Pharmacogenetics, Pharmacogenomics and Personalized Medicine: Are We There Yet?

Abstract

The genetic basis of a differential response to drugs has been understood for a limited number of agents for over 30 years. This knowledge has generated hope that the individual basis for response to a wide range of drugs would be quickly known, and individualized drug selection and dosing would be possible for many or all disorders. Understanding the variable response to drugs seems particularly pressing in the field of oncology, in which the stakes are high (failure to cure cancer usually leads to death), drugs commonly have a narrow therapeutic index, and toxicities can be severe (a significant frequency of toxic death is a feature of most acute myeloid leukemia protocols, for example). However, in common with many new technologies, the generalizability and clinical application of pharmacogenetics has proved more challenging than expected. Difficulties include, in many examples, a modest clinical effect relative to genotype, therapy-specific, not broad, applicability and the very major challenge of unraveling the complexity of gene-gene interactions. In addition, ethical and economic challenges to the application of pharmacogenetics have moved to the fore in recent years, particularly in the context of racial differences in outcome of therapy. Genomic, rather than candidate gene approaches to identification of relevant loci are increasingly being explored, and significant progress is being made. However, greater understanding of the complexities of multiple gene modifiers of outcome, and the statistical challenge of understanding such data, will be needed before individualized therapy can be applied on a routine basis.

Pharmacogenetics of the neurodevelopmental impact of anticancer chemotherapy

“…The fact that over the last 25 years, only two examples of pharmacogenetic approaches have gone from identification of gene variants to acceptance in practice (TPMT for 6-MP and UGT1 for irinotecan) in the prediction of acute systemic toxicity is by itself a measure of this challenge [Tomlinson et al, 1997;Davies, 2006]. Pharmacogenetic studies will also have to report data from studies performed as long as a decade previously, as clinical endpoints such as IQ loss must be reached before the effect of a genotype can be tested.…”

Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics

“…From studies elucidating differences in cytochrome P450 metabolism of numerous drugs, the field has evolved to evaluate both genetic pharmacokinetics and genetic effects on drug activity (pharmacodynamics). Several of the key findings in pharmacogenetics have been in the areas of cancer, hypertension, and coronary artery disease [15,16].…”

Pharmacogenetics and Personalized Medicine in Hematology

“…It also has major implications in hematological disorders, and precision and personalized medicine is considered one of the frontier areas of translational research today. Salient examples include the incorporation of CYP2C9 and VKORC1 genotypes in oral anticoagulant dosing algorithms and the influences of thiopurine S-methyltransferase (TPMT) and methylene tetrahydrofolate reductase (MTHFR) genotypes on the safety and efficacy of 6-mercaptopurine and methotrexate therapies respectively in acute lymphoblastic leukemia [3].…”