VITamin D and OmegA-3 TriaL: Effects on Mammographic Density and Breast Tissue

Study Overview
=================
Brief Summary
-----------------
The VITamin D and OmegA-3 TriaL (VITAL; NCT 01169259) is an ongoing randomized clinical trial in 25,875 U.S. men and women investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. This ancillary study is being conducted among participants in VITAL and will examine whether vitamin D effects mammographic breast density, mammographic texture features, and gene expression profiles in breast biopsy tissue.

Detailed Description
-----------------
Mammographic density is one of the strongest risk factors for breast cancer. It is predictive of breast cancer risk for at least 10 years in the futue and has been suggested as a surrogate marker of breast cancer risk. Several states now mandate release of mammographic density data to women. However, except for anti-hormonal therapies (e.g., tamoxifen), no interventions have been proven to reduce breast density. Thus, testing promising, well-tolerated interventions that might affect mammographic density is of substantial interest. Several lines of evidence suggest that vitamin D may play a role in breast density and breast carcinogenesis. Vitamin D reduces proliferation and promotes differentiation and apoptosis in breast cells in culture. However, no large-scale randomized studies have examined the impact of vitamin D on mammographic density. We propose to examine the randomized effects vitamin D3 on mammographic breast density in the NIH sponsored VITamin D and OmegA-3 TriaL (VITAL), an ongoing randomized, double blind, trial testing vitamin D3 (2,000 IU/day cholecalciferol) and omega-3 fatty acids (840 mg eicosapentaenoic acid [EPA]+ docosahexaenoic acid [DHA]) in the primary prevention of cancer and cardiovascular disease in a multi-ethnic population of over 24,000 men and women. In this ancillary sub study, mammograms will be obtained on 4000 women age 55-67 years (25% African-American), from baseline (pre-randomization) and after 1 and 4 years of randomized therapy. Centrally processed quantitative mammographic density and texture variation will be measured. We will determine if randomized vitamin D treatment is associated with change in mammographic features, and whether effects are modified by baseline mammographic density, and baseline 25(OH) vitamin D levels. In addition, tissue samples from women in VITAL undergoing breast biopsy/surgery, for both nonmalignant and malignant conditions, will be collected. Quantitative morphological measures, as well as gene expression assays targeting vitamin D activation and breast carcinogenesis pathways, will be performed on collected tissues among women on randomized vitamin D3 compared with placebo. This ancillary study provides a timely opportunity to test comprehensively the effects of vitamin D3 on mammographic features and breast tissue biology in a randomized setting at minimal additional cost.

Official Title
-----------------
THE EFFECTS OF VITAMIN D ON MAMMOGRAPHIC DENSITY AND BREAST TISSUE

Conditions
-----------------
Benign Breast Disease

Intervention / Treatment
-----------------
* Dietary Supplement: Vitamin D and fish oil placebo
* Dietary Supplement: Fish oil and vitamin D placebo
* Dietary Supplement: Vitamin D placebo and fish oil placebo
* Dietary Supplement: Vitamin D and fish oil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: part of parent VITAL trial Exclusion Criteria: Men, women with breast cancer

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 67 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vitamin D placebo and fish oil placebo<br>vitamin D placebo + fish oil placebo | Dietary Supplement: Vitamin D placebo and fish oil placebo<br>* placebo<br>|
| Active Comparator: Fish oil and vitamin D placebo<br>Vitamin D placebo and 840 mg of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]) | Dietary Supplement: Fish oil and vitamin D placebo<br>* 840 mg of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA])<br>* Other names: 840 mg of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]);|
| Active Comparator: Vitamin D and fish oil placebo<br>Vitamin D3 (cholecalciferol), 2000 IU per day and fish oil placebo | Dietary Supplement: Vitamin D and fish oil placebo<br>* Vitamin D3 (cholecalciferol), 2000 IU per day and fish oil placebo<br>|
| Active Comparator: Vitamin D and fish oil<br>Vitamin D3 (cholecalciferol), 2000 IU per day and 840 mg of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA]) | Dietary Supplement: Vitamin D and fish oil<br>* Vitamin D3 (cholecalciferol), 2000 IU per day and 840 mg of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid [EPA] and 375 mg of docosahexaenoic acid [DHA])<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mammographic breast density | We will collect baseline (pre-randomization), 1-year and 4-year follow-up mammograms, as well as tissue specimens from women undergoing breast biopsy/surgery for malignant and nonmalignant disease, to further elucidate the role of vitamin D on mammographic features and breast tissue biology | change baseline to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast tissue | Quantitative morphological measures, as well as gene expression assays targeting vitamin D activation and breast carcinogenesis pathways, will be performed on collected tissues among women on randomized vitamin D3 compared with placebo | 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
mammographic breast density, breast disease, breast tissue