NEW YORK – The National Comprehensive Cancer Network has taken a more favorable stance on DPYD pharmacogenetic testing in recently updated colon, anal, rectal, and small bowel cancer treatment guidelines.
While the guidelines body still does not explicitly advise oncologists to routinely perform DPYD testing prior to initiating fluoropyrimidine-based chemotherapies like 5-fluorouracil (5-FU) and Xeloda (capecitabine), it now tells doctors to at least discuss this testing with their patients and consider testing to assess the risk of severe or life-threatening toxicities from such chemotherapy based on patients' specific circumstances.
"This NCCN Panel endorses the principle of identifying the patients at the greatest risk for severe fluoropyrimidine toxicity," the colon cancer guidelines panel wrote.
Approximately one in 1,000 patients carry two copies of a variant in the DPYD gene that result in the absence of the dihydropyrimidine dehydrogenase (DPD) enzyme necessary to process fluoropyrimidines. Between 3 percent and 8 percent of the general population has one copy of a variant associated with lower levels of the DPD enzyme, and these variants are more common among African Americans. Fluoropyrimidines can quickly build up in patients with DPD deficiencies, increasing toxic exposure. Patients with DPYD genetic variants that make them poor metabolizers are at the greatest risk of experiencing severe, and at times fatal, treatment-associated toxicities, though intermediate metabolizers are also at risk.
The NCCN in its updated guidelines echoes the stance of the US Food and Drug Administration, which issued a safety alert earlier this year telling doctors they should discuss DPD deficiency with cancer patients before prescribing fluoropyrimidines. The agency has also updated the labels of Xeloda and 5-FU in recent years with more information on the risk of DPD deficiency but has stopped short of recommending that oncologists universally test all patients for DPYD variants.
Similarly, the NCCN states in its colorectal cancer guidelines that "no specific test is recommended at this time and there are insufficient data to inform dose adjustments for many of the DPYD variants."
The FDA and the American Association for Cancer Research earlier this year hosted a workshop to explore the potential benefits and harms of instituting universal DPYD testing. At the meeting, oncologists from various US cancer centers and FDA experts agreed that, at a minimum, testing should be performed to identify those who completely lack the ability to break down these medications and are likely to die from a fluoropyrimidine overdose.
However, they also expressed a host of reservations about instituting a policy of routinely testing patients considering Xeloda or 5-FU, given that the function of only a handful of DPYD variants are well characterized. Despite data from numerous studies showing that reducing the starting dose of chemotherapies in patients harboring well-characterized DPYD pathogenic variants can reduce the risk of toxicities and death, oncologists at the workshop continued to worry that dose reductions — or completely withholding fluoropyrimidines in those with a complete DPD deficiency — would diminish colorectal cancer patients' chances for a cure in earlier treatment settings, especially since 5-FU and Xeloda are mainstay, backbone treatments for which there are often no alternatives.
The NCCN, in its guidelines, also includes these caveats and tells oncologists to keep in mind a patient's specific circumstances when deciding whether to adjust chemotherapy dosing based on DPYD variants. "Patients receiving chemotherapy for palliation might more logically be dose-reduced than patients being treated in the curative setting," the guidelines state.
The guidelines panel, however, also acknowledges that proving DPYD-based dose reductions don't lead to inferior chemo efficacy may be difficult even in the best-designed studies, given the rarity of some DPYD variants in the population. "While preemptive dose adjustment of fluoropyrimidines based on DPYD genotype diminishes the risk of life-threatening toxicity in patients with well-characterized variants, it is not certain that dose reductions do not result in inferior efficacy," the NCCN guidelines panel stated, adding that "in fairness, proving non-inferiority in outcomes in any cancer treatment is a very high bar to achieve."
Ultimately, the changes in FDA labeling for fluoropyrimidines and to NCCN colorectal cancer guidelines come amid repeated petitions and increasing pressure from family members who have lost loved ones to fluoropyrimidine toxicities due to DPD deficiencies and the lack of timely testing. Karen Merritt, a founding member of Advocates for Universal DPD/DPYD Testing (AUDT), noted that members of the advocacy group have written to NCCN's colon and rectal cancer guidelines panels asking them to recommend DPYD testing in 2018 and 2024, and other oncologists and pharmacogenetics experts have submitted four similar requests from 2014 to 2022.
AUDT members in 2023 also requested that the NCCN's breast cancer panel recommend DPYD testing, since fluoropyrimidines are also commonly prescribed in this setting, but those guidelines have yet to be updated.
While pushing for updates to guidelines and drug labeling, AUDT members have also successfully effected changes at institutions like the Dana-Farber Cancer Institute and Mass General Brigham, convincing them to establish pretreatment DPYD testing programs. Similar programs are in place at Cleveland Clinic, Ochsner Health, Atrium Health, and elsewhere, though the majority of healthcare institutions haven't implemented pretreatment testing.
Kerin Milesky, another member of AUDT, was instrumental in convincing Mass General Brigham to institute pretreatment testing after her husband received DPYD testing too late and died from a lethal overdose of Xeloda. "Although this is not the blanket recommendation [or] requirement that we are working toward," Milesky said of the colorectal cancer NCCN guidelines update, "it is a major step toward our ultimate goal."