Genotyping of <i>UGT1A1</i> and <i>DPYD</i> polymorphisms in patients with colorectal cancer. A review

Abstract

The main treatment regimen for patients with metastatic colorectal cancer is still cycle-based chemotherapy with fluoropyridines combined with oxaliplatin and/or irinotecan. The activity of these chemotherapeutic agents depends on a predominant specific metabolism pathway. Therefore, the genetic features of the patient become important as a prognostic factor for the occurrence and severity of adverse events during therapy. The review addresses current views about the mechanisms of toxic activity of irinotecan and fluoropyrimidines, analyzes the results of pharmacogenotyping of UGT1A1 and DPYD polymorphisms, and published studies assessing the relationship between genetic variants of these genes and the safety of chemotherapy. A significant role of the population component is noted both in the distribution of gene allele frequencies and in their phenotypic expression. For some polymorphisms of the DPYD gene, dose-dependent associations with the toxicity of 5-fluorouracil have been established. Nevertheless, they determine only 1–8% of cases out of 40–60% of patients with adverse events and DPD protein deficiency associated with other enzyme activity reduction mechanisms. The pharmacological significance of UGT1A1 genetic variations is associated with toxicity prediction and helps allocate patients for more effective high-dose irinotecan therapy. Data is presented on the pharmacogenotyping of these markers to establish the dose of drugs in various national guidelines. Currently, the heterogeneity of the available pharmacogenetic data leaves open the question of determining the most appropriate dosing strategies for irinotecan and fluoropyrimidines. The widespread introduction of UGT1A1 and DPYD genotyping into clinical practice balances the economic feasibility and predictive value of biomarkers. As pharmacogenomics evolves rapidly, more robust research would overcome existing hurdles and facilitate personalized drug dosage decisions.