UGT1A1 Sequence Variant Testing for Predicting Response to Irinotecan Therapy in Colorectal Cancer
Irinotecan is an injectable anticancer agent used to treat colorectal cancer (CRC) and is a prodrug that is converted to its active form, SN-38, by carboxylesterase metabolism. Irinotecan has a narrow therapeutic range and causes toxicities, including severe diarrhea and neutropenia in 20% to 35% of patients, necessitating dose reduction and, often, hospital administration. Because these adverse events may be life threatening and are costly to manage, a method to accurately predict which patients are more susceptible to irinotecan adverse events before administration is desirable. One of the main enzymes that controls the metabolic breakdown of SN-38 to an inactive metabolite is uridine-diphosphate (UDP) glucuronosyltransferase 1A1 (UGT1A1). Several common sequence variants and polymorphisms of the UGT1A1 gene are known to have reduced UGT1A1 enzyme activity, and may be associated with an increased risk of irinotecan toxicities. The most common polymorphism in the white population is UGT1A1*28 and patients who are homozygous for this polymorphism (UGT1A1*28/UGT1A1*28) are thought to be at increased risk of diarrhea and neutropenia when treated with irinotecan. The normal or wild-type allele is termed UGT1A1*1. In white populations, the frequency of individuals with the UGT1A1*1/UGT1A1*1, UGT1A1*1/UGT1A1*28, and UGT1A1*28/UGT1A1*28 alleles is 56%, 28% to 36%, and 9 to 17%, respectively. A suggestion of a dose reduction of irinotecan in UGT1A1*28/UGT1A1*28 patients was introduced into the irinotecan prescribing information in 2005. Despite the mention of UGT1A1 genotyping prior to irinotecan administration in the Food and Drug Administration (FDA) prescribing guidelines and FDA approval of the Invader UGT1A1 Molecular Assay, there remains controversy as to whether genotyping for UGT1A1 polymorphisms has clinical utility in reducing adverse events
of individuals with UGT1A1 genotypes that result in reduced activity of the UGT1A1 enzyme. Alternatively, clinical utility may come through increased dosing in patients with UGT1A1 genotypes that results in normal or increased function of UGT1A1 enzyme activity, leading to improved efficacy.
- Antibodies, Monoclonal
- Colorectal Neoplasms
- Genetic Testing
- Treatment Outcome