NEW YORK – A multisite cancer center in the Carolinas is rolling out an in-house genotyping program to help oncologists identify safer doses of fluoropyrimidine chemotherapies, which are widely prescribed but known to cause severe and life-threatening toxicities in a subset of patients.
Within the testing program at Charlotte, North Carolina-based Levine Cancer Institute, part of Atrium Health system, patients can receive genetic testing to gauge if they have variations in the DPYD gene. These variants are all associated with decreased production of dihydropyrimidine dehydrogenase (DPD), the protein that helps break down fluoropyrimidines. Patients with these DPYD variants are likely to be intermediate or poor metabolizers of fluoropyrimidines and at risk of drug overexposure and toxicities such as infections, bleeding, diarrhea, sores in the mouth, and redness and peeling on the palms and feet, all of which can quickly become severe.
Atrium initially piloted the genotyping program in 2020 at two of its gastrointestinal cancer clinics, and in early 2022 began expanding it to all cancer patients considering fluoropyrimidine-based chemotherapies 5-FU (fluorouracil) and Xeloda (capecitabine). The health system considers DPYD testing a standard and routine diagnostic for these patients, said Jai Patel, chair of the department of cancer pharmacology and pharmacogenomics at the Levine Cancer Institute. So far, the testing program has identified risky DPYD variants in more than two dozen cancer patients, according to an abstract presented at the American Society of Clinical Oncology's annual meeting in June.
While oncologists at Atrium Health aren't required to order DPYD testing before prescribing 5-FU or Xeloda to patients, "it is something that is recommended," Patel said, estimating that between 60 percent and 70 percent of new patients prescribed these chemotherapies are receiving DPYD testing at Levine Cancer Institute.
Developing the protocol
Currently, pre-treatment DPYD testing isn't routinely performed across US cancer centers, despite recommendations from the Clinical Pharmacogenetics Implementation Consortium (CPIC), an internationally recognized guidelines body. That's in part because testing hasn't been recommended in practice guidelines by professional societies such as the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).
Physicians authoring these guidelines have held off recommending DPYD testing, reasoning that there are numerous other clinical factors that can lead to toxicities. Moreover, since 5-FU and Xeloda are such mainstays of therapy in hard-to-treat tumor types like GI cancer, some oncologists have worried that pre-treatment DPYD testing could delay the initiation of essential chemotherapy, and if doses are lowered according to DPYD variants, it might reduce efficacy and cause patients' cancers to progress.
Although the US Food and Drug Administration recently updated Xeloda's label to further clarify that patients with certain PGx variants are at increased risk for life-threatening adverse reactions, the agency stopped short of recommending routine PGx testing, stating "there are insufficient data to recommend a specific dose in patients with partial DPD deficiency."
The absence of a testing recommendation from the FDA and guidelines bodies is one of the most common reasons oncologists say they don't routinely order DPYD testing for patients. Patel's team was conscious of oncologists' reluctance in this regard. So, when designing the DPYD testing program at Levine Cancer Institute, Patel's team sought feedback from physicians, pharmacists, nurses, and laboratory personnel and tried to address commonly cited barriers.
In an article published in the American Journal of Health-System Pharmacy earlier this year, Patel and colleagues described their experience implementing the DPYD testing program. They wrote that a core challenge they needed to address upfront was commercial labs' test turnaround times. It typically takes one to two weeks for a patient to start fluoropyrimidine treatment after initially being identified as a candidate for the therapy. Many commercial labs take just as long to return PGx test results, Patel said, but doctors aren't going to withhold chemotherapy to wait for those results.
To mitigate this challenge, Levine Cancer Institute invested in developing its own in-house PCR-based test and standard operating procedures to ensure quick sample processing and return of results. Unlike commercial lab tests that might analyze only one common DPYD variant, Levine Cancer Institute's assay tests for five variants with moderate-to-strong evidence based on CPIC recommendations.
Given the importance of having DPYD test results quickly, Levine Cancer Institute was able to shorten the median turnaround time down to three days by implementing an in-house test. At the cancer institute's main GI oncology clinic, the first site to pilot the DPYD testing process, sample collection kits were placed at a nurse's station for easy access so patients prescribed 5-FU or Xeloda could provide cheek swab samples at the clinic. Those samples were then sent to the in-house CLIA-certified lab to be analyzed in batches once a week, and results were reported to patients through the health system's electronic health record (EHR) system.
