Preclinical and clinical studies for the prevention of ER-negative breast cancer.

CS09-04

Recent Phase III breast cancer prevention trials have demonstrated that anti-estrogen drugs such as tamoxifen or raloxifene prevent breast cancer development by 30% to 74%. These studies showed an even more profound reduction of ER-positive breast cancers. However, in each of these studies there was no suppression of the development of ER-negative breast cancers. Thus, there is an urgent need to develop agents that will prevent ER-negative breast cancer. Using in vitro and in vivo models of breast cancer, we have tested chemopreventive agents for the ability to prevent ER-negative breast cancer. We have tested rexinoids (RXR-selective retinoids), cox-2 inhibitors, and receptor tyrosine kinase inhibitors in several animal models of breast cancer. These studies showed that each of these agents prevent ER-negative breast cancer in MMTV-erbB2 mice and have moderate preventive activity in other mouse models. We also investigated the effect of these agents on the development of hyperplasias and carcinoma-in-situ lesions. Rexinoids and tyrosine kinase inhibitors were found to suppress the development of these premalignant lesions. This cancer preventive activity was associated with a reduction in epithelial cell proliferation and reduced cyclin D1 expression. Results from these preclinical studies provided the rationale for Phase II cancer prevention trials in women at high risk of breast cancer. We and others have tested cox-2 inhibitors in Phase II chemoprevention trials in women at risk of breast cancer. We have also conducted a Phase II multi-institutional clinical trial using the RXR-selective retinoid bexarotene. The clinical trial design and current accrual to this trial will be presented. After the results of these Phase II trials are available, phase III cancer prevention trials testing the combination of these agents plus anti-estrogen selective estrogen receptor modulators can be developed. By combining anti-estrogen drugs with the agent found most effective in preventing ER-negative breast cancer, it may be possible to prevent both ER-positive and ER-negative breast cancer.