ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 18 Impact of Genetic Polymorphisms in Normal Tissue on Pharmacokinetics and Side Effects Genetic anomalies in normal, non-tumor tissue may affect the pharmacokinetics in an individual patient, contribute to responses to therapy, and may play a role in an atypical response. For example, cytochrome P450 liver enzymes metabolize drugs, and one of these, CYP2D6, is involved in the metabolism of approximately 25% of all prescribed drugs [27]. CYP2D6 may metabolize drugs to inactivate molecules, or metabolize pro-drugs into active metabolites. Approximately 75% of people, depending on ethnicity, are “normal metabolizers” and harbor two wild-type copies of CYP2D6. However, a small percentage of people are “ultra-rapid” or “extensive” metabolizers. Due to CYP2D6 gene duplication, increased numbers of enzyme molecules are produced, resulting in increased drug metabolism. In contrast, some people are “poor metabolizers”. Due to allelic variants of CYP2D6, these individuals produce enzyme molecules with lower than normal CYP2D6 activity. CYP2D6 is important for breast cancer patients because this enzyme is needed to convert Nolvadex® (tamoxifen) to endoxifen, the active form of the drug. Thus, patients who are ultra- rapid metabolizers are expected to convert high levels of Nolvadex® to endoxifen, and those who are poor metabolizers do not obtain therapeutic levels of the active metabolite and therefore may not experience the expected therapeutic response. Hence, CYP2D6 phenotype-adjusted dosing may be required [28, 29]. Genotype/phenotype analyses for CYP2D6 are currently available (e.g., Genelex, Seattle, WA). Other cytochrome P450 genes expressed in the liver and small intestine also play a role in drug metabolism. Often drugs metabolized by the same cytochrome P450 can impede one another, and thus, drug interactions need to be carefully monitored to ensure patients receive the intended therapeutic dose [30]. Treatment with a prior CYP inhibitor is sometimes an exclusion criterion in clinical trial design. Multiple clinical trials are examining the contribution of various CYP genotypes to response to therapy. Some natural products consumed as CIM inhibit or activate different cytochrome P450 enzymes [31]. Although tests are available to determine the cytochrome P450 genotype and predicted phenotype, determining the pharmacokinetics profile of an individual patient and predicting a response to therapy can be extremely complex and is not yet incorporated into the standard of care. Another example in which a genetic mutation in normal tissue affects the response to therapy is dihydropyrimidine dehydrogenase (DPD) deficiency. About 5% of individuals are deficient in this enzyme due to a mutation in its gene, leading to insufficient breakdown of drugs such as Xeloda® (capecitabine) and subsequent severe toxicity [32]. Genetic anomalies in normal, non-tumor tissue can impact a patient’s response to a given therapy.