4 research outputs found
Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment
Abstract Background Pharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study. Methods Women planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication. Results A total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P < 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6. Conclusions CYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact
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Tamoxifen Pharmacogenetics: CYP2D6 and Other Variables Influencing Tamoxifen and Tamoxifen Metabolite Exposure
Tamoxifen is a selective estrogen receptor modulator (SERM) that is used for the treatment of estrogen receptor positive (ER+) breast cancer, most commonly as an adjuvant for the prevention of disease recurrence. Several retrospective studies suggest that functional CYP2D6 polymorphisms are associated with the clinical outcome of tamoxifen adjuvant therapy; variants that confer reduced enzymatic activity are associated with poorer outcomes. The biological basis for this association is that tamoxifen is a pro-drug and CYP2D6 metabolism is important for the formation of the potent anti-estrogenic metabolite, endoxifen. The general goal of this work was to investigate the effect of CYP2D6 polymorphisms and other variables on tamoxifen and tamoxifen metabolite exposure in order to clarify the best use of clinical tamoxfien pharmacogenetic test data. An LC-MS/MS assay was developed and validated for the quantitation of tamoxifen, N-desmethyltamoxifen, and endoxifen in human serum. The assay was found to be robust for the measurement of these analytes at physiologically relevant concentrations. In collaboration with the Women's Healthy Eating and Living (WHEL) study group, serum endoxifen concentrations were shown to be associated with the clinical outcome of tamoxifen adjuvant therapy, and a sub-therapeutic endoxifen risk group was defined. Extensive CYP2D6 genotypes were determined for WHEL study subjects using the Roche P450 AmpliChip, and an analysis was performed to determine the extent to which genotype cutoffs define the sub-therapeutic endoxifen risk group among Caucasian subjects. Of subjects who carried two null CYP2D6 alleles, approximately 72% fell into the sub-therapeutic endoxifen risk group, but this accounted for less than a quarter of all subjects within the risk group. Poor metabolizer phenocopies were present in all genotype groups. In addition, inter-ethnic differences in serum tamoxifen and tamoxifen metabolites were determined between Caucasian, Asian, Hispanic, and African American subjects within the WHEL cohort, with Asians and Hispanics exhibiting higher median endoxifen concentrations. Finally, an association study was performed in order to determine if variants in candidate genes (UGT2B7, ABCC2, CYP2C19) influence serum endoxifen concentrations in Caucasian subjects. Statistically significant associations were determined, but are unlikely to be clinically relevant due to small effect