This process has been broadly operationalized throughout Levine Cancer Institute's cancer clinics. At the institute's other sites, collection kits are outfitted with a prepaid overnight shipping label so staff can quickly mail patients' samples to the lab at the main clinic.
Initially, DPYD test results were provided as PDFs appended to a patient's chart in the EHR, but to drive adoption among physicians who aren't used to integrating PGx testing into patient care, Patel's team in mid-2022 added pre- and post-test decision support alerts into the EHR to remind physicians to order tests and review recommendations; prescribers can also request a consultation with the PGx team within the EHR.
"That resulted in us catching a lot more patients," Patel said, noting that once the interruptive alerts were added, "it wasn't an issue of [a provider] remembering or not. As soon as they placed the order [for 5-FU or Xeloda], the [test] alert pops up."
Between March 2020 and December 2022, nearly 500 patients across 14 clinics received DPYD genotyping, either in the pre-treatment setting or after already starting fluoropyrimidine chemotherapy, according to the abstract presented at ASCO.
Thirty patients who received testing, or 6.1 percent, were determined to be carriers of at least one of five PGx variants that made them intermediate or poor metabolizers of fluoropyrimidines. Based on the test results, physicians opted to modify the chemotherapy dose for 27 patients, or 90 percent. One patient avoided starting fluoropyrimidine chemo, one discontinued it, and the remaining 25 patients reduced their dose.
When Patel's group considered whether offering pre-treatment DPYD testing impacted outcomes, they found that about two-thirds of the 11 patients who were DPYD variant carriers but received testing after starting treatment experienced severe toxicity. That's roughly double the toxicity rate experienced by carriers who received pre-treatment testing and had their dosage adjusted proactively, according to Patel. Carriers who received pre-treatment testing and noncarriers had roughly the same toxicity rate.
"In essence, we were able to normalize the toxicity risk [for carriers], as long as we do the testing before they start treatment and we adjust their dose," he said.
Incremental progress
While most cancer centers in the US presently don't offer routine DPYD testing to patients, there has been forward progress, according to Catherine Oliver, system director of clinical pharmacy services at Ochsner Health, a New Orleans-based health system that has offered DPYD testing prior to administering 5-FU or Xeloda therapy since 2021. The American Cancer Society's Cancer Action Network (ACS CAN), for example, in June released a set of recommendations for spurring PGx testing in cancer care, including encouraging professional societies to incorporate PGx testing recommendations into treatment guidelines and improving payors' coverage of PGx tests.
"Hopefully, this will accelerate the availability and use of PGx to improve patient outcomes, including within cancer care," Oliver wrote in an email, adding that for payors the value of PGx testing is that it may help avoid costly management of severe drug-related toxicities. "We are slowly, very slowly, making progress."
In a review of published cost-effectiveness analyses in Clinical Pharmacology & Therapeutics last year, researchers reported that the DPYD testing was either deemed cost-saving or at least cost-effective, with no study deeming it not cost-effective.
Oliver noted that Levine Cancer Institute has implemented processes and support tools that are critical to a successful DPYD testing program, including achieving a test turnaround time that doesn't delay clinical decision-making, facilitating easy access to results within the EHR system, and developing clinical decision support tools.
While other cancer centers looking to implement DPYD programs can learn from the experience of early adopters like Levine Cancer Institute and Ochsner Health, cost remains a big detractor, since reimbursement for DPYD testing is variable.
Within Levine Cancer Institute's program, DPYD testing was initially covered under the hospital system's operating budget and then through grant funding. However, the only way to create a long-term and sustainable program, Patel and colleagues wrote in their paper, is to secure favorable payor coverage policies. Levine Cancer Institute plans to begin billing patients soon, Patel said, as some insurers have been expanding PGx test coverage.
Patel's team also plans to analyze if the DPYD testing program is incurring healthcare savings by avoiding toxicities that put patients in the hospital. If such analysis shows the program to be cost-effective, then it may sway more insurers to cover DPYD testing, Patel said.
"I'm really hoping that this [research] is going to drive more decisions for payors and [convince] the FDA and the professional society guideline writers to really get on board and recommend this as something that needs to be considered at other hospitals," he said.