Uridine Diphosphate Glucuronosyltransferase (UGT) 1A1 and Irinotecan: Practical Pharmacogenomics Arrives in Cancer Therapy

For 50 years the dosing of anticancer drugs has been empirical— small phase I trials predict a tolerable dose, and subsequent studies refine the accuracy of that prediction. Because of population variability, however, a proportion of patients will inevitably experience more severe toxicity at doses selected for general use. Phase III trials routinely report grade 4 myelosuppression rates of up to 80% in certain solid tumors, without a recommendation for a dose adjustment. Historically, this risk has been regarded as acceptable, compared with the greater risk of treating the greater part of the population with ineffective doses. Approaches to individualizing therapy have been sought through pharmacokinetic analyses, but recommendations to the community have never been practical. In recent years, the potential of pharmacogenetic analyses to improve the therapeutic index of cancer therapy in pediatric malignancies has been described. For example, thiopurines are subject to variable metabolic disposition through single nucleotide polymorphisms (mutations in a gene sequence that have a prevalence of at least 1%). Clinical studies have shown that identification of the variant population has the potential to ameliorate toxicity while enhancing therapeutic outcome. Similar genetic signatures have long been sought in adult solid tumors. In colorectal cancer, several candidate genes have been identified that have the potential to determine risk of toxicity and possibly efficacy of fluoropyrimidines and oxaliplatin. Such approaches have two distinct goals: to minimize toxicity and to maximize the effectiveness of therapy. In 2005, the US Food and Drug Administration (FDA) took two actions that may be perceived as an advance regarding how pharmacogenetic approaches might permit us to reduce the risk of chemotherapy. First, it was determined that a fraction of the population at higher risk for adverse effects associated with the use of standard doses of irinotecan can be identified prospectively. These are patients who, by virtue of a genetic polymorphism, have a lower than normal capacity to metabolize SN-38, the active metabolite of irinotecan. The polymorphism is found in the gene encoding uridine diphosphate glucuronosyltransferase (UGT) 1A1, which facilitates the excretion of SN-38. This risk was emphasized by a warning added to the package insert of irinotecan. The text added to the label states that “individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of CAMPTOSAR treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele.” Second, the FDA approved a test to identify these individuals. The genetic test (Invader UGT1A1 Molecular Assay; Third Wave Technologies Inc, Madison, WI), conducted on genomic DNA isolated from peripheral blood, identifies patients homozygous for the UGT1A1*28 allele. Such patients clear irinotecan and its metabolites more slowly than the rest of the population, and so have greater exposure to active drug after a standard dose. The FDAapproved label for the test states that “a reduced initial dose [of irinotecan] should be considered for patients known to be homozygous for the UGT1A1*28 allele.” What are practicing oncologists to do with this information?