DPYD Testing & Personalized Dosing for Chemotherapy Safety

Brad Power and Nanthana Ravichandran April 2, 2025 “When the NCCN just updated those guidelines, they said that there's no concrete evidence on how to reduce the dose, which, as an advocate, I disagree with.

As a cancer patient, you may not be aware that you are at risk of being overdosed, under- dosed, and being given drugs that are ineffective, or in tragic cases fatal, which testing could have predicted. You should get tested to identify your personal risks and to inform your personalized dosing levels before taking certain drugs or getting radiation treatment.

In the future, you will be able to measure the effective level of a drug in your body, and then modulate the dose empirically, as opposed to the one-size-fits-all (not personalized) rules for prescriptions.

Consider the story of Karen Merritt, patient advocate and Co-Founder of Advocates for Universal DPD/DPYD Testing , who suffered the heartbreaking loss of her mother—not to colorectal cancer, but to toxicity from an overdose of a chemotherapy meant to treat it. Her mother could have been tested, but wasn't, for a gene variation (DPYD) which is essential for breaking down and eliminating specific chemotherapies.

In most of Europe, testing for this gene variation before administering specific chemotherapies is standard practice. Unfortunately, this is not yet the case in the United States. In 2022, Karen co-founded the nonprofit organization Advocates for Universal DPD/DPYD Testing to push for change. S. before being administered certain chemotherapies. They have sent in a proposal to get this testing into the standard care guidelines. S.

cancer centers—such as Dana Farber Cancer Institute, Levine Cancer Institute, and Ochsner —are implementing DPYD testing for better patient safety and outcomes. Karen's goal is to see this become the norm across the country, ensuring that no more lives are lost due to preventable drug-gene interactions. Why do you need to know about pharmacogenomic testing?

Pharmacogenomic testing helps personalize cancer treatment by identifying how your genetic makeup affects your ability to metabolize certain drugs.

In the case of DPYD testing, it can prevent potentially life-threatening toxic reactions to chemotherapy drugs like fluorouracil (also known as 5-Fluorouracil or 5-FU), a chemotherapy medication used to treat various cancers and some skin conditions, and capecitabine, an oral drug that converts into fluorouracil.

By understanding your genetic variants, doctors can adjust drug dosages to minimize severe side effects while maintaining treatment effectiveness, ultimately improving patient safety and quality of life during cancer treatment. You should be tested for DPYD genetic variants if you are scheduled to receive chemotherapy treatments using fluorouracil (5-FU) or capecitabine. Testing is a simple blood test or cheek swab.

If you have a variant, your oncologist can adjust your dosage to reduce risks. How can you advocate to improve your access to new tests and personalized dosing in standard protocols?

Brad Power This is the Cancer Patient Lab. Welcome to our weekly webinar series. Today, we're honored to have with us Karen Merritt, a patient advocate who will be sharing her story. She was a caregiver for a loved one who experienced an unfortunate toxicity that could have been caught with diagnostic testing. She will tell us about that story as well as the challenges of getting a new diagnostic test into the standard of care.

Before we get started, I will make a disclaimer. This webinar is only informational, and is not medical advice. Our aim is to provide patients and caregivers with information they can take to their medical team to help improve their care. We are a 501(c)(3) nonprofit and welcome donations from anyone inspired by the services we provide to patients and caregivers. Karen Merritt 1:26 Thank you so much for having me.

It's so nice to see cancer survivors, and all those fighting to get a better diagnostic into the standard of care. My advocacy has specifically been around DPYD. The DPYD (dihydropyrimidine dehydrogenase) gene tells your body to make the DPD enzyme which is needed to break down fluorouracil (5-FU) and capecitabine in your body. Genetic variants in the DPYD gene can lead to insufficient or no enzyme function, depending on the specific variant.

Those with reduced or absent DPD enzymes, a condition called DPD deficiency, can experience toxicity and fluorouracil overdose that can be life threatening. My mom, Linda, was diagnosed in 2014 with stage three anal cancer. At 73, she was otherwise healthy and enjoying retirement. Her treatment plan after a routine colonoscopy was 5-FU chemotherapy with chemo radiation or radiation.

Her oncologist told her chemo radiation was fairly well tolerated. She was not prescreened with the pharmacogenetics test for DPYP and not informed about the risks of DPD deficiency. She started her first infusion on June 9, a 46 hour drip. She had been a registered nurse, so on that Friday, she called her oncologist because she knew she had become dehydrated from the continual diarrhea, neutropenia and mucositis.

Mucositis sores beginning in her mouth ran all the way down her digestive tract to her anus. There was no conversation about her mouth sores or that it could be signs of a toxic reaction. A couple days later, she falls, while getting up in the middle of the night to go to the bathroom. At this time, she's not eating or drinking because the sores hurt so badly. Swallowing anything is like swallowing razor blades. She goes to the hospital.

She's in the ICU. She has round the clock care. We are told by the oncologist on call that there's no way to have known this could have been her reaction before treatment. With what we now know, that is incorrect. She could have had a DPYD test done before treatment started to figure out if she had enough of the DPD enzyme. They told us she was very sick. She'd be in the hospital for a few weeks.

She died on July 2, 2014 and unfortunately, her death certificate lists cardiac arrest as cause of death because as part of the toxicity to 5-FU and capecitabine, you end up with multi organ failure. We should have fought to change that death certificate to make it an adverse drug event. Toxicity to 5-FU is the number one cause of death, and as an adverse drug event, it would have been reported to the FDA and MedWatch. How often does this happen?

It used to be considered a rare and acceptable risk in the NCCN treatment guidelines. But 3-8% of the population have a DPYD variant. That is about one in 20 people who are DPYD variant carriers and have a chance of severe toxicity and a 3% chance of death. This is estimated at over 1000 deaths per year in the United States, as in the US National Libraries of Medicine from a study written by a Dr. Innocenti. That is three jumbo jets every year.

If this was regulated by the FAA, they would ground the planes until they resolved the issue. Most people are unaware of this deficiency until it's too late. In 2015 there was a supposed antidote, and I say supposed antidote because Vistoguard has to be administered within 96 hours of the last dose or the end of the infusion. Oftentimes, the toxicity is not diagnosed until after this time.

Importantly, VISTOGUARD is about $80,000 and also needs prior authorization, which can be tricky and unreliable when you're working with the time constraint. Pre screening for DPD deficiency and dose adjustment based on CPIC dosing recommendations are imperative. CPIC is the Clinical Pharmacogenomics Implementation Consortium.

In Kristine Ashcraft’s presentation with Cancer Patient Lab, she talked a lot about the highways drugs go through, and how CPIC gives guidance for DPYD, as well as other medications. This is my mom in the middle. We like to say she was so easy to live with and so hard to live without. Our mission as a nonprofit is to improve the standard of care for cancer patients undergoing 5- FU and capecitabine chemotherapy to include DPYD testing.

We became a nonprofit in 2022 after many families came together. The human cost of not testing is actually what brought us together. Single treatment, fluoropyrimidine chemotherapy with no pre screening, no information about the risks of DPD deficiency or severe adverse reaction. The suffering is horrific with the sores from her mouth to her anus. Capecitabine patients end up with scabs on the outside of their body. They look like a burn victim.

There are other nonprofits who have written letters of support for pre-treatment DPYD testing. Where does this stand in the United States? The President of our nonprofit, Ken Surprenant learned that you can write a citizen petition to the FDA to revise drug labels. So in 2016 he did just that, and they dropped the word “rare” from the drug label.