Breast cancer continues to be a major health problem despite efforts in early detection and improvements in treatment. Current research focus is now on the prevention of breast cancer. In that effort, a large phase III chemoprevention trial of tamoxifen showed a reduced incidence of estrogen receptor (ER) positive breast cancer. But, tamoxifen had no impact on the development of ER negative breast cancers. Therefore, non-hormonal agents beside tamoxifen are needed for the chemoprevention of breast cancer. Furthermore, currently there are no validated surrogate biomarkers for the use of breast cancer prevention. Finally, less invasive methods than core biopsies or fine needle aspirations (FNA) need to be developed for breast tissue acquisition during phase II chemopreventive interventions. Recently, Cyclooxygenase 2 (COX-2) expression has been observed in breast cancer and early breast lesions. Celecoxib is a selective COX-2 inhibitor that has antiproliferative and proapoptotic properties. In addition, ductal lavage was recently shown to be a feasible way to obtain ductal epithelial cells from the breast tissue. Our goal is to test, in a pilot fashion, the modulation of biomarkers in response to celecoxib in breast tissue of women who are at high risk for breast cancer and to develop a less invasive tissue acquisition method for the future use of phase II chemopreventive interventions. Specifically, first, we aim to evaluate cyclooxygenase-2 inhibitor (celecoxib) induced modulation of cytologic atypia, and modulation of proliferation (ki-67, ER, COX-2, Her-2/neu, EGFR, p53) and apoptosis markers (bcl-2, 15-LOX) in breast tissue of women who are high risk to develop breast cancer. Second, we aim to compare breast epithelial cell yield and cytologic atypia in specimens obtained via FNA versus ductal lavage and test the feasibility of evaluating biomarkers in ductal lavage fluid obtained from breast tissue of women at high risk for breast cancer for the use of future chemopreventive interventions. Forty high-risk women (history of previous breast cancer or history of lobular carcinoma in situ or estimated 5 year Gail risk > 1.67) will undergo basline ductal lavage and random FNA for the analysis of cytologic atyipia and above-mentioned markers. Women then will be treated with celecoxib 400 mg/day BID per oral for 6 months, after which the ductal lavage and FNA will be repeated for the same marker analyses. Demonstration of a decrease in Ki-67 and other proliferation markers, increase in apopototic markers and reversal of atypia will provide us with preliminary data to proceed with our planned phase II, placebo controlled chemoprevention study with celecoxib. Ultimately, the development of non-hormonal chemoprevention agents, and identification of surrogate markers will allow us to plan large-scale, phase III chemoprevention studies with the endpoint of cancer incidence.
| Bayraktar, S; Gutierrez-Barrera, A M; Lin, H et al. (2013) Outcome of metastatic breast cancer in selected women with or without deleterious BRCA mutations. Clin Exp Metastasis 30:631-42 |
