of implementing pharmacogenetic screening for DPYD variants in cancer patients before initiating fluoropyrimidine-based chemotherapy. This approach could allow for personalized dose adjustments or alternative treatment strategies for patients identified as high-risk carriers, potentially improving treatment safety and efficacy.
The meta-analysis aligns with and strengthens existing guidelines from expert groups like the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG), which recommend DPYD genotyping and dose adjustments based on variant status. The study's findings may encourage wider adoption of these practices in oncology settings.
Furthermore, the research highlights the need for more comprehensive studies on DPYD variants in diverse patient populations. While the study provided some insights into differences in variant frequencies between European and Asian populations, more research is needed to fully understand the impact of ethnicity on DPD deficiency and fluoropyrimidine toxicity risk.
In conclusion, this meta-analysis provides strong evidence supporting the clinical utility of DPYD genotyping in predicting and potentially preventing severe toxicity and mortality in cancer patients receiving fluoropyrimidine-based chemotherapy. As personalized medicine continues to advance in oncology, integrating pharmacogenetic testing for DPYD variants into standard clinical practice could significantly improve patient safety and treatment outcomes. However, further research is needed to refine genotype-guided dosing strategies and to better understand the implications of DPYD variants across diverse patient populations and cancer types.
References
de Moraes FCA, de Almeida Barbosa AB, Sano VKT, Kelly FA, Burbano RMR. Pharmacogenetics of DPYD and treatment-related mortality on fluoropyrimidine chemotherapy for cancer patients: a meta-analysis and trial sequential analysis. BMC Cancer. 2024;24(1):1210. Published 2024 Sep 30. doi:10.1186/s12885-024-12981-5
