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Raloxifene Hydrochloride

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Omega 3 Fatty Acid

Lovaza 4 gm/day oral capsule with meals plus Raloxifene 30 mg oral tablet daily

Dietary supplement; Take 4 mg oral capsules daily

Lovaza 4gm oral

Raloxifene 60 Mg Oral Tablet

Raloxifene 30 Mg Oral Tablet

Lovaza 4gm and Raloxifene 30 Mg orally once per day for 2 years

Lovaza 4gm & Raloxifene 30mg

Andrea Manni, MD

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.

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.

Nutritional Supplements and Hormonal Manipulations for Breast Cancer Prevention

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

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.

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.

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.

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).

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).

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).

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.

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.

Changes in complete blood count levels as measured through hemoglobin. Specific time points for evaluation are baseline, Year +1, and Year 2.

Changes in complete blood count levels as measured through hematocrit percentage. Specific time points for evaluation are baseline, Year +1, and Year 2.

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.

Milton S. Hershey Medical Center

Professor and Chief Division of Endocrinology, Diabetes, and Metabolism

Group 1: Control

Group 2: Raloxifene 60 mg

Group 3: Raloxifene 30 mg

Group 4: Lovaza 4 gm

Lovaza 4 gm/day orally with meals plus Raloxifene 30 mg orally daily

Group 5: Lovaza 4 gm and Raloxifene 30 mg

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Dr. Andrea Manni

Absolute density at baseline

Absolute density at 1 year

Absolute density at 2 years

The decrease in the population groups is accounted for through subject withdrawals, subjects lost to follow-up, and other reasons for not completing study.

Change in Absolute Breast Density

Baseline

1 year

Biomarker measurements were not taken for the entire population of the study due to non-significant trends for treatment effects found in this population (n = 47).

Changes in Biomarkers for Oxidative Stress:Urinary 8-(Isoprostane) F-2α

Changes in Biomarkers for Oxidative Stress: Urinary 8-hydroxy-deoxyguansine

Baseline: Urinary 2-OHE1

1 year: Urinary 2-OHE1

Baseline: 16α-OHE1

1 year: 16α-OHE1

Changes in Biomarkers for Estrogen Metabolism: 2-hydroxy Estrone (Urinary 2-OHE1) and 16-α-hydroxy Estrone (16α-OHE1)

Baseline: Serum hsCRP

1 year: Serum hsCRP

Baseline: Serum IL-6

1 year: Serum IL-6

Biomarker measurements were not taken for the entire population of the study (N = 266) due to non-significant trends for treatment effects found in this initial population (n = 89).

Changes in Serum Biomarkers for Inflammation From Levels of High Sensitivity C-reactive Protein (hsCRP) and Interleukin 6 (IL-6)

Baseline: IGF-1

1 year: IGF-1

Baseline: IGFBP-3

1 year: IGFBP-3

Measurements were not taken for the entire population of the study due to non-significant trends for treatment effects found in this population (n = 46).

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