UDP-glucuronosyltransferase 1A1 (UGT1A1) is a polymorphic enzyme responsible for the metabolism of endogenous compounds and drugs, including the chemotherapeutic agent irinotecan (trade name CAMPTOSAR®). Studies have shown that impaired metabolism in patients who are homozygous for the UGT1A1*28 allele can result in severe, dose-limiting toxicity during irinotecan therapy. These findings led to a recent update in the irinotecan label to include dosing recommendations based on the presence of a UGT1A1*28 allele.Individuals with the UGT1A1*28 allele may require dose modifications for other drugs that are metabolized by the UGT1A1 enzyme. On Aug. 22, the FDA approved this assay for use in identifying patients that may be at increased risk of adverse reactions to the chemotherapy drug irinotecan HCl (Camptosar, made by Pfizer, Inc.) used in the treatment of colorectal cancer. The Drug Information mentions that known homozygous patietns should not be treated with irinotecan. It includes the caution that “the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment.”The question is whether routine testing is indicated. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia).
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-glucuronasyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22(8); 1382-1388. http://www.egappreviews.org/docs/EGAPPWG-UGT1A1Rec.pdf