Genetic Screening in Cancer Treatment: Optimizing Drug Safety and Effectiveness with Personalized Medicine
Arguably, the devastating nature of a cancer diagnosis stems both from the prospect of treatment and from the prospect of death. Drugs used to treat cancer, in particular, can cause serious and sometimes fatal adverse reactions. Clinicians strive to minimize the negative effects of potentially life-saving treatments, but there are several drawbacks when adopting new technologies proven to advance human health, personalized medicine, or pharmacogenomics (PGx).
Fluoropyrimidine drugs, such as fluorouracil (5-FU) and capecitabine, are basic chemotherapy drugs used to treat colorectal cancer, breast cancer, and other common cancers. A recent update from the U.S. Food and Drug Administration (FDA) highlights the potential for life-threatening consequences when patients with certain genetic variations in the DPYD enzyme take flupyridine. Personalized medicine or pharmacogenomics (PGx) can solve this dilemma.
The genetic dilemma of dosage
Genetics play a key role in a patient's response to medications. For example, certain genetic variations in the dihydropyridine dehydrogenase (DPYD) gene may lead to the accumulation of harmful fluoropyrimidines in some patients, resulting in a greater risk of serious adverse effects. Although only 3-8% of patients carry DPYD mutations that reduce their DPD activity, the consequences can be fatal. Fluoropyrimidine toxicity can be prevented if patients are screened before starting treatment.
Clinicians have no way of knowing whether a patient has DPYD deficiency unless genetic testing is performed. PGx testing addresses this clinical pain point by providing a comprehensive output of a patient’s genetic biomarkers to determine their risk level. After the test is completed, patients are classified according to their metabolic status: normal metabolizers, intermediate metabolizers, and poor metabolizers. Different genotypes may require different medication recommendations, including dosage adjustments or even avoiding certain medications altogether.
clinical and financial requirements
The clinical evidence supporting pretreatment screening is compelling. A large meta-analysis including more than 16,005 patients shows that patients with at least one DPYD risk variant are nearly 36 times more likely to die. compared with patients not taking fluoropyrimidine. Furthermore, another study showed that pretreatment DPYD testing reduced hospitalizations and toxicities compared with reactive testing, thereby normalizing patient risk to that of wild-type or “normal” patients.
Currently, the US FDA advocates informed decision-making, but retains genetic testing as optional, pending further policy formulation. The FDA has requested updated product information for fluoropyrimidines, warning clinicians of an increased risk of adverse reactions in patients with partial enzyme activity, and recommending that patients with DPD deficiency should not receive fluoropyrimidines at all.
The European Medicines Agency has taken a more proactive stance, recommending routine DPYD screening before starting fluoropyrimidine therapy. Both regulatory agencies recognize the clinical importance of DPYD variants in preventing severe toxicities and improving patient safety. The National Comprehensive Cancer Network (NCCN) guidelines on colon cancer mention that PGx testing is available to clinicians who wish to use it, which helps demonstrate and drive better guidelines and clinician adoption.
In addition to improving patient safety and treatment outcomes, DPYD testing can also provide positive economic benefits. Multiple analyzes have concluded that pretreatment DPYD PGx testing in patients receiving fluoropyrimidine therapy improves patient care and results in significant cost savings by reducing adverse events associated with costly emergency room visits.
Choosing the right pharmacogenomics tool
For physicians seeking to incorporate PGx to address clinical challenges, particularly in oncology, it is critical to assess the capabilities of available genomic tools. The right technology can push the field of precision medicine forward by using data to predict how individuals will respond to drugs. Clinicians can choose tools that provide comprehensive analysis, high accuracy and comprehensive clinical decision support.
• Speed and integration: Some PGx analysis tools can return results quickly, sometimes in as little as 25 minutes, which shortens the time from test to result and supports rapid treatment decisions. Tools that effectively integrate with other electronic data systems, such as electronic health records, can enhance data interoperability and ease of adoption.
• Accuracy and comprehensiveness: Doctors can choose tools that provide accurate recommendations for medications and dosages, including those to avoid. Some platforms offer a high degree of consistency and are validated against benchmarks such as the 1000 Genomes Project, ensuring a high degree of confidence in the results. The most complete data can come from technologies that utilize a person's entire genome (whole-genome sequencing, or WGS), rather than from limited testing methods (such as DNA microarrays) that fail to capture important genomic criteria, including limited variant detection, low sensitivity for rare alleles, and the inability to detect structural or copy number variants. Therefore, WGS provides a more complete picture to optimize treatment options and can be used to better predict drug treatments beyond cancer, such as painkillers or depression treatments.
• Actionable insights: To make PGx useful in practice, some technologies provide targeted clinical recommendations, such as dosing recommendations based on PGx profiles, or the selection of alternative drugs where inappropriate. Leveraging artificial intelligence and advanced deep learning models can improve the accuracy of variant identification, the process of distinguishing true variants from errors, which is particularly complex for pharmacogenetics.
PGx is already helping to impact healthcare. By proactively identifying patients at risk for serious adverse effects through DPYD screening, physicians can develop better personalized treatment plans. With the right technology, clinicians can establish new standards of care that are both precise and patient-centered.
Photo: Yuichiro Chino, Getty Images
Dr. Marco Schito is the Director of Business Development at UGenome AI, a biotechnology company focused on developing genomics and bioinformatics software for personalized medicine for research and clinical applications.
Husna Rahim is the Director of Clinical Content and Brand at UGenome AI, a biotechnology company focused on developing genomics and bioinformatics software for personalized medicine for research and clinical applications.
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