Chemotherapy may harm or kill you if you have this genetic trait

Chemotherapy has been used for decades to treat patients with cancer. One common type of chemotherapy, called fluorouracil (5-FU) when given IV or capecitabine (Xeloda or CAPE) when taken in tablet form may be toxic or fatal to a small percentage of people who carry a genetic change in a gene called DPID. The prevalence of this genetic finding varies among different populations. Data shows that for people wearing one DPID option, 2-3% will die from a treatment-related death if they take one of these drugs. (25 times higher than the risk of the average person receiving the same medications at an average dose).

Why? Each of us has two copies of a gene called DPID which produces a chemical (DPD) that helps our body break down and get rid of these drugs after our body uses them. This process helps prevent the patient from developing toxic or fatal side effects from this chemotherapy. But, up to 8% of people wear one option in this gene causes partial DPD deficiency. This may double the toxic effects of these medications at standard doses. Two in 1,000 patients are carriers of two variants that result in 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 it is immediately recognized, an antidote called uridine triacetate (uridine triacetate) may be given.total cost >$180,000 for medications and care). But this process must happen quickly, so patients experiencing serious side effects should contact their providers without delay. An example used to illustrate such side effects. This is a case of “an active and independent patient who begins a planned 14-day course of capecitabine and is unable to go to the toilet independently by day 10.” Patients who have two gene variants are likely to feel much worse and faster.

Medicines regulators in the UK and European Union have recommended pre-treatment. DPID testing since 2020. If patients there carry one copy of the variant (genetically intermediate metabolizers of the drug), they are first given half the standard dose to see how they do. If patients feel well while taking the drug, doctors may increase the dose. If the patient is a carrier of two gene variants (complete absence of DPD), other drugs are recommended instead, if possible, or a quarter of the usual starting dose is used.

Only recently did the US FDA issue warnings on this matter. In 2024, the agency issued a statement saying that physicians should “consider testing” before prescribing 5-FU and capecitabine and “should inform the patient of the presence DPID testing and consequences of testing.” FDA stopped recommending Doctors prescribe genetic testing for DPID to their patients before prescribing 5-FU or capecitabine. These rather vague recommendations and the fact that highly influential cancer organizations did not support testing contributed to the problem. Only 3% of oncologists in the United States order such testing before giving these drugs to patients. Carrying out pre-processing DPID Genetic testing can be challenging, but some large health systems have done it successfully. Most US insurers, both private and public, cover genetic testing for DPID (which typically costs less than $450), and studies have shown that this testing is cost-effective.

So why is there reluctance to offer genetic testing to cancer patients before prescribing them 5-FU and capecitabine?

· Genetic testing is complex.

o There are many genetic changes (variants) in DPID gene. Some variants affect gene function, while others do not. Different laboratories offer different panels of options in DPIDand not all panels are complete.

o Different gene variants are found in people of different ethnic backgrounds. Canadian physician, Dr. Anil Kapoor, who was diagnosed with colon cancer and test negative for four common DPIDvariants died after one dose of 5-FU. Why? These four common variants are most common in people of European descent, and Dr. Kapoor was of South Asian descent. Testing carried out after his death showed that Dr Kapoor did indeed carry a different variant of this gene. The Association for Molecular Pathology (AMP) recently published recommendations that DPID options should be included in panels before the use of these drugs so that the tests better account for ethnic diversity.

· Genetic testing is changing rapidly. Most clinicians are unable to address the genetic factors that influence drug response (a specialty called pharmacogenetics) outside of their own field of work.

o Pharmacists and certified genetic counselors who specialize in this area can help. But, notably, these college-educated health care providers are not recognized as “health care providers” by Medicare and Medicaid and, therefore, by many insurance companies. Without this recognition from our federal government, these providers will have a difficult time getting reimbursed 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 side effects, fewer hospitalizations, shorter hospital stays, patient satisfaction, etc.) can easily outweigh the cost of maintaining a dedicated full-time employee” to support such services, Jai explains. Patel, PharmD, CPP, is director of cancer pharmacology and pharmacogenomics at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

o Besides the offer DPID testing, genetic panels are available that can help assess a patient’s risk of adverse reactions to other chemotherapy drugs and medications, for example, those 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. Thus, pharmacogenetic testing can be very helpful in guiding the selection or dosing of other medications, with one study showing that the use of such panels in cancer treatment has reduced the number of side effects by more than 50%.

o Some doctors fear that genetic testing will delay treatment or believe they can manage symptoms if they occur and are reluctant to prescribe lower doses of these medications. However, there are there is now evidence to suggest that dose reduction in these patients does not have a negative impact on their survival..

o Interpreting the results of genetic testing panels can be challenging. Some doctors fear that if they order this testing, they will be responsible for interpreting the results and using them correctly, and fear that this will create liability for them and their health care system. But some health systems like OSHwere sued because they did not offer this testing and the patient died.

Clinical decision support tools for pharmacogenetics are available. They assist the clinician by providing recommendations about when genetic testing should be used and what drug or dose to use to maximize safety and effectiveness. Christine Ashcraft, President and Founder USScript, has spent the last two decades creating such tools. “Most health care professionals have little exposure to genetics in their medical training and are understandably afraid to include something they don’t understand in their clinical decision-making process. But most health care providers say that once they have the tools to guide them, it becomes easy to navigate.”

But many health systems do not use these tools, or these tools are not easily accessible in electronic medical records (EMR) or pharmacy systems. One pharmacist spent a year building his own digital tools in an EMR called Epic. These tools will only help his healthcare system and will require updates as the situation changes. Many of the larger, multi-billion dollar EMR companies make it difficult for smaller companies to integrate their own digital tools, often requiring costly and time-consuming integration between hospitals and charging hefty fees to be included in their networks. The FDA and our federal government must examine these power structures and how they impact the daily practice of medicine.

The Right Drug Dose Act of 2024 is working to require that drug-gene interactions be given the same attention as drug interactions.

If chemotherapy has been recommended for you or a loved one, consider the following: to start of treatment:

1. Ask your doctor, pharmacist, or genetic counselor if genetic testing for drug response can help guide your treatment. The FDA labels for 5-FU and capecitabine have been updated to indicate that Patients should be informed about the availability of genetic testing.. Genetic testing may also be helpful for people receiving other types of chemotherapy.

2. If genetic testing for hereditary cancers (for example, mutations in BRCA1 or 2 genes or genes associated with Lynch syndrome), ask if testing for genes associated with drug response can also be ordered.

3. Ask your healthcare provider what the possible side effects of your treatment are, which side effects require immediate attention to your healthcare team, and how you can contact them quickly if an adverse reaction occurs.

Chemotherapy has been a standard and successful part of cancer treatment for decades, and genetic testing can make it safer and more successful. Pharmacogenetic testing and counseling is often useful for patients with cancer to determine which medications to use to treat cancer or those used to treat conditions commonly seen in patients with cancer.