Chemotherapy has been used for decades to treat patients with cancer. One common type of chemotherapy - called fluorouracil (5-FU) when given by IV, or capecitabine (Xeloda or CAPE) when given by pill - can be toxic or fatal to 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 suggest that for people who carry one DPYD variant, 2-3% will die of a treatment-related fatality if they take one of these medications (25x higher than the risk of an average person receiving the same drugs at an average dose).
Why? We all carry 2 copies of a gene called DPYD that makes a chemical (DPD) that helps our bodies 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 chemo. But, up to 8% of people carry one variant in this gene that causes a partial deficiency of DPD. This can double their exposure to the toxic effects of these medications 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 it is recognized immediately, an antidote called uridine triacetate can be administered (at a total cost of >$180,000 USD for medication and care). But this process must occur quickly, so patients experiencing severe side effects must contact their providers without delay. 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 cannot walk to the bathroom independently by day 10." Patients who have two variants in the gene will likely be much sicker, much faster.
Drug authorities in the UK and European Union have recommended pre-treatment DPYD testing since 2020. If patients there are found to be genetically intermediate metabolizers of the drug, they are first given a half of the standard dose. Doctors can raise the dose if the patient responds well to the drug. If the patient is found to have a complete absence of DPD, other drugs are recommended if possible, or a quarter of the starting dose is used.
However, only recently has the United States FDA issued warnings about this. In 2024, the agency issued a statement that physicians should "consider testing" before prescribing 5-FU and capecitabine and "must inform patient of availability of DPYD testing and the implications of testing." The FDA stopped short of recommending that clinicians order genetic testing for DPYD on their patients before prescribing 5-FU or capecitabine. These rather loose recommendations, and the fact that the highly influential cancer organizations ASCO and NCCN, have either not weighed in or have not supported testing, have contributed to the lack of mandated DPYD testing within healthcare organizations. Only 3% of oncologists in the United States order such testing before giving patients these drugs. The logistics of implementing pre-treatment genetic testing can be challenging, but some major healthcare systems have implemented pre-treatment DPYD testing successfully. Most U.S. insurers, both private and public, will cover genetic testing for DPYD (which typically costs less than $450), and studies have shown that such testing is cost-effective.
So why is there reluctance about offering genetic testing to cancer patients before administering 5-FU and capecitabine?
· Genetic testing is complicated.
o There are many genetic changes (variants) in the DPYD gene. Some variants impact the function of the gene and others do not. Different labs offer various panels of variants in DPYD, and not all panels are comprehensive.
o Different gene variants are found in people from various ethnic backgrounds. A Canadian physician, Dr. Anil Kapoor, who was diagnosed with colon cancer and tested negative for four common DPYDvariants died after one dose of 5-FU. Why? Those four common variants are found most often in people of European ancestry and Dr. Kapoor was of South Asian ancestry. Testing performed after his death showed that Dr. Kapoor indeed carried another variant in this gene. The Association of Molecular Pathology (AMP) recently published guidelines for which DPYD variants should be included on panels before these drugs are administered to ensure that tests better account for ethnic diversity.
· Genetic testing is changing rapidly. Most clinicians cannot keep up with the genetics factors that play into drug reactions (a specialty called pharmacogenetics) and genetic counseling in addition to their own areas of work.
o Pharmacists and certified genetic counselors who specialize in this area can help. But, remarkably, these graduate-trained health care professionals are not recognized as 'healthcare providers' by Medicare and Medicaid, and therefore many other insurance companies. Without this recognition by our federal government, it is difficult for these providers to get reimbursed for their services. Therefore, they are not utilized in patient care as often as they could and should be. However, "The downstream cost benefits (fewer adverse events, fewer hospitalizations, decreased length of stay in the hospital, patient satisfaction, etc.) can easily outweigh the cost of having a dedicated full-time employee" to support such services, explains Jai Patel, PharmD, CPP, Director, Cancer Pharmacology & Pharmacogenomics at Atrium Health Levine Cancer Institute in Charlotte, NC.
o In addition to offering DPYD testing, genetic panels are available that can help assess patients' risk for adverse reactions to other chemotherapies and medications, such as those used to treat pain, depression, nausea, and acid-reflux. While many people experience these conditions, they are even more common in people with cancer. Therefore, pharmacogenetic testing may be very helpful in guiding the selection or dosing of other medications, with one study showing that the use of such panels in cancer care reduced adverse events by more than 50%.
o Some clinicians fear that genetic testing will delay treatment or feel that they can manage the symptoms if they occur, and do not wish to give lower doses of these medications. However, there are now data to suggest that lowering doses in these patients does not have a negative impact on their survival.
o Interpreting genetic testing panels can be challenging. Some clinicians fear that if they order this testing, they are then responsible for interpreting the data and using it correctly, and this creates a liability for them and their health system. But some health systems, like OSHU, have been sued because they didn't offer this testing and a patient died.
Clinical decision support tools for pharmacogenetics are available and integrate into the clinical workflow to provide guidance on when genetic testing should be used and what the current evidence advises on what drug or dose to use to maximize safety and efficacy. Kristine Ashcraft, President and Founder of YouScript, has devoted the last two decades to creating and implementing such tools. "Most providers have little exposure to genetics in their medical training and are understandably fearful of incorporating something they don't understand into clinical decision-making. But when provided with tools to guide them, the majority of healthcare providers say this becomes easy to navigate."
But many health systems don't use these tools, or the tools are not easily and readily available in electronic medical records (EMR), or pharmacy tools. One pharmacist described that he had to build his own tools for his health system in Epic, and it took an entire year. Those tools will help only his health system and will require updating as the field changes. Many of the large multi-billion dollar EMR companies make it difficult for smaller companies to integrate their digital tools into their systems, often requiring expensive and time-consuming hospital-by-hospital integration and charging hefty fees to be included in their networks. The FDA and our federal government should examine these power structures and how they influence the everyday practice of medicine.
The Right Drug Dose Now Act of 2024 is working to require that drug-gene interactions get the same attention that drug interactions receive.
If you or a loved one has cancer and chemotherapy has been recommended, consider the following before you start chemo:
1. Ask your physician, pharmacist, or genetic counselor whether genetic testing for medication 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 be useful for individuals receiving other types of chemotherapy as well.
2. If genetic testing for hereditary cancer is recommended (e.g., for mutations in the BRCA1 or 2 genes, or genes associated with Lynch syndrome), ask whether testing for genes associated with medication response can also be ordered.
3. Ask your healthcare team what the possible side effects are of your treatment, which side effects require an immediate call to your care team, and how you can reach them quickly if an adverse reaction 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 either the medications used in their cancer treatment or those used to treat conditions commonly seen in patients with cancer.