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Outside the Lab Oncology, Genetics and epigenetics, Precision medicine, Profession, Omics

The Undisputable Value of Pharmacogenetic Testing

Ron H. N. van Schaik

Pharmacogenetic testing is escalating in both the number of requests and its importance – these are undisputable facts. But out of this rising interest spring five important questions:

  • How useful is it, exactly?
  • What is the current perception amongst clinicians and laboratory specialists?
  • What are the clinical recommendations?
  • How can it be integrated into routine diagnostic testing?
  • How can we assure quality standards?

The task force on pharmacogenetics was established to address all of these questions, with the aim of supporting the full, efficient and effective integration of pharmacogenetic testing into labs.

We must overcome the existing barriers to pharmacogenetic testing, which include: a lack of access; missing clinical guidelines (even when pharmacogenetic information is present in the drug label); a lack of knowledge on what is possible and available; a lack of clarity on reimbursement strategies – and, sometimes, disagreement on the level of evidence needed to accept testing as valuable.

If someone questions the value of genetic testing to patients in terms of adapting drug type or dosage, I offer several convincing examples. A first positive example is the fact that 99 percent of people who are hypersensitive to the HIV/AIDS treatment abacavir, test positively for HLA-B*5701, a known genetic risk factor (1).

A second example, which has been widely debated, is CYP2D6 testing for tamoxifen therapy. Patients with little or no working CYP2D6 represent around 5–10 percent of the population – are not able to activate tamoxifen, and so are theoretically at risk for undertreatment on standard doses. About 10–15 papers have shown that the CYP2D6 variant genotype is related to a poorer outcome with tamoxifen, but 8–12 papers have shown otherwise (2). So, how much evidence does one require? Is common sense enough? I think not. Should it be confirmed with pharmacokinetics? Yes – that’s much better. Confirmation with pharmacodynamics would be another step further, but is a distribution of 10–15 papers showing an effect enough to routinely include this type of testing? Or is the fact that not all studies find the association sufficient to deprive a large group of patients from this test? Actually, these aspects were all solved by a meta-analysis showing that there is indeed significant evidence that patients with deficient CYP2D6 have a poorer outcome on tamoxifen (3). Yet, despite the evidence, the clinical community still hesitates to propagate this type of testing.

Another example is CYP2C19 testing for clopidogrel – again a drug that needs activation by a genetically polymorphic enzyme (4, 5). CYP2C19 carriers of one or two inactive alleles (approximately 20 percent of the Caucasian population) are less effective in activating clopidogrel, and have been shown to have an increased risk of myocardial infarction, stroke or death. The US FDA has now a boxed warning in the drug label on CYP2C19 for this, but still CYP2C19 testing for clopidogrel use has not been implemented in clinical guidelines. Our task force is trying to facilitate the discussion between clinical chemistry and, in this instance, cardiology, to ensure the uptake of this testing in routine clinical care.

So far, a strong association between genetics and drug sensitivity has been proven for at least 60 different drugs (6) and, in fact, pharmacogenetic information is now included on the drug label for more than 120 drugs.

To date, we’ve successfully established connections with many other organizations operating in this field to support the implementation of guidelines, to update our members and to answer questions. But, as a task force, we still have lot of work to do.

Our ultimate goal is to secure the proper implementation of pharmacogenetics into patient care within the next two years throughout the world. It’s a huge undertaking, but we believe that we can achieve it, if we:

  • create an international clinical laboratory network,
  • ensure high quality testing,
  • create a forum for interaction and information exchange,
  • interact with clinical organizations.

The anticipated result? The production of globally-accepted clinical guidelines for pharmacogenetic testing.

Ron H. N. van Schaik is a professor of pharmacogenetics at Erasmus University Medical Center, Rotterdam, The Netherlands, and chair of the IFCC task force for pharmacogenetics.

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  1. C. Della Russo et al., “Novel Sensitive, Specific, and Rapid Pharmacogenomic Test for the Prediction of Abacavir Hypersensitivity Reaction: HLA-B*5701 Detection by Real-Time PCR”, Pharmacogen., 12, 567–576 (2011).
  2. V. O. Dezentje et al., “Clinical Implications of CYP2D6 Genotyping in Tamoxifen Treatment for Breast Cancer”, Clin. Cancer Res., 15, 15–21 (2009).
  3. M. A. Province et al., “CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Population”, Clin. Pharmacol. Therp., 95, 216–227 (2014).
  4. T. Simon et al., “Genetic Determinants of Response to Clopidogrel and Cardiovascular Events”, New Eng. J. Med., 360, 363–375 (2009).
  5. J. P. Collet et al., “Cytochrome P450 2C19 Polymorphism in Young Patients  Treated With Clopidogrel After Myocardial Infarction: A Cohort Study”, Lancet, 37, 309–317 (2009).
About the Author
Ron H. N. van Schaik

Ron H. N. van Schaik is a professor of pharmacogenetics at Erasmus University Medical Center, Rotterdam, The Netherlands, and chair of the IFCC task force for pharmacogenetics.

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