Gulf Today

A common gene test could save hundreds of lives

- Arthur Allen,

Rosen was one of more than 275,000 cancer patients in the United States who are infused each year with fluorourac­il, known as 5-FU, or, as in Rosen’s case, take a nearly identical drug in pill form called capecitabi­ne

One January morning in 2021, Carol Rosen took a standard treatment for meta static breast cancer. Three gruesome weeks later, she died in excruciati­ng pain from the very drug meant to prolong her life. Rosen, a 70-year-old retired schoolteac­her, passed her final days in anguish, enduring severe diarrhea and nausea and terrible sores in her mouth that kept her from eating, drinking, and, eventually, speaking. Skin peeled off her body. Her kidneys and liver failed. “Your body burns from the inside out,” said Rosen’s daughter, Lindsay Murray, of Andover, Massachuse­ts. Rosen was one of more than 275,000 cancer patients in the United States who are infused each year with fluorourac­il, known as 5-FU, or, as in Rosen’s case, take a nearly identical drug in pill form called capecitabi­ne. These common types of chemothera­py are no picnic for anyone, but for patients who are deficient in an enzyme that metabolize­s the drugs, they can be torturous or deadly.

Those patients essentiall­y overdose because the drugs stay in the body for hours rather than being quickly metabolize­d and excreted. The drugs kill an estimated 1 in 1,000 patients who take them — hundreds each year — and severely sicken or hospitaliz­e 1 in 50. Doctors can test for the deficiency and get results within a week — and then either switch drugs or lower the dosage if patients have a genetic variant that carries risk. Yet a recent survey found that only 3% of US oncologist­s routinely order the tests before dosing patients with 5-FU or capecitabi­ne. That’s because the most widely followed US cancer treatment guidelines — issued by the National Comprehens­ive Cancer Network — don’t recommend preemptive testing. The FDA added new warnings about the lethal risks of 5-FU to the drug’s label on March 21 following queries from KFF Health News about its policy. However, it did not require doctors to administer the test before prescribin­g the chemothera­py.

The agency, whose plan to expand its oversight of laboratory testing was the subject of a House hearing, also March 21, has said it could not endorse the 5-FU toxicity tests because it’s never reviewed them. But the FDA at present does not review most diagnostic tests, said Daniel Hertz, an associate professor at the University of Michigan College of Pharmacy. For years, with other doctors and pharmacist­s, he has petitioned the FDA to put a black box warning on the drug’s label urging prescriber­s to test for the deficiency. “FDA has responsibi­lity to assure that drugs are used safely and effectivel­y,” he said. The failure to warn, he said, “is an abdication of their responsibi­lity.” The update is “a small step in the right direction, but not the sea change we need,” he said.

British and European Union drug authoritie­s have recommende­d the testing since 2020. A small but growing number of US hospital systems, profession­al groups, and health advocates, including the American Cancer Society, also endorse routine testing. Most US insurers, private and public, will cover the tests, which Medicare reimburses for $175, although tests may cost more depending on how many variants they screen for. In its latest guidelines on colon cancer, the Cancer Network panel noted that not everyone with a risky gene variant gets sick from the drug, and that lower dosing for patients carrying such a variant could rob them of a cure or remission. Many doctors on the panel, including the University of Colorado oncologist Wells Messersmit­h, have said they have never witnessed a 5-FU death. In European hospitals, the practice is to start patients with a half- or quarter-dose of 5-FU if tests show a patient is a poor metabolize­r, then raise the dose if the patient responds well to the drug. Advocates for the approach say American oncology leaders are dragging their feet unnecessar­ily, and harming people in the process.

“I think it’s the intransige­nce of people siting on these panels, the mindset of ‘We are oncologist­s, drugs are our tools, we don’t want to go looking for reasons not to use our tools,’” said Gabriel Brooks, an oncologist and researcher at the Dartmouth Cancer Center. Oncologist­s are accustomed to chemothera­py’s toxicity and tend to have a “no pain, no gain” atitude, he said. 5-FU has been in use since the 1950s. Yet “anybody who’s had a patient die like this will want to test everyone,” said Robert Diasio of the Mayo Clinic, who helped carry out major studies of the genetic deficiency in 1988. Oncologist­s oten deploy genetic tests to match tumors in cancer patients with the expensive drugs used to shrink them. But the same can’t always be said for gene tests aimed at improving safety, said Mark Fleury, policy director at the American Cancer Society’s Cancer Action Network. When a test can show whether a new drug is appropriat­e, “there are a lot more forces aligned to ensure that testing is done,” he said. “The same stakeholde­rs and forces are not involved” with a generic like 5-FU, first approved in 1962, and costing roughly $17 for a month’s treatment.

Oncology is not the only area in medicine in which scientific advances, many of them taxpayerfu­nded, lag in implementa­tion. For instance, few cardiologi­sts test patients before they go on Plavix, a brand name for the anti-blood-cloting agent clopidogre­l, although it doesn’t prevent blood clots as it’s supposed to in a quarter of the 4 million Americans prescribed it each year. In 2021, the state of Hawaii won an $834 million judgment from drugmakers it accused of falsely advertisin­g the drug as safe and effective for Native Hawaiians, more than half of whom lack the main enzyme to process clopidogre­l.

The flu oro pyrimidine enzyme deficiency numbers are smaller — and people with the deficiency aren’t at severe risk if they use topical cream forms of the drug for skin cancers. Yet even a single miserable, medically caused death was meaningful to the Dana-farber Cancer Institute, where Carol Rosen was among more than 1,000 patients treated with fluoropyri­midine in 2021. Her daughter was grief-stricken and furious ater Rosen’s death. “I wanted to sue the hospital. I wanted to sue the oncologist,” Murray said. “But I realized that wasn’t what my mom would want.”

Instead, she wrote Dana-farber’s chief quality officer, Joe Jacobson, urging routine testing. He responded the same day, and the hospital quickly adopted a testing system that now covers more than 90% of prospectiv­e fluoropyri­midine patients. About 50 patients with risky variants were detected in the first 10 months, Jacobson said. Dana-farber uses a Mayo Clinic test that searches for eight potentiall­y dangerous variants of the relevant gene. Veterans Affairs hospitals use a 11-variant test, while most others check for only four variants.

The more variants a test screens for, the beter the chance of finding rarer gene forms in ethnically diverse population­s. For example, different variants are responsibl­e for the worst deficienci­es in people of African and European ancestry, respective­ly. There are tests that scan for hundreds of variants that might slow metabolism of the drug, but they take longer and cost more. These are biter facts for Scot Kapoor, a Toronto-area emergency room physician whose brother, Anil Kapoor, died in February 2023 of 5-FU poisoning. Anil Kapoor was a well-known urologist and surgeon, an outgoing speaker, researcher, clinician, and irreverent friend whose funeral drew hundreds. His death at age 58, only weeks ater he was diagnosed with stage 4 colon cancer, stunned and infuriated his family.

 ?? File/associated Press ?? Survey found that only 3% of US oncologist­s routinely order the tests before dosing patients with 5-FU or capecitabi­ne.
File/associated Press Survey found that only 3% of US oncologist­s routinely order the tests before dosing patients with 5-FU or capecitabi­ne.

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