The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines

Fluoropyrimidines (FP) are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast, head and neck and gastric cancer. FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity. With the high number of patients receiving FP-based therapies, and the significant effects of toxicities on their quality of life, the prevention of FP-related adverse events is of major clinical interest. Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD) gene are related to the occurrence of extremely severe, early onset toxicity in FP treated patients. The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines. Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice. Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways, TYMS and MTHFR, but no additional clinically validated genetic markers of toxicity are available to date. The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers. Moreover, the investigation of the genetic variation in the patients immunological system, a pivotal target in cancer treatment, could bring notable advances in the field. This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.