Study of Vitamin D for Premenopausal Women at High Risk for Breast Cancer

Vitamin D has diverse biological effects relevant to carcinogenesis, including known
cross-talk between the vitamin D receptor (VDR) and insulin-like growth factor (IGF)
signaling pathways. Based upon observational data, women with serum 25(OH) D levels greater
than 40-50 ng/ml had a 50% lower risk of breast cancer compared to women with vitamin D
deficiency.

Vitamin D is a fat-soluble vitamin which is produced in the body and may come from food
sources. Epidemiologic studies suggest that vitamin D may influence breast cancer
development, which has resulted in increased interest in the use of vitamin D for the
treatment and prevention of breast cancer. Numerous experimental studies have shown that
vitamin D compounds have anti-carcinogenic properties against breast cancer. Given the
epidemiologic data and the extensive preclinical evidence of the anti-tumor effects of
vitamin D, it is therefore reasonable to test the biological effects of high-dose vitamin D
in early phase clinical trials. The investigators hypothesize that vitamin D3,
cholecalciferol, will modulate biomarkers of breast cancer risk.

The relationship between vitamin D status and mammographic density (MD), a strong predictor
of breast cancer risk, remains unclear [8]. MD refers to the relative proportions of
radiolucent fat and radiodense epithelial and stromal tissue and may serve as a useful
intermediate biomarker for breast cancer risk assessment in investigations of potential
chemopreventive agents. Cross-sectional studies evaluating the association between vitamin D
intake and MD observed an inverse association among premenopausal women, particularly with
high serum IGF-1 and low serum IGF binding protein-3 (IGFBP-3). However, there is limited
data on the biologic effects of vitamin D supplementation for breast cancer prevention in
human intervention trials.

Inclusion Criteria:

- Elevated risk of breast cancer defined as having at least one of the following: (1)
Predicted 5-year modified Gail model risk of 1.7% or greater, (2) Lobular carcinoma in
situ, (3) Known BRCA1 or BRCA2 deleterious mutation carrier, (4) Prior history of
ductal carcinoma in situ, if no current tamoxifen use or prior radiation to the
contralateral breast.

- Age 21 years or older.

- Premenopausal defined as < 6 months since the last menstrual period, no prior
bilateral oophorectomy, not on estrogen replacement, and serum Follicle-stimulating
hormone (FSH) values consistent with institutional normal values for the premenopausal
state.

- Normal breast exam and mammogram (BIRADS score of 1 or 2).

- Baseline mammographic density ≥25% as assessed qualitatively by the mammographer
(25-50% = "scattered fibroglandular densities"; >50-75% = "heterogeneously dense
breasts"; >75% = "extremely dense breasts").

- Baseline serum 25-hydroxyvitamin D <32 ng/ml.

- Prior tamoxifen use is allowed provided treatment is discontinued at least 28 days
prior to enrollment.

- Willingness to allow submission of core needle breast biopsy for pathology review and
collection of blood for biomarker analysis and banking.

- At least one breast available for imaging and biopsy.

- Willingness to not take calcium or vitamin D supplements during the one year
intervention, due to the potential risk of hypercalcemia/hypercalciuria with high dose
vitamin D. Premenopausal women who need to take calcium supplementation for any
medical condition will be excluded from the study. Dietary restrictions on calcium
intake may be imposed if the subject is found to have borderline high serum or urine
levels of calcium during the study intervention and a list of dietary sources of
calcium will be provided.

- Normal serum calcium.

- No history of kidney stones.

- Adequate renal and hepatic function: serum creatinine, bilirubin, aspartate
aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase < 2.0 x
the institutional upper limit of normal (IULN).

- No hypersensitivity reactions to vitamin D.

- Performance status of 0 or 1.

- Not pregnant or nursing.

- Agree to use effective contraception, hormone-based oral contraceptives allowed but
switching birth control methods is discouraged while on-study.

- No significant medical or psychiatric condition that would preclude study completion.

Exclusion Criteria:

- Not meeting one or any of inclusion criteria