It can be argued that the devastation of a cancer diagnosis is rooted as much in the prospect of treatment as it is in the prospect of death. In particular, drugs used to treat cancer can cause severe and sometimes fatal adverse reactions. Clinicians strive to minimize the negative consequences of potentially life-saving treatments, but there are shortcomings when it comes to the adoption of newer technologies proven to advance human health, personalized medicine, or pharmacogenomics (PGx).
Fluoropyrimidines, like fluorouracil (5-FU) and capecitabine, are cornerstone chemotherapy agents used in the treatment of colorectal, breast, and other common cancers. Recent updates by the U.S. Food and Drug Administration (FDA) highlight the life-threatening consequences that may result when patients with certain genetic variants in the DPYD enzyme take fluoropyridine. Personalized medicine, or pharmacogenomics (PGx), can offer a solution to this dilemma.
Genetic dilemma of dosing
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Genetics play a key role in how patients respond to medication. For example, certain genetic variants in the dihydropyridine dehydrogenase (DPYD) gene may lead to a harmful buildup of fluoropyrimidines in some patients, resulting in a much greater risk of severe adverse effects. While only 3–8% of patients carry a DPYD variant that reduces their DPD activity, the consequences can prove fatal. Fluoropyrimidine toxicity may be preventable if patients are screened before initiating treatment with it.
Clinicians cannot know whether their patients have a DPYD deficiency unless they perform genetic testing. PGx testing addresses this clinical pain point by providing a comprehensive output of a patient’s genetic biomarkers which determines their risk level. Once tested, patients are categorized based on their metabolizer status: normal metabolizers, intermediate metabolizers, and poor metabolizers. Different genotypes might call for different medication recommendations, including adjusting the dosage or even avoiding certain drugs altogether.
Clinical and economic imperatives
The clinical evidence supporting pretreatment screening is compelling. One large meta-analysis, which included over 16,005 patients, demonstrated that patients possessing at least one of the DPYD risk variants were nearly 36 times more likely to die from fluoropyrimidines compared to patients who did not. Furthermore, another study indicated that pretreatment DPYD testing reduced hospitalizations and toxicities when compared with reactive testing, thereby normalizing the patient’s risk to that of wild-type, or “normal”, patients.
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Currently, the U.S. FDA promotes informed decision-making, but leaves genetic testing optional, pending further policy development. The FDA has already required updates to product information for fluoropyrimidines, warning clinicians of the increased risk of adverse effects in patients with partial enzyme activity and recommends that patients who are DPD deficient should not receive fluoropyrimidines at all.
The European Medicines Agency takes a more proactive stance, recommending routine DPYD screening before initiating fluoropyrimidine therapy. Both regulatory agencies recognize the clinical importance of DPYD variants in preventing severe toxicity and improving patient safety. The National Comprehensive Cancer Network (NCCN) guidelines on colon cancer mention that PGx testing is available for clinicians who wish to use it, which helps demonstrate and drive better guidelines and adoption by clinicians.
In addition to improving patient safety and outcomes, DPYD testing offers positive economic benefits. Multiple analyses have concluded that pretreatment DPYD PGx testing for patients receiving fluoropyrimidine leads to improved patient care and significant savings through reduction of costly emergency room visit-related adverse events.
Selecting the right pharmacogenomic tools
For physicians seeking to incorporate PGx to address clinical challenges, particularly in oncology, evaluating the features of available genomic tools is essential. The right technology can move the field of precision medicine forward by leveraging data to predict individual responses to medications. Clinicians can select tools that offer comprehensive analysis, high accuracy, and integrated clinical decision support.
• Speed and integration: Some PGx analysis tools can return results quickly, sometimes in as little as 25 minutes, which shortens the timeline from test to results and supports rapid treatment decisions. Tools that integrate efficiently with other electronic data systems, such as Electronic Health Records, enhance data interoperability and ease of adoption.
• Accuracy and comprehensiveness: Physicians can select tools that offer accurate suggestions for medications and dosages, including those to avoid. Some platforms offer high concordance, validated against benchmarks like the 1000 Genomes Project, ensuring high confidence in results. The most complete data can come from technology that utilizes a person’s entire genome (whole genome sequencing, or WGS) rather than limited testing methodologies (such as DNA microarrays) that fail to capture important genomic criteria, including restricted variant detection, low sensitivity for rare alleles, and inability to detect structural or copy number variations. Thus, WGS offers a more complete picture to optimize treatment options, which can be used to better predict drug treatment beyond cancer, such as for pain medication or for treatment for depression, to name a few.
• Actionable insights: To make PGx useful in practice, some technology offers targeted clinical recommendations, such as dosing suggestions based on the PGx profile or alternative medications if one is unsuitable. Utilizing AI and advanced deep-learning models can improve the accuracy of variant calling — the process of distinguishing genuine variants from errors — which is particularly complicated for pharmacogenes.
PGx is already helping to impact health care. By proactively identifying patients at risk for severe adverse effects through DPYD screening, physicians can create better, individualized treatment plans. With the right technology in hand, clinicians can establish a new standard of care that is both precise and patient-centered.
Photo:Yuichiro Chino, Getty Images
Marco Schito, PhD, is the Business Development Director at UGenome AI, a biotechnology company focusing on developing genomics and bioinformatics software for personalized medicine with both research and clinical applications.
Husna Rahim is the Director of Clinical Content & Branding at UGenome AI, a biotechnology company focusing on developing genomics and bioinformatics software for personalized medicine with both research and clinical applications.
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