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.

Public Health Relevance

Thus far, only hormonal therapies such as tamoxifen have been shown to reduce breast density, and these are associated with a high side effect burden. We propose to examine the randomized effects of vitamin D on mammographic breast density and texture in the ongoing, already-funded VITamin D and OmegA-3 TriaL (VITAL) study. 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. Identifying well-tolerated, promising nutritional agents that could reduce breast density would have important public health implications for women at high risk of breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Kim, Young S
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Brigham and Women's Hospital
United States
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