PHARMACOGENOMIC VARIABILITY IN CHEMOTHERAPEUTIC DRUG RESPONSE AMONG CANCER PATIENTS

Abstract

The heterogeneity in pharmacogenomics plays a critical role in the modulation of the response of the chemotherapeutic drugs, both therapeutic efficacy and toxicity in cancer patients.  This research was done using genome-wide and gene-specific polymorphisms in order to determine the level of correlation between them and interindividual differences in drug metabolism, treatment response and outcomes of adverse events in a heterogeneous group of cancer patients.  The results showed that there were significant differences in key genes including CYP2D6, TPMT, DPYD, UGT1A1, and ABCB1, which altered the plasma drug levels, dose-limiting toxicity and progression-free survival significantly, and the p-values were always below 0.05.  Carriers of reduced-function DPYD alleles proved to have much higher toxicity induced by fluoropyrimidine, and anti-UGT1A1 *28/*28 precursors showed a strong relationship with neutropenia induced by irinotecan.  Moreover, there was a relationship between mutations in ABC transporters with varying levels of intracellular accumulation of drugs which affects the response rates of the platinum-based therapies.  Polygenic risk modelling enhanced the fidelity of the treatment outcomes prediction by 28 which means that there is a high potential of integrated pharmacogenomic profiling in personalised oncology.  All of the data collectively support the idea that genetic variation is significant in terms of chemotherapeutic response pathways and again underlines the need to have genomics-based dosage regimens so as to increase the therapeutic effect and reduce the toxicity effects in cancer patients.