In a recent study, researchers have shown the impact that certain pathogenic gene variants can have on the risk of fatal toxicity from common chemotherapy drugs used to treat colorectal and other cancers.
Chemotherapy
Despite rapid advances in targeted therapies, chemotherapy is still the mainstay treatment for many cancers. These drugs provide a potent but non-specific approach for destroying rapidly growing cells in the body. Fluoropyrimidine chemotherapy drugs in particular, including 5-fluorouracil and its oral prodrug capecitabine, play a key role in treating gastrointestinal, breast, and head and neck cancers. The toxicities of these drugs are well known, including neutropenia, diarrhoea and mucositis. Despite reductions in treatment-related toxicities due to changes in dosing and administration, around 15-20% of patients receiving fluoropyrimidine monotherapy still suffer from severe drug-related adverse effects (grade 3 or higher). In addition, around 1% of patients die due to these treatments (grade 5).
Researchers have previously found that uncommon variants of the DPYD gene are associated with severe and sometimes fatal fluoropyrimidine toxicity. The DPYD gene encodes the enzyme dihydropyrimidine dehydrogenase (DPD). This enzyme is involved in fluoropyrimidine metabolism. Deficiency of DPD enzymatic function can lead to the toxic accumulation of fluoropyrimidine metabolites. Germline variants in this gene are the main cause of DPD deficiency. Pathogenic variants in the DPYD gene have been linked to 5-8 times increased odds of grade 3 or higher toxicity. There are at least four DPYD alleles that are significantly associated with severe toxicity, with a combined carrier frequency in European and American populations of 2-8%.
Exploring variants related to severe toxicity
While much research has explored the impact of pathogenic DPYD variants on moderate-to-severe toxicity, reliable estimates for the risk of treatment-related deaths are lacking. In a recent study, published in The Oncologist, researchers conducted a systematic review and meta-analysis to estimate the risk of treatment-related deaths associated with DPYD gene variants.
Of the 2,923 references screened, the researchers included 35 studies involving 13,929 patients. In total, 566 DPYD variants were identified (4.1%). The team found that these uncommon variants were associated with a 25-times increased risk of fatal toxicity after treatment with standard chemotherapy. The absolute risk of fatal toxicity was 0.1% in patients without DPYD gene variants, and as high as 3.7% in patients who carried the three most severe DPYD variants.
DPYD testing
Although DPYD gene testing has been recommended by the European Medicines Agency, it is still not widely conducted in patients before they are administered chemotherapy treatment. This study demonstrates that implementing pre-treatment screening could help prevent avoidable chemotherapy-related deaths. Most importantly, this would not impact standard of care as patients who carry these abnormal gene variants could still be treated with these drugs but at a reduced dose.
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