Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.

CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.

Purpose Aromatase inhibitors (AIs) are effective for treatment of hormone receptor–positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. Patients and Methods Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. Results Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. Conclusion Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.

After completing this course, the reader will be able to:1. List the four different genotypes for CYP2D6 polymorphism.2. Understand the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme.3. List the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme. Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

Background Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. We propose a novel CYP2D6 scoring systems that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Method Training (n=159) and validation (n=81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: one genotype-independent and one genotype-based. Three CYP2D6 gene score systems, and their combination with the inhibitor factors, were compared. These three scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. Results The overall performance of the three gene score systems without consideration of CYP2D6 inhibiting medications in predicting CYP2D6 phenotype was poor both in the training (R2=0.24, 0.22 and 0.18) and the validation set, (R2=0.30, 0.24 and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R2 values in the training and validation data sets are nearly twice as high as the genotype only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41) respectively. Conclusion The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 Activity Score doubled our ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, yet unidentified, factors must be involved in tamoxifen activation.