Abstract CN04-04: Pharmacogenetic findings translated into clinical predictive biomarkers.
Authors: Guchelaar Henk-Jan 
Published: June 2012

Pharmacogenetics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established “one size fits all” and “trial and error” approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years, commercially available pharmacogenetic tests have been approved by the Food and Drug Administration (FDA) and pharmacogenetic information was added to several drug labels, but their application in patient care remains very limited. More generally, the implementation of pharmacogenetics in routine clinical practice presents significant challenges. The presentation discusses specific clinical examples of such challenges and discusses how main obstacles to implementation of pharmacogenetic testing can be addressed.

To be clinically useful, a pharmacogenetic test must predict the outcome of drug treatment or guide dose-adjustment. However, not every drug needs a biomarker for predicting response. Biomarkers predicting drug response are especially useful when the drug's effect cannot be easily monitored or when treatment delay has important clinical consequences, or when it predicts the occurrence of severe side effects.

Complex pathways are involved in the action and metabolism of most anticancer drugs and nongenetic factors such as age, tumor size, line of treatment also contribute to the drug's response. In case of anticancer drugs also the tumor characteristics (for example: hormone receptor expression, mutations) are known to highly influence drug response. Therefore, pharmacogenetic testing for single genetic germline polymorphisms may account for only part of the variability in drug response. Indeed, drug response is a complex trait meaning that besides genetic variation in genes encoding enzymes/proteins and transporters involved in the pharmacokinetics and pharmacodynamics (pharmacogenetics) also several non-genetic determinants contribute to variability of drug response. Therefore, predictive models incorporating both genetic and nongenetic determinants of response may help better explain variability in response. The diagnostic test criteria sensitivity, specificity, and predictive value are applicable to tests for which response is determined as a dichotomous variable. However, drug response cannot always be considered an all-or-none phenomenon. In these situations the relative contribution of the genotype to the variability in response (the percentage explained variance, R2) provides additional information. Diagnostic test criteria of pharmacogenetic tests are not commonly reported, but are important for clinical implementation.

The literature on pharmacogenetics is expanding rapidly. However, a Pubmed search with the MeSH term “pharmacogenetics” showed that almost 45% were review articles. The relative paucity of original research articles is not the only problem. Many original articles involve a small, specific study population, administration of single doses, use of healthy volunteers instead of patients, or use of a different translation from genotype to phenotype. Moreover, most positive association studies lack validation of findings in an independent patient population. In addition, pharmacogenetic studies published to date usually report that carriers of a specified genotype in a particular patient population have an increased likelihood (Odd ratios varying form 1.1–2.0) of a desired (or undesired) outcome of drug treatment. Such studies have not, however, resulted in the distillation of practical prescribing recommendations based on genotype.

Moreover, for most pharmacogenetic tests (such as tests for genetic variants of cytochrome P450 enzymes) a detailed knowledge of pharmacology is a prerequisite for application in clinical practice, and both physicians and pharmacists might find it difficult to interpret the clinical value of pharmacogenetic test results. Guidelines that link the result of a pharmacogenetic test to therapeutic recommendations might help to overcome these problems, but such guidelines are only sparsely available. However, the use of such recommendations in routine clinical practice remains difficult, because they are currently outside the ambit of the clinical environment and are not accessible during the decision-making process by physicians and pharmacists, namely the prescription and dispensing of drugs. Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).

Genotyping of patients in a routine clinical setting requires robust and reliable genotyping methods. Since most of these methods are homebrew tests, the analytical validity of genotyping methods needs special attention. A survey of pharmacogenetic association studies for use of quality control samples in the two most prominent pharmacogenetic journals revealed that only a minority of papers report the use of such quality controls, and no standard procedures are applied. We have developed plasmid-derived external controls and advocate their use in pharmacogenetic testing.

We conclude that pharmacogenetic testing in cancer therapy has the potential to result in safer and more effective use of drugs by permitting individualized therapy. Providing the scientific evidence that pharmacogenetic testing leads to improved patient outcome presents a significant challenge.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr CN04-04.