Rare Gene Mutations Linked to Increased Risk of Fatal Chemotherapy Toxicity

Uncommon variants in the DPYD gene are linked to a 25-times increased risk of fatal toxicity after treatment with standard doses of either chemotherapy drug, stated a meta-analysis of previously published studies, researchers at Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (NCCC), led by Gabriel A. Brooks, MD, MPH. Patients with abnormal variants (mutations) in the DPYD gene are known to be at risk for severe toxicity from treatment with 5-fluorouracil or capecitabine—chemotherapies commonly used to treat colorectal cancer, as well as pancreatic, breast, gastroesophageal and other cancers. But previous studies have not reported the extent to which these DPYD gene variants are linked to fatal chemotherapy toxicity, as fatal toxicity is rare in any individual study. Pooling studies is needed to examine the association of DPYD gene variants with this severe outcome.

The absolute risk of fatal toxicity was 0.1% in patients without DPYD gene variants, and as high as 3.7% in patients with any of the three most severe DPYD gene variants.

The team’s study, “Pathogenic DPYD variants and treatment-related mortality in patients receiving fluoropyrimidine chemotherapy: A systematic review and meta-analysis,” is newly published online in The Oncologist.

Though DPYD and other gene testing has been recommended by the European Medicines Agency since spring of 2020, gene testing is not widely done in the US before patients are administered chemotherapy with 5-fluorouracil or capecitabine. Brooks’ study suggests that adding pre-treatment screening may help prevent avoidable chemotherapy-related deaths without interrupting standard of care, as most patients who carry abnormal gene variants can still be treated with reduced doses of these chemotherapies. NCCC has already implemented routine screening for DPYD gene variants in most gastrointestinal cancer patients.

“US organizations such as the Food & Drug Administration (FDA), the American Society of Clinical Oncology, or the National Comprehensive Cancer Network should consider recommending this testing. The FDA is currently considering a citizen’s petition advocating for more widespread genetic testing, of which I am a cosigner,” says Brooks.

Source-Eurekalert