Pharmacogenetics of capecitabine and oxaliplatin in treatment of advanced colorectal cancer

Abstract

Treatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects. Furthermore, treatment is not effective in all patients. Currently, pre-treatment predictors for efficacy and toxicity in systemic treatment of ACC are scarce. Germline genetic variation in genes encoding for enzymes involved in pharmacokinetics or pharmacodynamics of cytotoxic drugs could explain intra-patient differences in treatment effects. Pharmacogenetic studies aim at finding such germline genetic predictors. This thesis focusses on pharmacogenetics of capecitabine and oxaliplatin in treatment of ACC. First, it is established that results derived from DNA in archived tumor samples can be reliably compared to those using DNA from peripheral blood leukocytes. Then, germline genetic markers in MTHFR and MTRR, as well as markers derived from an in vitro genome-wide association study (GWAS) are tested for their association with capecitabine toxicity. Next, effects of ERCC1 genotype on oxaliplatin cytotoxicity in vitro and in clinical association analysis are addressed. The influence of genetic variation in organic cation transporters on oxaliplatin-induced neurotoxicity is examined. Lastly, the results of a GWAS searching for germline predictors of treatment efficacy of capecitabine, oxaliplatin and bevacizumab, with or without cetuximab, are presented.