Clinical application of pharmacogenetics markers in colorectal cancer therapy

Resumo

The observation of the existence of a great variability in both response and toxicity to the same drug among different patients culminated in the development of a new field of study, the pharmacogenetics, the evolution of which was parallel to the studies carried out to determine the genetic basis of cancer. Pharmacogenetics responds to an inescapable need for modern medicine to tailoring treatments to the unique characteristics of each tumor and to the unique genetic background of each patient. The development of this doctoral thesis, performed in a genetic laboratory linked to a healthcare assistance work in the health field, had as main objective the identification and validation of pharmacogenetic markers for its subsequent inclusion in a predictive kit of both response and toxicity to the treatment of the colorectal cancer, in order to minimize the risk-benefit cost of oncological treatments, and that could be easily implemented in the decision-making tree used in clinical practice. However, although the literature on pharmacogenetics in colorectal cancer is prolific, few markers have been included in pharmacological guidelines and few more exist with sufficient evidence for their implementation. This low number of validated markers is a consequence not only of the inherent limitations of functional and association studies, but also of a relatively new and remarkably complex field of study in which expectations must be met. The above limitations in the studies are reflected in the TYMS analysis. Although our finding of a stop-codon mutation confirms the importance of this gene not only as a predictor of oncologic treatment but possibly as a prognosis in tumor evolution, the results of numerous studies for the evaluation of the role played by certain polymorphisms, although very promising at first, have been limited to a modest predictive capacity of both toxicity and response. Likewise, the finding of the hypermutation phenomenon underscores the complexity of the study of cancer pharmacogenetics; a finding that not only characterizes a subgroup of patients in colorectal cancer, but also questions the use of germline samples for predicting tumor response, especially regarding polymorphic positions, since the mutational rate found in our study exceed those found in monomorphic sequences published in later studies, which is consistent with the functional role attributed to polymorphisms in the modulation of protein activity as well as the hot-spot mutations theory, as observed in the evolution of genomes. All of this suggests that pharmacogenetics should evolve to a broader and more dynamic approach in the analysis of genetic factors influencing the response to drugs, taking into account not only the interactions between genes, but of these with the environment, in agreement with the dynamic behavior of the tumor and the patient's physiological state. Contextualization of genetic information will help to understand the variability among patients and to clarify the reasons for the non-replication of the studies, as well as the existence of seemingly contradictory results. Although greater knowledge must be acquired, there is no doubt that the study of pharmacogenetics will guide individualized medicine.