Houda Hachad , 2025-04-20 13:47:00
Genomic medicine leverages an individual’s genetic information to guide healthcare decisions, with drug-gene testing (also known as pharmacogenomics, or PGx) being a key application that personalizes medication needs based on genetics. Although PGx testing offers a more precise, personalized approach to prescribing medications more safely and effectively, benefiting both patients and healthcare systems, its widespread clinical adoption remains limited. The shift toward the implementation of PGx testing by medical institutions shows promise, but evidence supporting its broad realization is still emerging. A notable example of PGx adoption lagging is the lack of testing for genetic variants that can lead to severe toxicities with cancer treatments.
Clinical problem
Chemotherapy has long been a cornerstone in cancer treatment, with medications like fluorouracil and capecitabine widely used. While these medications are effective, overdosing can be toxic or even fatal for a small percentage of patients who carry specific variants of the DPYD gene. Testing for these variants is crucial to preventing serious adverse reactions, as carriers metabolize fluorouracil and capecitabine improperly, putting them at a higher risk of severe toxicity. Revealing these variants with DPYD testing can help personalize cancer treatment and improve patient outcomes.
The DPYD gene produces dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for metabolizing fluorouracil and capecitabine. DPD breaks down these medications in the liver to prevent toxic accumulation in the body. However, DPYD gene variants can cause partial or complete deficiencies in the DPD enzyme, leading to dangerously high levels of the medications. DPD deficiency can be detected in 39–61% of patients experiencing severe toxicities. Between 3% and 8% of the general population carries one copy of a variant associated with lower levels of the DPD enzyme.
The impact of DPYD variants on treatment outcomes
Patients with DPYD gene variants may experience severe toxicity with standard doses of fluorouracil or capecitabine. Toxicity can include life-threatening neutropenia, gastrointestinal toxicity, mucositis, and hand-foot syndrome, which may require hospitalization and could be fatal. In the United States, approximately 275,000 cancer patients receive fluorouracil annually, and it is estimated that 3% develop some degree of toxic reaction. Each year, 1,300 patients experience fatal toxicity. Identifying patients who carry harmful DPYD gene variants through PGx testing before chemotherapy administration is critical for preventing these severe toxicities. PGx testing typically costs a few hundred dollars, which is relatively inexpensive compared to the high costs associated with managing severe chemotherapy side effects.
The Clinical Pharmacogenetics Implementation Consortium, an internationally recognized expert group, is a key resource for providing practical and actionable clinical recommendations around DPYD testing. The group issued a guideline to support the safer use of fluorouracil and capecitabine using DPYD test results. The guidelines recommend reducing the initial dose in patients with partial DPD deficiency and adjusting doses in subsequent cycles based on tolerability. For patients with complete DPD deficiency, alternative medications are recommended. Studies have shown that for patients who undergo pre-treatment DPYD testing, the incidence of severe toxicity-related hospitalizations drops significantly, and the number of fatalities decreases.
Why DPYD testing is crucial for cancer care
Testing for DPYD variants is essential to improving cancer care and ensuring that patients receive chemotherapy in the safest and most effective way possible. In Europe, guidelines have recommended preemptive DPYD testing since 2020 and pre-treatment testing is becoming a standard practice. In the United States, the Food and Drug Administration (FDA) has taken multiple actions in recent years to address the risk of severe toxicity from fluorouracil and capecitabine. In January, the FDA issued a safety announcement emphasizing the importance of oncology care teams being aware of DPD deficiency risks and informing their patients about these risks. The agency also informed the oncology community that tests are available and encourages oncologists to consider testing patients for DPD deficiency before treatment begins. Until recently, only 3% of U.S. oncologists ordered DPYD testing.
With the new FDA safety announcement, the pharmacogenomics community hopes hospitals will create effective protocols for preemptive DPYD testing in oncology settings, which will increase the adoption of pre-treatment testing. This month, the National Comprehensive Cancer Network updated its treatment guidelines for colon, anal, rectal, and small bowel cancers to recommend that oncologists discuss DPYD testing with patients before prescribing chemotherapy. The guidelines emphasize the importance of considering individual patient circumstances when making treatment decisions. While the guidelines do not fully support universal testing, patient advocates view this as a move in the right direction.
