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Testing for genetic variant flags patients at risk of chemotherapy side effects

Contributed by Nicole Fawcett

By identifying patients with the DPYD gene variant, oncologists can alter treatment to avoid life-threatening toxicity

Close up of an IV drip

A routine blood test can determine when a genetic anomaly puts someone at high risk of dangerously toxic side effects from a common chemotherapy.

But with no clinical guidelines or requirements to test for the gene, uptake has been limited.

Researchers from the University of Michigan Health Rogel Cancer Center have developed a monitoring system using a research genetics program to trigger alerts about cancer patients suspected to have the DPYD gene variant.

They hope that alerting oncologists to patients at risk could lead to more testing.

“Pharmacogenetics can help inform clinical treatment decisions. In the case of DPYD testing, it can be lifesaving,” said study author Daniel L. Hertz, Pharm.D., Ph.D., associate professor of pharmacy at the University of Michigan College of Pharmacy.

“Unfortunately, the U.S. Food and Drug Administration does not recommend routine testing, which creates a barrier for oncologists to adopt this practice. We wanted to create a strategy to make it easier.”

Fluoropyrimidine-based chemotherapies, which include 5-fluorouracil and capecitabine, are metabolized by an enzyme encoded by the DPYD gene.

About 6% of people have a genetic variant in DPYD that makes them metabolize fluoropyrimidine more slowly, which can lead to severe and fatal toxicity.

It’s a small number but the impact is serious: more than half experience severe toxicity and about 2% die.

Testing for variants in this gene can identify patients who are at this unacceptably high risk of severe, life-threatening toxicity from these drugs.

Oncologists can then begin treatment at lower doses to limit side effects or opt for another drug. Testing involves a blood sample submitted to a clinical lab. Results are returned within several days. Cost is $250-$500, which may be paid by insurance.

Researchers tapped into the Michigan Genomics Initiative, a research genetic database at the University of Michigan that is tied to patients’ electronic health record.

Participants provide blood or saliva for genetic screening and agree to be recontacted to enroll in additional research studies.

Rogel researchers searched the database for participants whose genetic data suggests they may have a DPYD variant, flagging 3,583 suspected carriers.

Because the participants had undergone a research-grade test, the anomaly would need to be confirmed through a more rigorous clinical test.

The team set up an alert system to notify when those patients were about to be prescribed fluorouracil or capecitabine.

When an alert came, the study team reached out to the oncologist to confirm the treatment plan and ask patients to consider clinical DPYD testing.

“We got a ping on the very first day,” Hertz said.

That patient underwent DPYD testing and was confirmed to be at high risk of toxicity.

Their oncologist initiated 5-fluorouracil at half the standard dose, which was well-tolerated and eventually escalated to three-quarters the standard dose.

In two years, the system triggered 57 notifications.

“We want all clinicians to order testing because we think evidence supports this. The Michigan Genomics Initiative is a novel use of existing genetic data at U-M. We know these patients exist. This was a straightforward way to identify potential carriers and intervene,” Hertz said.

Hertz is the medical adviser for Advocates for Universal DPD/DPYD Testing, a non-profit organization that seeks to expand pretreatment DPYD testing.

The group includes family members of people with DPYD variants who died because of toxic side effects. Hertz’s role is unpaid. Hertz also co-authored a paper urging the U.S. Food and Drug Administration to recommend DPYD testing for patients before receiving fluoropyrimidine chemotherapy.

“There are examples where pharmacogenomics has been rapidly taken up into clinical practice, but it’s always required a decision from the FDA or clinical guidelines agencies,” Hertz said.

“If there’s a law or guideline, that will change practice. Otherwise, we have to convince one clinician at a time, one patient at a time. It’s going to be a long process.”

European clinical care guidelines and the European Medicines Agency recommend DPYD testing before beginning fluoropyrimidine chemotherapy.

At the Rogel Cancer Center, leaders in the oncology clinics that use these chemotherapies embrace routine DPYD testing.

Hertz said the Michigan Genomics Institute monitoring system is an example that other research institutions can implement until DPYD testing is required.

The U-M team continues to monitor Michigan Genomics Initiative participants for potential DPYD testing.

They are also beginning to monitor for a marker linked to toxicity from the chemotherapy irinotecan.

Additional authors: Amy L. Pasternak, Robinson Seda, Joseph Lipa, Rachel L. McDevitt, Oxana V. Crysler, Paul L. Swiecicki, Bryan J. Schneider, Brett Vanderwerff, N. Lynn Henry, John C. Krauss, Vaibhav Sahai.

Funding for this work is from Precision Health at the University of Michigan.

Paper cited: “Confirmatory DPYD Testing in Patients Receiving Fluoropyrimidines Who are Suspected DPYD Variant Carriers Based on a Genetic Data Repository,” Clinical Pharmacology & Therapeutics. DOI: 10.1002/cpt.2936.