Vitamin D in Postmenopausal Women at High Risk for Breast Cancer

Participants will receive oral vitamin D3, cholecalciferol 20,000 IU or 30,000 IU weekly.
Before beginning the intervention, the participants will have a general physical exam
including a clinical breast exam and anthropometric measures, a morning blood draw (for
analysis of 25(OH)D, 1,25(OH)D, parathyroid hormone (PTH), insulin-like growth factor
(IGF)-I, insulin-like growth factor-binding protein 3 (IGFBP-3), estradiol, estrone,
testosterone, and sex hormone-binding globulin (SHBG) at baseline, 6 months, and 12 months)
and a bilateral mammogram (at baseline and 12 months). Participants will also complete a
baseline questionnaire, collecting data on demographic information and breast cancer risk
factors. In addition, we will be collecting data on vitamin D sources from diet and sunlight
exposure using a validated questionnaire administered at baseline and 12 months.

For follow-up visits, the participant will be seen at the study site at months 3, 6, 9, and
12. During these visits, drug will be dispensed, adherence ascertained, and adverse events
will also be assessed. In addition, blood (serum calcium, albumin, creatinine) and urine
(urine calcium, creatinine) will be collected to monitor for toxicity. A 24-hour urine
collection will be conducted at baseline and 12 months to assess for hypercalciuria. After
the 1 year intervention, all participants will have a complete physical exam including
clinical breast exam, a bilateral mammogram, blood draw, and complete a follow-up
questionnaire.

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 1.67% 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.

- Postmenopausal defined as > 6 months since the last menstrual period, prior bilateral
oophorectomy, or serum follicle-stimulating hormone (FSH)/luteinizing hormone (LH)
values consistent with institutional normal values for the postmenopausal state.

- 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.

- Normal breast exam and mammogram (Breast Imaging Reporting and Data System (BIRADS)
score of 1 or 2) or abnormal breast imaging with a benign breast biopsy without
evidence of cancer. Normal baseline breast magnetic resonance imaging (MRI) (BIRADS
score of 1, 2, or 3).

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

- At least one breast available for imaging. No bilateral breast implants.

- Willingness to not take vitamin D supplements during the one year intervention, but up
to 1000mg of calcium supplementation is allowed.

- Normal serum calcium.

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

- Performance status of 0 or 1.

Exclusion Criteria:

- Other prior malignancy. The following is allowed: adequately treated basal cell or
squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II
cancer from which the participant is currently in complete remission, or any other
cancer (including breast cancer) for which the participant has been disease-free for 5
years.

- History of kidney stones.

- Hypersensitivity reactions to vitamin D.

- On estrogen replacement therapy.

- Significant medical or psychiatric condition that would preclude study completion.