Pharmacogenetic testing: time for clinical practice guidelines.

Our knowledge regarding genetic factors that affect drug effectiveness and adverse drug reactions is continuously increasing, and a growing number of pharmacogenetic gene– drug interactions are included in drug labels. Nevertheless, the uptake of this important information into clinical practice has been minimal. The development of concise, evidence-based clinical practice guidelines (CPGs) on pharmacogenetic testing is urgently needed to overcome the barriers hindering clinical implementation by providing guidance on test use and interpretation. After great initial euphoria followed by a period of disillusion-ment, pharmacogenetics research is now beginning to show consistent, reproducible findings for an increasing number of genetic markers for drug effectiveness and adverse drug reactions. Whereas this growing body of evidence has resulted in an increasing number of pharmacogenetic effects being included in drug labels (Table 1), the number of pharmacogenetic tests that are routinely used in the clinic has remained extremely small. There are several factors that may have hindered the uptake of pharmacogenetic testing into clinical practice, including lack of reimbursement, liability concerns, insufficient medical training , unclear understanding of the evidence, insufficient sense of competence, and information overload. 1 Many of these impeding factors appear to be more prominent in relation to genetic tests as compared with other biomarkers. 2 Genetic information is thought by many to require exceptional treatment, resulting in excessively high standards for pharma-cogenetic evidence. 2,3 The creation of rigorously developed pharmacogenetic CPGs could help overcome some of these obstacles by providing systematic reviews of existing evidence, concise summaries of the underlying pharmacological mechanisms , recommendations on pharmacogenetic test utility, and genotype-specific treatment options. Drug–Drug anD gene–Drug InteractIons The different perceptions of pharmacogenetic information as compared with nongenetic therapy–relevant information can be illustrated with the example of tamoxifen's effectiveness in breast cancer treatment. Tamoxifen is a selective estrogen receptor modulator that is frequently used for the treatment of estrogen receptor–positive breast cancer. 4 Tamoxifen is a prodrug that is converted into its active metabolite endoxifen by cytochrome P450 isoenzyme 2D6 (CYP2D6). 5 Any factor that reduces CYP2D6 activity is expected to result in lower endoxifen levels and consequent reduction in the effectiveness of tamoxifen. Gene polymorphisms as well as concomitant drugs have been shown to reduce CYP2D6 activity. 6 Studies have also shown a reduced response to tamoxifen both for CYP2D6 gene variants resulting in reduced or absent enzyme activity and for CYP2D6-inhibitory drugs such as selective serotonin reuptake inhibitor (SSRI) antidepressants, …