Optimizing Care Through Pharmacogenomics: Part 3 of 3

On March 21, 2024, the FDA modified the black box warning for the injectable form of the chemotherapy drug 5-fluorouracil (5-FU) and an orally administered form of the medication, capecitabine. The new warning is designed to bolster awareness of specific gene variants, or “misspellings,” that can decrease the breakdown of 5-FU, increasing the likelihood of severe adverse side effects of the drug due to toxicity.

Over 80% of 5-FU is broken down or the enzyme dihydropyrimidine dehydrogenase or DPD metabolizes it. 1 The DPD enzyme is coded by the DPYD gene, and changes in the “spelling” of the gene can decrease or eliminate its activity. Patients who harbor DPYD gene variants that diminish enzyme activity are at an increased risk of severe side effects and death due to 5-FU toxicity from decreased breakdown of the drug.

What is 5-FU?

5-FU is a chemotherapy that mimics a molecule necessary for DNA replication in the cell. When the cell takes up 5-FU, it prevents the cell from making a building block essential for DNA replication. Because DNA replication is necessary for cells to divide, 5-FU effectively slows down the rapid cell division characteristic of many cancers. 5-FU is used to treat a variety of cancers, including:

  • Breast cancer
  • Colorectal and anal cancers
  • Pancreatic cancer
  • Stomach cancer
  • Head and neck cancers
  • Skin cancer

The FDA revised the black box warning for injectable 5-FU and orally administered capecitabine because of the potential for severe side effects and death in patients with decreased DPD activity and breakdown of 5-FU. While the official labeling for the chemotherapy has been changed, National Comprehensive Cancer Network (NCCN) treatment standards have not changed, slowing the integration of DPYD variant testing in oncology treatment guidelines.

Why aren’t physicians testing for DPYD variants?

Interestingly, a recent survey revealed that 96% of US oncologists would change 5-FU or capecitabine dosing for a patient with a known DPD deficiency. Still, only 3% of these clinicians test at least 10% for DPD deficiency in their patients who receive this chemotherapy. The same survey indicated that oncologists are reluctant to order DPYD gene testing for two primary reasons:

  • It is statistically unlikely that a patient will have a pharmacogenomic (PGx) variant or gene “misspelling” that affects how a medication functions in the body in the DPYD gene. DPD partial deficiency is observed in roughly two to eight percent of the general population. Approximately 0.3% of the Caucasian population has a complete DPD deficiency, putting this group at the highest risk of severe 5-FU side effects.
  • Pharmacogenomic testing of DPYD before treatment with 5-FU is not standard practice in the US, and few guidelines exist.

Despite the lack of DPYD pharmacogenomic testing guidelines in current NCCN practice standards, testing for DPD deficiency is standard in Europe. Some additional reasons oncologists forego DPD-deficiency testing include:

  • Lack of clarity regarding reduced 5-FU dosage effectiveness in patients with partial DPD deficiency — While dosage effectiveness for patients harboring specific DPYD variants may not be well communicated, Clinical Pharmacogenomics Implementation Consortium (CPIC) guidelines exist outlining current evidence-based therapeutic recommendations.
  • DPYD pharmacogenomic variant screening cost — Genomic screening for DPD deficiency is often considered investigational and may not be covered by traditional health insurance plans. Despite this, the cost of treating DPD-deficient patients with severe side effects far exceeds the cost of pharmacogenomic testing.
  • Patient care delay — While pharmacogenomic test results may delay treatment, test results are typically available within two to 10 days.
  • Affordability of treatment — Clinicians are unaccustomed to pharmacogenomic testing of patients for more accessible chemotherapy therapies.

Benefits of pharmacogenomic testing.

With all the pros and cons of pharmacogenomic testing, one point is clear: it can benefit many cancer patients based on variants they may or may not harbor in the DPYD gene. According to the updated black box warning, testing for genetic variants of DPYD should be considered to reduce the risk of severe adverse reactions before initiating 5-FU therapy. The decision to test should be based on the patient’s clinical status and clinical judgment.

Notably, pharmacogenomics doesn’t apply only to gene variants affecting the activity of the DPD enzyme — it applies to all genes affecting how our bodies metabolize, transport, and respond to medication. This personalized approach to healthcare and medication management can optimize therapies and reduce the likelihood of side effects and overall costs.

The DPYD gene is included in the Kadance Pharmacogenomic test. Clinical pharmacists can recommend customized therapies based on testing results, allowing the policyholder's healthcare team to optimize the patient’s overall treatment plan. Access to the healthŌme One Pharmacogenomic testing empowers policyholders and their oncologists to make informed, personalized treatment choices tailored to each unique individual.

The Kadance Precision Health Management program is designed to help you understand how your genetics influence medication interactions. This article is the third of a three-part series outlining how PGx currently optimizes medication therapy for patients. You can access part one of this series here and part two here.

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