Changes in Breast Cancer Biomarkers Using Synergistic Prostaglandin Inhibitors

This is a biomarker study with the goal of measuring changes in protein and RNA expression.
This study is not intended for use in diagnosing, mitigating, treating, curing, or preventing
disease.

66 women at high risk for breast cancer (gail risk >/= 1.66% for 5 year risk, or personal or
family history)will be recruited and enrolled. 22 women will be randomized into each arm,
with anticipation of 2 women in each group will not be evaluable, leaving 20 in each group
for evaluation.

A combination of vitamin D and celecoxib act synergistically to decrease breast cancer risk
by decreasing cell proliferation in the mammary epithelium through their action on
prostaglandin synthesis and metabolism.

Specific Aims:

In women at increased breast cancer risk, determine the effect of vitamin D, with or without
celecoxib, on

1. PG synthesis and metabolism, through the measurement of 15-PGDH, COX-2, and PGE2 in the
breast

Rationale: 1,25(OH)2D, the active form of vitamin D, has been shown in vitro to decrease
PGE2 both by interfering with its production and by increasing its breakdown, leading to
lower cell proliferation. Celecoxib potentiated the antiproliferative effect, allowing a
much lower dose of each agent when used in combination than in isolation.

2. Proliferative activity in the breast, as measured by Mammary Ductoscopy (MD) cell
morphology

Rationale: Both MD and Nipple Aspirate Fluid (NAF) contain ductal epithelial cells, but
MD samples contain more cells for cytologic review than NAF. Findings on MD cytology
correlate with likelihood of breast cancer (2), NAF cytology relates to breast cancer
risk and improves risk stratification (3), and bioactive food components can alter NAF
cytology (4).

3. Circulating levels of 25(OH)D, 1,25(OH)2D, and celecoxib, and determine if the levels of
these compounds correlate with response to markers of PG synthesis and metabolism or
cell proliferation.

Inclusion Criteria:

- Women 18 years of age or older

- Increased risk for breast cancer (demonstrated by strong family history [one 1st
degree or two 2nd degree relatives], history of DCIS, IBC, or precancerous changes in
breasts). OR Gail Model risk of developing IBC in a 5-year period of >1.66%

- Women with a history of breast cancer, must be free of disease and finished with
treatment

- ECOG Performance Status score 0-1

- Premenopausal women must not be pregnant.

Exclusion Criteria:

- History of bilateral mastectomy, or bilateral breast irradiation

- Significant medical or psychiatric problems making the participant a poor candidate

- Evidence of excess use of narcotics or drug dependency

- Have been pregnant and lactating in the past 2 years

- Significant history of peptic ulcer disease or upper gastrointestinal bleeding

- History of severe congestive heart failure that requires hospitalization or
intervention

- History of asthma requiring medication for treatment

- Allergy to sulfonamides or NSAID medications

- History of myocardial infarction or stroke

- Currently on Coumadin

- Currently on Tamoxifen (nolvadex),Evista (raloxifene), Femara (letrozole), Arimidex
(anastrozole), or Aromasin (exemestane)

- Undergone prior subaeolar breast surgery