A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6

Study Overview
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Brief Summary
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The investigators plan to examine endoxifen and 4-OH-Tam as a function of the tamoxifen dose in patients with a genetic CYP2D6 polymorphism. The investigators also plan to investigate other genetic variations in the metabolism of tamoxifen.

Detailed Description
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Endocrine therapy has proven to be an extremely effective therapy in breast cancer. For women with hormone-receptor-positive tumors, tamoxifen given for as little as two years results in a statistically significant recurrence and survival benefit. The benefits increase as the duration of treatment increase, up to 5 years, so that among women treated for five years, tamoxifen can result in up to a 46 percent annual reduction in the recurrence rate and up to a 28 percent annual reduction in the death rate. This means that about half of the recurrences and more than one fourth of the deaths each year are prevented by tamoxifen treatment. However, despite initial successful responses, many patients on tamoxifen relapse and die from progressive disease. Consequently, tamoxifen resistance remains a major clinical problem in the management of breast cancer. Tamoxifen is metabolized by cytochrome P450 2D6 (CYP2D6) to the more potent metabolites 4-hydroxy-tamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyltamoxifen (endoxifen). Variations in the metabolic capacity of this enzyme have shown to be an independent predictor of breast cancer relapse and death. To date, studies have not correlated tamoxifen doses to CYP2D6 genotype status or associated tamoxifen doses to endoxifen and 4-OH-tamoxifen. The investigators plan to examine endoxifen and 4-OH-Tam as a function of the tamoxifen dose in patients with a genetic CYP2D6 polymorphism. The investigators also plan to investigate other genetic variations in the metabolism of tamoxifen. The possible identification of gene variants that alter tamoxifen's metabolism may improve initial dose selection and therefore optimize treatment outcome in the future. In addition to examining polymorphisms in CYP2D6, other genes will be examine that may influence the metabolism of medications.

Official Title
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A Pilot Study of Varying Doses of Tamoxifen in the Setting of Genetic Polymorphisms of CYP2D6

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Tamoxifen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women taking tamoxifen 20mg a day Tamoxifen use for > 90 days. Use an accepted barrier form of contraception. Exclusion Criteria: Patients are excluded if they are pregnant or lactating; if pre- menopausal, the patient will have a documented negative pregnancy test and use an accepted barrier form of contraception. Patients are excluded if they have a medical history of Hepatitis B. Hepatitis C or HIV Patients are excluded if they use Tobacco Patients are excluded if they have a medical history of hereditary hemochromatosis Patients are excluded if they have elevated AST (SGOT), ALT (SGPT), Bilirubin or Alkaline Phosphate o Defined as greater than 2 1/2 times the upper limit of normal Patients are excluded if they are being treated with chemotherapy Patients are excluded if they are taking any of the following oral medications, as they are potent CYP2D6 inhibitors: Fluoxetine (Prozac) Miconazole (Monistat) Paroxetine (Paxil) Quinidine Ritonavir (Norvir) Atorvastatin (Lipitor) Carvedilol (Coreg) Clarithromycin (Biaxin) Dipyridamole (Persantine) Erythromycin Grapefruit Juice Itraconazole (Sporanox) Ketoconazole Mefloquine Nelfinavir (Viracept) Nicardipine (Cardene) Nilotinib Propranolol (Inderal) Ranolazine (Ranexa) Saquinavir ( Invirase) Verapamil Covera-HS Warfarin (Coumadin) Chlorpromazine (Thorazine) Cinacalcet (Sensipar) Delavirdine (Rescriptor)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Tamoxifen<br>20mg daily | Drug: Tamoxifen<br>* 20 mg daily<br>* Other names: Nolvadex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Specific human 2D6 variants measurement(s) or observation(s) |  | every two weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tamoxifen, Breast Cancer