Abstract ED05-02: Targeting estrogen receptors for breast cancer prevention

Abstract

Abstract Before “targeted” therapy was part of the oncology lexicon, the estrogen receptor (ER) was already a much touted target of drug development for breast cancer treatment and prevention. Selective estrogen receptor modulators (SERMs) were developed for the purpose of binding to the ER. Tamoxifen, the first SERM studied for breast cancer treatment and prevention, inhibits the action of the ER in the breast. In the 1980s it elicited improvements in overall and disease-free survival in women with breast cancer and was subsequently tested with a primary endpoint of breast cancer prevention in high-risk women. The Breast Cancer Prevention Trial demonstrated a 49% reduction in new breast cancers in high-risk women, leading to FDA approval of tamoxifen for this purpose in 1998. The was the first FDA approval of an agent for a cancer prevention indication. Subsequently a series of SERMs have been developed for osteoporosis, most notably raloxifene. The Study of Tamoxifen and Raloxifene showed the two SERMs to be equivalent in terms of their ability to target the ER and prevent ER-positive breast cancer, with raloxifene exhibiting overall less toxicity. This agent, already approved for osteoporosis treatment and prevention, was approved for breast cancer prevention in postmenopausal women in 2007. More recently, meta-analyses of these and other studies comparing SERMs to placebo in a variety of disease settings have consistently shown benefits for breast cancer prevention in the SERM arm. The latest approach to targeting the estrogenic effect on breast cancer development involves inhibition of estrogen production, as opposed to estrogen action. The aromatase inhibitors (AIs) prevent the enzyme, aromatase, from converting androgens to estrogens. In postmenopausal women, in whom the majority of AI studies have been carried out, the inhibition of estrogen production is almost complete. The Mammary Prevention 3 trial showed that the AI exemestane decreased the incidence of breast cancer by up to 70% compared to placebo, with different toxicities than tamoxifen. The International Breast Cancer Intervention Study II, which is comparing the AI anastrozole to placebo in high-risk postmenopausal women, is still ongoing. Both the SERM and AI classes of targeted breast cancer prevention agents are effective in preventing ER-positive breast cancers, leaving an urgent need to develop drugs to prevent ER-negative breast cancers. Citation Format: Leslie G. Ford, Barbara K. Dunn. Targeting estrogen receptors for breast cancer prevention. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr ED05-02.