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The Importance of DPYD Pharmacogenetic Testing in Cancer Care: Optimizing Treatment and Minimizing Toxicity

DPYD pharmacogenetic (PGx) testing identifies patients at higher risk of developing severe drug toxicity from treatment with fluoropyrimidine chemotherapy drugs such as fluorouracil (5-FU) and its oral version, capecitabine.



Woman comforting cancer patient at table.


DPYD PGx Testing Explained

Genetic variations in the DPYD gene can lead to decreased dihydropyrimidine dehydrogenase (DPD) enzyme activity. The DPD enzyme is responsible for metabolizing 5-FU and when not functioning properly, severe, even life-threatening toxicity can occur (1).


DPYD testing identifies the genetic variations that lead to this deficiency, allowing providers to adjust the patient’s treatment regimen accordingly.


Prevalence of DPD Deficiency

Fluorouracil injection (5-FU) and its oral version, capecitabine, are commonly used for treatment of solid cancers such as colorectal, breast, lung and other malignancies.


DPYD gene variants are found in up to 32% of the population (2). These variations lead to DPD enzyme deficiency and thus reduced ability to metabolize fluoropyrimidines such as 5-FU and its oral version, capecitabine, putting the patient at an increased risk for severe toxicity (3). 


Patients with DPYD gene variations have been shown to have a 25.6 times increased risk of treatment-related death (4).


The Benefits of DPYD PGx Testing

A simple cheek swab to test for genetic variations in the DPYD gene before administering 5-FU or capecitabine to patients can:

  • Identify patients at higher risk of experiencing severe, even fatal, toxicity

  • Personalize the patient’s treatment regimen

  • Maximize the benefit of patients’ chemotherapy treatment

  • Increase patient safety


Clinical Adoption of DPYD PGx Testing

The FDA has updated the safety labeling for 5-FU and capecitabine to alert to the risk of serious adverse reactions for patients with DPD deficiency (5). The updated labeling suggests testing for genetic variants of DPYD should be considered by healthcare providers before administering 5-FU or capecitabine (6).


The European Society for Medical Oncology has recommended genetic testing prior to treatment with fluoropyrimidines since 2020 (7). Although cancer societies in the United States have not recommended systemic DPYD testing, some medical institutions have begun to implement testing. 


Selecting a Laboratory for DPYD PGx Testing

Clinical laboratories may offer DPYD PGx testing as part of their comprehensive PGx panel or as part of a dedicated oncology panel.


Key considerations for healthcare providers when selecting a laboratory for DPYD PGx testing include:

  1. Verify the laboratory is CLIA compliant.

  2. Ensure the laboratory using a technology that can detect key DPYD alleles.

  3. Identify the expected turnaround time for sample testing as treatment may be dependent upon sample results.

  4. Verify the source of guidelines and level of scientific evidence used to develop clinical recommendations related to the drugs affected (5-FU and capecitabine).

Conclusion

DPYD pharmacogenetic testing is a simple and effective way to reduce the risk of fluoropyrimidine toxicity and personalize cancer treatment. It allows doctors to tailor therapy based on a patient's individual genetic makeup, maximizing the benefits of chemotherapy while minimizing the risk of severe adverse events.


Always consult with a healthcare provider before making any changes to your medications or treatment regimen.


References

  1. Accessed July 2, 2024. https://ascopubs.org/doi/10.1200/OP.20.00553

  2. Accessed July 2, 2024. https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/

  3. Accessed July 2, 2024. https://emedicine.medscape.com/article/1746057-overview#:~:text=Dihydropyrimidine%20dehydrogenase%20(DPD)%2C%20an,for%20treatment%20of%20solid%20cancers.

  4. Accessed July 2, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8649021/

  5. Accessed July 2, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-safety-labeling-changes-regarding-dpd-deficiency-fluorouracil-injection-products#xd_co_f=Njg3NmEyZDItMmEyNS00MDYzLWEwYjctNGUxODhkMmFjNTY5~

  6. Accessed July 2, 2024. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling 

  7. Accessed July 2, 2024. https://www.esmoopen.com/article/S2059-7029(23)00419-2/fulltext

  8. Accessed July 2, 2024. https://www.cms.gov/medicare/quality/clinical-laboratory-improvement-amendments 

  9. Accessed July 2, 2024. https://www.pharmgkb.org/vip/PA166169426 


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