New way to find which patients at risk of highly toxic chemotherapy side effects

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Routine blood tests can now play a crucial role in identifying patients at high risk of severe and potentially fatal side effects from common chemotherapy treatments.

A genetic anomaly related to the DPYD gene can make some individuals more susceptible to these adverse reactions. However, without clinical guidelines mandating DPYD testing, its adoption has been limited.

Researchers at the University of Michigan Health Rogel Cancer Center have developed a monitoring system that utilizes a research genetics program to raise alerts about cancer patients who may possess the DPYD gene variant.

The goal is to alert oncologists to patients at risk and encourage more testing to prevent adverse reactions and improve patient outcomes.

The Importance of DPYD Testing: Saving Lives

Chemotherapies like 5-fluorouracil and capecitabine, known as fluoropyrimidine-based chemotherapies, rely on an enzyme encoded by the DPYD gene for metabolism.

Approximately 6% of individuals have a genetic variant in DPYD that causes slower metabolism of fluoropyrimidine, leading to severe and potentially fatal toxicity.

While the percentage may seem small, the impact is substantial, with over half of those affected experiencing severe toxicity, and about 2% dying as a result.

Testing for DPYD gene variants can identify patients at high risk of life-threatening toxicity from these chemotherapy drugs.

Oncologists can then adjust treatment by either starting with lower doses to minimize side effects or opting for alternative medications.

DPYD testing involves a simple blood sample submitted to a clinical lab, with results typically returned within a few days, at a cost ranging from $250 to $500, often covered by insurance.

Leveraging the Michigan Genomics Initiative: An Innovative Approach

The University of Michigan researchers tapped into the Michigan Genomics Initiative, a genetic database linked to patients’ electronic health records.

This initiative collects genetic data from participants who provide blood or saliva samples for genetic screening and consent to be contacted for additional research studies.

The researchers searched this database for participants whose genetic data suggested a potential DPYD variant, flagging 3,583 suspected carriers.

To confirm the anomaly, the team established an alert system to notify oncologists when these patients were about to be prescribed fluorouracil or capecitabine.

The study team would then reach out to the oncologists to discuss the treatment plan and suggest clinical DPYD testing for the patients.

Promising Results and the Road Ahead

The monitoring system successfully triggered 57 notifications in two years, leading to one patient being confirmed as high-risk for toxicity.

This patient received chemotherapy at a reduced dosage, which was well-tolerated, and eventually escalated to three-quarters of the standard dose.

The researchers hope to encourage all clinicians to order DPYD testing, believing that the evidence supports its importance. While the FDA and clinical guidelines agencies have not mandated DPYD testing, advocates are working to expand its use.

The Michigan Genomics Institute monitoring system serves as a model for other research institutions until DPYD testing becomes a requirement.

Despite the challenges of changing clinical practice without specific guidelines, the potential to save lives and prevent severe side effects makes DPYD testing a crucial consideration in chemotherapy treatment decisions.

European clinical care guidelines already recommend DPYD testing before initiating fluoropyrimidine chemotherapy, demonstrating its importance on a global scale.

The University of Michigan team continues to monitor participants in the Michigan Genomics Initiative for potential DPYD testing, taking steps towards safer chemotherapy administration for all.

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The research findings can be found in Clinical Pharmacology & Therapeutics.

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