It has long been observed that interpatient variability in response to medications is associated with a spectrum of outcomes, ranging from failure to demonstrate an expected therapeutic effect to an adverse reaction resulting in significant patient morbidity and mortality, as well as increasing healthcare costs.1,2
Interpatient variation is due, at least in part, to genetics. The term “pharmacogenetics” represents the study of genetic factors that influence response to drugs and chemicals and was first termed in 1959.3
Recently, advances in large genome scale sequencing and improvements in bioinformatic tools in processing large amounts of data have led to the transition of pharmacogenetics to pharmacogenomics, involving studies of the entire spectrum of genes in the human genome.3
The goal of the emerging disciplines of pharmacogenetics and pharmacogenomics (abbreviated jointly as PGx) is to personalize therapy based on an individual’s genotype. To date, the success of PGx has spread across all fields of medicine. Genetic information has been used in the identification of disease risk (eg, the BRCA1 mutation test to evaluate breast cancer risk), choice of treatment agents (eg, CYP2D6 in breast cancer treatment; HLA-B*1502 for carbamazepine), and guiding drug dosing (eg, CYP2C9 and VKORC1 for warfarin dosing, UGT1A1 for irinotecan, and TPMT for 6-mercaptopurine and azathioprine). This is particularly important for chemotherapeutic agents, which in general affect both tumor and nontumor cells and thus have a narrow therapeutic index, with the potential for life-threatening toxicity. Medical oncologists and hematologists are striving to individualize cancer treatment in an effort to maximize efficacy and minimize toxicity in patients. Identifying host genetic variations that contribute to drug efficacy and/or the risk of toxicity will provide a means with which to tailor therapy. Genetic variation could explain variations including pharmacokinetics, alterations in activity or expression of the target, or proteins involved in the mechanism of action of the drug. PGx studies of anticancer agents are potentially complicated by somatic mutations in the tumor, although this is unlikely to impact toxicity.
In the scope of anticancer PGxs, genotypic information can encompass, but is not limited to, single nucleotide polymorphisms (SNPs; a change in which a single base in the DNA differs from the usual base at that position), haplotypes (a set of closely linked genetic markers present on one chromosome that tend to be inherited together), microsatellites or simple sequence repeats (polymorphic loci present in DNA that consist of repeating units of 1-6 base pairs in length), insertion and/or deletion and copy number variations (CNVs; genetic trait of differences in the number of copies of a particular sequence present in the genome of an individual), and aneuploidy (a change in the number of chromosomes that can lead to a chromosomal abnormality) and loss of heterozygosity in the tumor. Phenotype is defined as the characteristics determined by genetic, environmental factors or their combination. Phenotype can take many different forms. For example, it could simply be eye color, or it can be a pharmacokinetic finding (eg, a specific metabolite formation), a clinical marker (eg, tumor volume), or a more complicated trait (eg, overall survival after treatment). Interestingly, researchers from different fields may define phenotypes differently. For example, mRNA expression is treated as a phenotype by geneticists because it is a product of DNA; however, clinicians often lump gene and gene products (eg, RNA and protein) together as genetic predictors.4
A clear definition of phenotype is critical both in conducting and interpreting PGx studies. As an example, when evaluating the genetic contribution to platinum agent-induced toxicity in patients with non-small cell lung cancer, a genetic polymorphism in the ERCC1
gene (C8092A) was found to be associated with an increased risk of grade 3 or 4 gastrointestinal toxicity (defined by the National Cancer Institute Common Toxicity Criteria version 3.0). However, when using overall toxicity or hematologic toxicity as the phenotype of interest, no genotype-phenotype associations were identified.5
Furthermore, the treatment conditions under which the phenotypes were obtained may affect the interpretation of the genotype-phenotype association. Through a meta-analysis, Hoskins et al demonstrated that the UGT1A1
polymorphism is associated with an increasing risk of hematologic toxicities only at medium or high doses of irinotecan.6
This review will provide an overview of the progress made in the field of PGx using a five-stage architecture (). Although considerable effort has been applied to identifying gene expression markers that affect drug response, this review will focus mainly on the germline genetic effects on drug sensitivity. Examples will be provided to illustrate the identification, validation, utility, and challenges of these PGx markers with a focus on the current application of PGx knowledge in cancer therapy.
Five Stages of Pharmacogenetics and Pharmacogenomics in Cancer Therapy.