Pharmacogenetics in oncology: Where we stand today?

Abstract

Most anticancer medications have narrow therapeutic indices low overall response rates, rapid and severe systemic toxicity and unpredictable efficacy. Therefore, nowhere is pharmacogenomics research needed more than in cancer treatment to guide clinicians to better predict the differences in drug response, efficacy, resistance and toxicity among chemotherapy and targeted therapy patients, and to optimize the treatment regimens based on these differences. [4] In oncology, efficacy and safety of many chemotherapeutic drugs show substantial individual and/or population variability. It can be explained, to a great extent, by gene polymorphism encoding drug-metabolizing enzymes, drug transporters and drug targets which influence the pharmacokinetics and pharmacodynamics and affect clinical outcomes. [5,6] There are several known genes which are largely responsible for variations in drug metabolism and response. The most common are the CYP genes, which encode enzymes that influence the metabolism of more than 80% of current prescription drugs.In addition, the application of pharmacogenomics in oncology is in the discovery of biomarkers that guide selective therapy, ABSTRACTIn a given population, there is considerable variation between individuals with regard to response to as well as toxicity of different drugs. The term "Pharmacogenetics" has largely been used in relation to genes determining drug metabolism, while "Pharmacogenomics" is a broader based term that encompasses all genes in a genome that may determine drug response. In oncology, efficacy and safety of many chemotherapeutic drugs show substantial individual and/or population variability. It can be explained, to a great extent, by gene polymorphism encoding drug-metabolizing enzymes, drug transporters, and drug targets which influence the pharmacokinetics and pharmacodynamics and affect clinical outcomes. Single nucleotide polymorphisms (SNPs) are the most studied genetic variants at present due to ease, accuracy, and reduced the cost of processing as well as due to public availability of online resources for SNPs. Candidate genes for a therapeutic and adverse response can be divided into three categories: Pharmacokinetic, receptor/target, and disease-modifying. Many anticancer drugs are evaluated for their variation in response according to germline variations. This information can be easily incorporated in day-to-day practice to improve efficacy and/or safety of these drugs. In the future, advances gained from pharmacogenetics research will provide information to guide doctors in advising just enough of the right medicine to a person -The practice of "personalized medicine."

Application of pharmacogenetics in oncology

“…Yet not all of the cases with decreased DPD activity can be explained with DPYD polymorphisms. In summary, genetic testing for DPYD*2A as a predictive marker of 5-FU toxicity has a positive predictive value of about 50%, compared to about 95% negative [5]. Furthermore, 5-FU toxicity cannot only be due to DPD deficiency.…”

“…Thiopurines are used not only for non-malignant diseases (IBD, rheumatoid arthritis), but they are also applicable for anticancer treatment in haematological malignancies [5]. The following three prodrugs azathioprine, mercaptopirune and thioguanine (TG) are inactivated by TPMT and produce the same active TG nucleotide (TGN) metabolites.…”

“…In patients who are homozygous for the inactive allele, severe myelosuppression is observed. Moderate to severe myelosuppression may be also seen in individuals who are heterozygous when normal thiopurine dosage is administered [5].…”

Pharmacogenomics Driving Precision Cancer Medicine

“…The correlation between genetic variations and drug effects provided the clinical opportunity to stratify patients according to their response to the medicine or the extent to they experience its toxicity. More recently, the word pharmacogenomics started to be more commonly employed in the literature as it is a broader-based term that encompasses all the genes in the genome with relevant effects on drug response and toxicity [18][19][20]. Pharmacogenomics also comprises the development of new drugs targeting specific disease-causing genes [21].…”

“…Although the terms pharmacogenetics and pharmacogenomics are often interchangeable, pharmacogenomics will be a term used in the remainder of this review. Knowledge of genetic variants is particularly relevant in the field of oncology as the therapeutic index of cancer drugs is often narrow, the consequence of toxicity might be severe and failed treatment is often lifethreatening [19,22,23]. This review will look at the current state of pharmacogenomics in connection with the treatment of cancer and how this field is increasingly being employed in "personalizing" therapy and departing from a "one-size-fits-all" approach.…”