Genotype-based therapeutic approach for colorectal cancer: state of the art and future perspectives

Background: There is a considerable need to increase efforts in maximizing clinical outcome in the treatment of colorectal cancer, and the identification of genetic factors underlying drug response seems to be one of the most promising areas in this research field. Methods: Clinical trials and pharmacogenetic association studies were reviewed to offer an overview of the most commonly reported polymorphisms in candidate genes critically involved in the response to the chemotherapeutics used at present in the management of colorectal cancer. Results: Several studies investigating the association between genotype and therapeutic results show contrasting data, thus determining increasing uncertainty in the identification of reliable predictive genetic markers of drug response. However, some of the genetic variations identified in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, glutathione S-transferase pi, and uridine diphosphate glucosyltransferase 1A1 seem to be promising predictors of drug efficacy and/or toxicity. Conclusion: Additional investigation is needed to validate fully the clinical relevance of individual genetic differences in the variability of drug response. It is hoped that this knowledge base will offer, in the not too distant future, the opportunity to overcome the empirical trial-and-error method in favor of therapeutic drug optimization based on individual genetic make-up.