Women at increased breast cancer risk include those with a strong family history of breast cancer, those with a history of ductal carcinoma in situ (DCIS) or invasive breast cancer (IBC), and those with precancerous changes in their breasts. Eligibility for enrollment in the first National Surgical Adjuvant Breast and Bowel Project (NSABP) breast cancer prevention trial required that a participant have a > 1.66% projected 5 year probability of developing IBC . The only accepted treatment for these women is tamoxifen, which has side effects of hot flashes, deep vein thrombosis, and uterine cancer. An effective alternative treatment is desirable.
Cyclooxygenase (COX)-1 and COX-2 may be present in breast tumors to catalyze the conversion of arachidonic acid to prostaglandins, prostacyclins, or thromboxanes. While COX-1 expression is constitutive, COX-2 is inducible  and is upregulated in a variety of tumors, including breast cancers . Prostaglandin (PG)E2 is produced from arachidonic acid by either COX-1 or -2. PGE2 has tumor and cell growth promoting activity . Women with breast cancer with PGE2 levels above 15 ng/g appear to have a significantly worse survival rate than those with levels ≤ 15 ng/g . Malignant breast tumors produce more PGE2 than benign breast tumors or normal breast tissue . A retrospective analysis of women with and without breast cancer seen at a single hospital for a one year period found that the women without breast cancer were more likely to have taken celecoxib than women who had developed breast cancer .
Nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, indomethacin and ibuprofen, inhibit both COX-1 and COX-2. Inhibition of COX-1 leads to a number of adverse effects, including gastrointestinal ulcers and renal toxicity . Recent efforts have, therefore, focused on pharmacologic agents such as celecoxib, a clinically available medication which selectively inhibits COX-2. Preclinical studies suggest that celecoxib is effective both in preventing and in treating breast cancer in a dose dependant manner [8, 9].
We are currently able to collect breast nipple aspirate fluid (NAF) from 95% of nonlactating adult females ages 18 to 80 with the use of a modified breast pump . Using our NAF collection technique, we performed a preliminary study to determine if 200 mg bid of the COX-2 inhibitor celecoxib administered for two weeks to women at increased breast cancer risk would significantly decrease PGE2 levels in the breast, as measured both in NAF and in plasma, providing both organ specific and systemic information . We observed that PGE2 is concentrated in NAF compared to matched plasma, but that celecoxib 200 mg bid administered for two weeks did not significantly decrease PGE2 concentrations in NAF or plasma.
Subjects with familial adenomatous polyposis (FAP) who received celecoxib for six months at 400 mg bid, but not those receiving 100 mg bid, demonstrated a significant reduction, compared to placebo, in mean polyp number . Consequently, we sought to determine if a short two week course of celecoxib at a dose of 400 mg bid would alter NAF and/or plasma PGE2 levels in women at high risk for, or with newly diagnosed breast cancer. We observed that celecoxib 400 mg bid lowered PGE2 levels in the NAF and plasma of women with breast cancer, and in the NAF of high risk postmenopausal women.