Using Pharmacogene Polymorphism Panels to Detect Germline Pharmacodynamic Markers in Oncology

Abstract

The patient (germline) genome can influence the pharmacokinetics and pharmacodynamics of cancer therapy. The field of pharmacogenetics (PGx) has primarily focused on genetic predictors of pharmacokinetics, largely ignoring pharmacodynamics, using a candidate approach to assess single-nucleotide polymorphisms (SNP) with known relevance to drug pharmacokinetics such as enzymes and transporters. A more comprehensive approach, the genome-wide association study, circumvents candidate selection but suffers because of the necessity for substantial statistical correction. Pharmacogene panels, which interrogate hundreds to thousands of SNPs in genes with known relevance to drug pharmacokinetics or pharmacodynamics, represent an attractive compromise between these approaches. Panels with defined or customizable SNP lists have been used to discover SNPs that predict pharmacokinetics or pharmacodynamics of cancer drugs, most of which await successful replication. PGx discovery, particularly for SNPs that influence drug pharmacodynamics, is limited by weaknesses in both genetic and phenotypic data. Selection of candidate SNPs for inclusion on pharmacogene panels is difficult because of limited understanding of biology and pharmacology. Phenotypes used in analyses have primarily been complex toxicities that are known to be multifactorial. A more measured approach, in which sensitive phenotypes are used in place of complex clinical outcomes, will improve the success rate of pharmacodynamics SNP discovery and ultimately enable identification of pharmacodynamics SNPs with meaningful effects on treatment outcomes.

Genome-Wide Association Study: A Useful Tool to Identify Common Genetic Variants Associated with Drug Toxicity and Efficacy in Cancer Pharmacogenomics

“…As most of the identified variants from the GWAS of cancer pharmacogenomics did not surpass this stringent and conservative threshold, verification with an independent set of samples would be useful to support the findings from GWAS. One reasonable way to compromise the GWAS stringent significant threshold is the use of pharmacogene panels (this topic is addressed extensively in this CCR Focus section), which screened SNPs in genes with known relevance to drug pharmacokinetics and pharmacodynamics (53). To provide additional supportive evidence of variants identified from GWAS, functional analyses, such as electrophoretic mobility shift assay and luciferase reporter assay, could be carried out to investigate the effects of the variants affecting the phenotypes.…”

Evidence for Association of SNPs in ABCB1 and CBR3 , but not RAC2, NCF4, SLC28A3 or TOP2B , with Chronic Cardiotoxicity in a Cohort of Breast Cancer Patients Treated with Anthracyclines

“…SNPs in genes relevant to anthracycline metabolism and elimination may contribute to differences in drug exposure, which may account for variability in the development of cardiomyopathy. Alternatively, variation in genes related to the pharmacological mechanism of cardiotoxicity could dictate a patient's sensitivity to the development of cardiomyopathy [7].…”

In Vivo Imaging as a Pharmacodynamic Marker

“…As a result, the development and clinical validation of radiolabeled drugs is very expensive and time-consuming and cannot yet be used on a large scale (21). Nevertheless PET using radiolabeled taxanes is a promising technique for several investigations (66) (68)(69)(70)(71). For newly developed taxanes, future PET studies using radiolabeled taxanes could serve as pre-phase I studies (72).…”