Optimizing DPYD testing modalities
There are several challenges to making DPYD testing routine in clinical practice. One significant obstacle is the complexity of genetic testing itself. Different laboratories offer various panels of variants, and not all panels are comprehensive or account for the full range of variants seen across ethnic populations. For example, common variants may be well-documented in individuals of European descent but less recognized in other populations, such as those of Asian or African descent. This can lead to missed diagnoses or improper treatment adjustments in non-European populations.
At least four DPYD variants in Europeans are widely recognized in fluorouracil and capecitabine FDA prescribing labels for their association with severe toxicity. Recent work has identified other deleterious variants in patients of African and Asian genetic ancestries, offering the opportunity to establish standards for designing tests that will benefit a multi-ethnic population. The Association for Molecular Pathology issued a set of guidelines in 2024 recommending which variants should be tested so fewer patients are missed, especially those from non-European populations.
Paving the way for broader PGx testing in cancer care
A real-world analysis of 22,223 cancer patients found that 88.3% of them received at least one medication impacted by PGx variants, for which actionable recommendations exist. These medications are used to manage cancer or other conditions that may coexist or be triggered by the disease or its treatments. Patients with cancer frequently receive supportive PGx medications to manage pain, nausea, depression, anxiety, neurological symptoms, and cardiovascular disorders during cancer treatment. The value of multi-gene PGx testing, which covers DPYD and other important genes, allows the oncology team to optimize not only anticancer medications but also all other medications impacted by genetics. The use of a personalized care plan augmented with PGx insights, ideally at the time of diagnosis, increases the care team’s confidence and facilitates patient participation in creating a tailored care plan. Establishing a unique PGx signature for each patient enables the reuse of test results for future treatment decisions. Moreover, economic modeling has shown that using a multi-gene panel test at the start of treatment is associated with greater cost-effectiveness.
Tips for effective implementation of DPYD testing
Implementers are encouraged to establish hospital-wide protocols and policies for preemptive DPYD testing before relevant treatments are initiated. The deployment of testing should be integrated into existing clinical workflows to ensure easy access to test ordering and result acquisition. It is essential to engage ordering providers early in the process and train them on the significance, interpretation, and dose adjustments based on test results. To scale and maintain a DPYD testing program, organizations will need to collaborate with experienced software partners who offer longitudinal digital health platforms that expand beyond laboratory test integration. Solutions that allow clinicians to perform all operations for their genomic workflows within electronic health systems and provide decision support tools are better positioned to ensure a program is scalable and sustainable.
Although the healthcare industry has a long way to go before PGx testing for DPYD and other genes becomes widespread, it’s encouraging that regulatory bodies and professional organizations are making recommendations and raising awareness among healthcare providers. Introducing such testing will help oncologists and other clinicians enhance patient outcomes, reduce costs, and minimize risks.
Editor’s note: The author is a member of the Clinical Pharmacogenetics Implementation Consortium (CPIC) Scientific Advisory
Board
Photo: Liana Nagieva, Getty Images
Houda Hachad, Vice President of Clinical Operations, Aranscia, serves on the Clinical Pharmacogenetics Implementation Consortium (CPIC) Scientific Advisory Board and is an active member of the Pharmacogene Variation Consortium (PharmVar). She is involved with several pharmacogenomics working groups and committees aimed at standardizing pharmacogenomic testing modalities and at facilitating their adoption by the clinical community. Houda has overseen the development of pharmacogenetic product line extensions from inception to delivery and spearheaded the operational efforts for translating scientific requirements into technology solutions.
This post appears through the MedCity Influencers program. Anyone can publish their perspective on business and innovation in healthcare on MedCity News through MedCity Influencers. Click here to find out how.
