The association between variants of the DPYD gene and serious side effects from the cancer drug 5-fluorouracil (5–FU) in colon cancer patients has been bolstered by the results of recent large-scale study.
The largest study to date investigating the association between DPYD variants and 5-FU adverse drug events has found a statistically significant association between two variants that decrease DPYD activity and patients experiencing low white blood cell and blood platelet counts, nausea and vomiting, dehydration and diarrhea. The study appeared in the November issue of the Journal of the National Cancer Institute and was reported first on the University of Florida’s Personalized Medicine Program blog.
Study authors Lee et al. found that 88 percent of study participants carrying the DPYD*2A variant experienced severe or worse adverse events related to 5-FU. The researchers also found 81.5 percent of carriers of the other variant, known as D949V, had severe 5-FU-related side effects.
According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for DPYD variants and 5-FU dosing, between 3 percent and 5 percent of people have decreased DPYD activity.
Specifically, Lee et al. linked the *2A variant with nausea/vomiting and neutropenia, or an abnormally low count of a type of white blood cell that fights off infections. The D949V variant was associated with dehydration, diarrhea, neutropenia, leukopenia (low white blood cell count), and thrombocytopenia (low blood platelet count). In an extreme case in the study, one patient with completely deficient DPYD activity died from complications of severe 5-FU toxicity.
The researchers also studied the I560s variant, also designated *13, and found two of four total study participants with this variant experienced severe side effects from 5-FU. Though a statistically significant association between severe side effects and this variant could not be demonstrated in this study because of the low number of *13 patients, other research supports an association. The current CPIC guidelines provide recommendations for patients who carry the *13 variant, in addition to *2A and D949V.
An editorial published in the same issue of the Journal of the National Cancer Institute calls Lee and colleagues’ work the “ultimate evidence” for DPYD variation as a major determinate in patient safety.
“The occurrence of these heritable variants poses considerable risk for patients and a challenge to patient management to preserve dose intensity,” writes Dr. Federico Innocenti, of the University of North Carolina Chapel Hill.
5-FU is one of the most common drugs used to treat colon cancer, which about one in 20 people will be diagnosed with in their lifetimes. According to the Colon Cancer Alliance, colon cancer is the second leading cause of cancer-related death in the U.S.
However, colon cancer can often be found early with regular screenings, with more than 90 percent of individuals diagnosed when the cancer is found in the local stage (confined to the colon or rectum) surviving more than five years. The colon cancer death rate has steadily dropped since the mid-1980s due in part to increased awareness and screenings, according to the Colon Cancer Alliance.
Genelex is dedicated to keeping up to date on the most relevant clinical research on genes that influence response to medications. To further this mission, Genelex has introduced 17 new genetic tests, including one that tests for the presence of these three common DPYD variants. Learn more here.