Medical infusion with patient in hospital.
Chemotherapy has been used for decades to treat patients with cancer. One common form of chemotherapy – called fluorouracil (5-FU) if given by IV, or capecitabine (Xeloda or CAPE) when given as a pill – can be toxic or fatal for a small percentage of people who carry a genetic change in a gene called DPYD. The prevalence of this genetic finding varies in different populations. Data suggests that for people who wear one DPYD variant, 2-3% will die as a result of treatment if they take one of these medications (25x higher than the risk of an average person receiving the same medication in an average dose).
Why? We all have two copies of a gene called DPYD which produces a chemical (DPD) that helps our bodies break down and get rid of these medications after our bodies use them. This process helps prevent the patient from developing toxic or fatal side effects from this chemotherapy. But, up to 8% of people have one variant in this gene that causes a partial deficiency of DPD. This can double their exposure to the toxic effects of these drugs at standard doses. Two in 1000 patients carry two variants that result in a complete absence of DPD function – in such patients, exposure to 5-FU is often fatal.
If a patient develops toxicity to 5-FU or capecitabine and this is recognized immediately, an antidote called uridine triacetate may be administered.for a total of >$180,000 USD for medication and care). But this process must happen quickly, so patients who experience serious side effects should contact their healthcare providers immediately. An example used to illustrate such side effects is that of “an active and independent patient who starts a planned 14-day cycle of capecitabine and is unable to walk to the toilet independently on day 10.” Patients with two variants of the gene are likely to be much sicker and much faster.
Medicines authorities in the United Kingdom and the European Union have recommended pretreatment DPYD testing since 2020. If patients have one copy of the variant (genetic intermediate metabolizers of the drug) with them, they first receive half the standard dose to see how they fare. If patients are doing well when taking the drug, doctors may increase the dose. If the patient carries two variants of the gene (a complete absence of DPD), other drugs are recommended if possible, or a quarter of the usual starting dose is used.
Only recently has the US FDA issued warnings about this issue. In 2024, the agency issued a statement that physicians “should consider testing” before prescribing 5-FU and capecitabine and “inform the patient of the availability of DPYD testing and the implications of testing.” The FDA stopped short of it recommend for which doctors order genetic tests DPYD about their patients before prescribing 5-FU or capecitabine. These rather loose recommendations, and the fact that highly influential cancer organizations have not supported testing have contributed to the problem. Only 3% of oncologists in the United States order such tests before giving these drugs to patients. Carry out pre-treatment DPYD Genetic testing can be challenging, but some large healthcare systems have done it successfully. Most U.S. insurers, both private and public, cover genetic testing DPYD (which typically costs less than $450), and studies have shown these tests to be cost-effective.
Why then is there reluctance in offering genetic testing to cancer patients before receiving 5-FU and capecitabine?
DNA, conceptual image.
· Genetic testing is complicated.
o There are many genetic changes (variants) in the DPYD gene. Some variants affect the function of the gene, others do not. Different laboratories offer different panels with variants DPYDand not all panels are comprehensive.
o Different gene variants are found in people with different ethnic backgrounds. A Canadian doctor, Dr. Anil Kapoor, who was diagnosed with colon cancer tested negative for four in common DPYDvariants died after one dose of 5-FU. Why? These four common variants are most commonly found in people of European descent and Dr. Kapoor was of South Asian descent. Tests conducted after his death showed that Dr. Kapoor indeed carried another variant of this gene. The Association of Molecular Pathology (AMP) recently published guidelines for what DPYD variants should be included on panels before these drugs are administered to ensure that testing better takes into account ethnic diversity.
· Genetic testing is changing rapidly. Most doctors cannot understand the genetic factors involved in drug responses outside of their own field of practice (a specialty called pharmacogenetics).
o Pharmacists and certified genetic counselors who specialize in this area can help. But remarkably, these university-level health care professionals are not recognized as “health care providers” by Medicare and Medicaid, and therefore by many insurance companies. Without this recognition by our federal government, it is difficult for these service providers to receive compensation for their services. Therefore, they are not used in patient care as often as they could and should be. “However, the downstream cost benefits (fewer adverse events, fewer hospital admissions, shorter hospital stays, patient satisfaction, etc.) can easily outweigh the costs of having a dedicated full-time employee” to support such services, Jai explains. Patel, PharmD, CPP, director of cancer pharmacology and pharmacogenomics at Atrium Health Levine Cancer Institute in Charlotte, NC.
o In addition to offering DPYD In testing, genetic panels are available that can help assess patients’ risk of side effects other chemotherapeutic agents and medications, such as medicines used to treat pain, depression, nausea and acid reflux. Although many people suffer from these conditions, they are even more common in people with cancer. Therefore, pharmacogenetic testing can be very useful in guiding the selection or dosing of other medications, with one study showing that the the use of such panels in cancer care reduced side effects by more than 50%.
o Some doctors are concerned that genetic testing will delay treatment or believe that they can control symptoms if they occur, and do not want to give lower doses of these medications. However, there are Now data suggests that reducing doses in these patients has no negative effect on their survival.
o Interpreting genetic test panels can be challenging. Some physicians fear that if they order these tests, they will be responsible for interpreting the results and using them correctly, and worry that this will create liability for them and their health care system. But some healthcare systems such as OSHUwere sued because they did not offer this testing and a patient died.
Clinical decision support tools for pharmacogenetics are available. They assist the doctor by providing advice on when to use genetic testing and what drug or dose to use to maximize safety and effectiveness. Kristine Ashcraft, President and Founder of YouScript, has dedicated the past twenty years to creating such instruments. “Most providers have little exposure to genetics during their medical training and are understandably afraid to incorporate something they do not understand into clinical decision making. But when given the tools to guide them, the majority of caregivers say it is easy to navigate.”
But many health care systems do not use these tools, or the tools are not easily and readily available in electronic medical records (EMR) or pharmacy systems. One pharmacist spent a year building his own digital tools in the EHR, called Epic. These tools will only help his healthcare system and will require updates as the field changes. Many of the large multi-billion dollar EMR companies make it difficult for smaller companies to integrate their own digital tools, often requiring expensive and time-consuming hospital-to-hospital integration and charging high fees to integrate into their networks. are included. The FDA and our federal government should examine these power structures and how they impact the day-to-day practice of medicine.
The Right Drug Dose Now Act of 2024 is working to require that drug-gene interactions receive the same attention as drug-drug interactions.
If chemotherapy has been recommended for you or a loved one, consider the following for start treatment:
1. Ask your doctor, pharmacist, or genetic counselor if genetic testing for drug response can inform your care. The FDA labels for 5-FU and capecitabine have been updated to read that Patients should be informed about the availability of genetic testing. Genetic testing may also be useful for individuals receiving other types of chemotherapy.
2. If genetic testing for hereditary cancer is recommended (for example, for mutations in the BRCA1 or 2 genes, or genes associated with Lynch syndrome), ask if tests can also be ordered for genes associated with medication response.
3. Ask your care team about the possible side effects of your treatment, which side effects require you to contact your care team immediately, and how to reach them quickly if a side effect occurs.
Chemotherapy has been a standard and successful part of cancer care for decades, and genetic testing can make it safer and more successful. Pharmacogenetic testing and counseling is often useful for patients with cancer to guide the medications used in their cancer treatment or the medications used to treat conditions common in patients with cancer.