Nutritional Supplements and Hormonal Manipulations for Breast Cancer Prevention

Study Overview
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Brief Summary
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The overall hypothesis is that the combination of a low dose of the antiestrogen Raloxifene with omega-3 fatty acids will exert a synergistic breast cancer chemopreventive effect due to the crosstalk of their downstream cellular effects leading to decreased proliferation and increased apoptosis of premalignant mammary cells. Based on the investigators hypothesis that upregulation of functional estrogen receptors in the premalignant lesions is also responsible for the development of hormone independent tumors, the investigators postulate that the combination of antiestrogens and omega-3 fatty acids will reduce the development of both hormone-dependent and -independent tumors. At present, there are no known interventions able to decrease the development of hormone-independent tumors, which are more prevalent, more aggressive, leading to the patient's demise. In addition, the investigators postulate that this approach will be safe since it will combine a lower and hence a less toxic dose of Raloxifene with the administration of omega-3 fatty acids which are known to have health benefits, i.e., reduction in cardiovascular risk, beyond their possible chemo preventive effect in breast cancer.

Detailed Description
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The main objectives of this study are to determine the individual and combined effects of Raloxifene and omega-3 fatty acids on surrogate markers of breast cancer development in healthy, postmenopausal women. The primary endpoint will be mammographic density for which the study has been powered. Breast density is a major risk factor for breast cancer and hence it is chosen to evaluate the potential chemopreventive efficacy of our interventions. Secondary endpoints would include markers of oxidative stress, parameters of estrogen metabolism, markers of inflammation, and markers of IGF-I signaling, all of which have been shown in the literature to have an influence on mammary carcinogenesis. Study Population: Healthy, postmenopausal women between the ages of 35-70 years, undergoing yearly mammograms as part of routine screening practice. Method of Identification of Subjects/Samples/Medical Records: Women reporting for yearly mammograms will be considered for this protocol. They will be given first a screening questionnaire to rule out any co-existing medical condition that would predispose them to thromboembolic events.

Official Title
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Combination of Low Dose Antiestrogens With Omega-3 Fatty Acids for Prevention of Hormone-independent Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Dietary Supplement: Lovaza 4gm oral
* Drug: Raloxifene 60 Mg Oral Tablet
* Drug: Raloxifene 30 Mg Oral Tablet
* Drug: Lovaza 4gm & Raloxifene 30mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal status defined as history of at least 12 months without spontaneous menstrual bleeding or a documented hysterectomy and bilateral salpingo oophorectomy Breast density greater than 25% No hormone replacement therapy for at least six months prior to entry into this study Non-smokers. Exclusion Criteria: History of stroke, pulmonary embolism or deep vein thrombosis History of atherosclerotic heart disease Presence of any known hypercoagulable state either congenital (e.g., protein S deficiency) or acquired (e.g., corticosteroid treatment) Diabetes mellitus Uncontrolled hypertension (BP ≥140/90) Presence of a psychiatric condition that would interfere with adherence to the protocol.

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group 1: Control<br>Control, no intervention | |
| Experimental: Group 2: Raloxifene 60 Mg Oral Tablet<br>Raloxifene 60 mg Orally Daily | Drug: Raloxifene 60 Mg Oral Tablet<br>* 60 mg orally every day for two years<br>* Other names: Evista 60 Mg Oral Tablet;|
| Experimental: Group 3: Raloxifene 30 Mg Oral Tablet<br>Raloxifene 30 mg Orally Daily | Drug: Raloxifene 30 Mg Oral Tablet<br>* 30 mg orally daily for two years<br>* Other names: Evista 30 Mg Oral Tablet;|
| Experimental: Group 4: Lovaza 4 gm oral<br>Lovaza 4 gm/day Orally with Meals | Dietary Supplement: Lovaza 4gm oral<br>* Dietary supplement; Take 4 mg oral capsules daily<br>* Other names: Omega-3 Fatty Acid Capsules; Fish Oil capsules; Triklo;|
| Experimental: Group 5: Lovaza 4gm & Raloxifene 30mg<br>Lovaza 4 gm/day oral capsule with meals plus Raloxifene 30 mg oral tablet daily | Drug: Lovaza 4gm & Raloxifene 30mg<br>* Lovaza 4gm and Raloxifene 30 Mg orally once per day for 2 years<br>* Other names: Pitavastatin 4 gm and Evista 30 mg oral tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Absolute Breast Density | Change of absolute breast density as indicated by mammography from baseline to Year +1 and completion of study (Year +2). No other mammograms will be obtained or used for the purpose of this study. Absolute breast density volume is based on breast thickness and the x-ray attenuation at each pixel of the image. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Biomarkers for Oxidative Stress:Urinary 8-(Isoprostane) F-2α | Changes in biomarkers for oxidative stress. Specific time points for evaluation are baseline and Year +1 (only). Urinary 8-(isoprostane) F-2α as measured through urine analysis. | 1 year | 
| Changes in Biomarkers for Oxidative Stress: Urinary 8-hydroxy-deoxyguansine | Changes in biomarkers for oxidative stress. Specific time points for evaluation are baseline and Year +1 (only). Urinary 8-hydroxy-deoxyguansine as measured through urinary analysis. | 1 year | 
| Changes in Biomarkers for Estrogen Metabolism: 2-hydroxy Estrone (Urinary 2-OHE1) and 16-α-hydroxy Estrone (16α-OHE1) | Changes in biomarkers for estrogen metabolism: 2-hydroxy estrone (Urinary 2-OHE1) and 16-α-hydroxy estrone (16α-OHE1) as measured by urinary analysis. Specific time points for evaluation are baseline and Year +1 (only). | 1 year | 
| Changes in Serum Biomarkers for Inflammation From Levels of High Sensitivity C-reactive Protein (hsCRP) and Interleukin 6 (IL-6) | Changes in serum biomarkers for inflammation including highly sensitive C-reactive protein and IL-6 obtained through a blood draw. Specific time points for evaluation are baseline and Year +1 (only). | 1 Year | 
| Changes in Insulin-like Growth Factor-1 (IGF-1) and Insulin-like Growth Factor-1 Binding Protein-3 (IGFBP-3) | Changes in insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1 binding protein-3 (IGFBP-3) obtained through blood sample. Specific time points for evaluation are baseline and Year +1 (only). | 1 year | 
| Changes in Serum Lipid Levels | Changes in serum lipid levels as measured through total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years | 
| Changes in Complete Blood Count: Red Blood Cells | Changes in complete blood count levels as measured through red blood cells (RBC). Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years | 
| Changes in Complete Blood Count: Hemoglobin | Changes in complete blood count levels as measured through hemoglobin. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years | 
| Changes in Complete Blood Count: Hematocrit | Changes in complete blood count levels as measured through hematocrit percentage. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years | 
| Changes in Complete Blood Count: White Blood Cells and Platelets | Changes in complete blood count levels as measured through white blood cells (WBC) and platelets. Specific time points for evaluation are baseline, Year +1, and Year 2. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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omega-3 fatty acids, antiestrogens, breast cancer prevention, breast density, biomarkers of mammary carcinogenesis