Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab

Disclosures

Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article

Consequences for Molecular Diagnostics

The current evidence highlights CYP2D6 to be the most relevant molecular diagnostic factor to be utilized for stratified use of tamoxifen in the endocrine treatment setting of postmenopausal breast cancer. The highest standard in CYP2D6 genetic testing equates to comprehensive allele coverage by using the FDA-approved AmpliChip CYP450 test system in order to accurately predict the metabolizer phenotype.[40,61] However, a limited analysis of the most common CYP2D6 variants listed in Table 1 also seems appropriate for most molecular diagnostic purposes[45] and represents an acceptable compromise if AmpliChip testing is deemed impractical for routine testing. Suitable options are the FDA-approved xTAG® CYP2D6 kit and the INFINITI® CYP450 2D6I assay, which both simultaneously interrogate 15 genetic variants.[103] It must be stressed that testing for only one variant, such as *4, is highly unacceptable for research purposes and unethical for clinical practice. This may not only be relevant for tamoxifen, but also for other CYP2D6 substrates.

Another critical requirement is obtaining the most appropriate source of DNA for genetic testing. Because DNA from tumor samples is susceptible to somatic gene deletions, a blood sample that provides constitutional DNA must be the requirement for diagnostic genetic testing.

In addition to high standard diagnostic test criteria, it is critical to consider that testing results should be accompanied with an expert interpretation.[104] This should include suggestions for other valid treatment options, the avoidance of known CYP2D6 inhibitors and dosing adjustments where appropriate, thereby effectively conveying the clinical ramifications that are critical to treatment decision-making.[104]

Diagnostic testing relies on the professional experience associated with patient management and treatment, which cannot be sufficiently covered by specialist molecular knowledge and analytical expertise alone. In fact, genetic testing laboratories require interdisciplinary cooperation involving clinicians, clinical pharmacologists and molecular scientists with appropriate training in molecular diagnostics, to produce testing reports of the highest standard of care.

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