Abstract P5-14-02: Effects of bazedoxifene and/or letrozole in the prevention of chemically-induced mammary cancers

Abstract

Abstract Bazedoxifene is described as a third-generation selective estrogen receptor modulator (SERM) that has been approved in Europe for the prevention and treatment of postmenopausal osteoporosis. The agent has also been shown to have therapeutic activity against estrogen receptor positive (ER+) breast cancer. Our laboratory has evaluated bazedoxifene for chemopreventive efficacy against mammary cancers when given alone or in combination with the aromatase inhibitor letrozole. Initially, the agents were evaluated alone to determine effective chemopreventive doses in the methylnitrosourea (MNU) ER+ mammary cancer model using female Sprague-Dawley rats. Bazedoxifene was mixed directly into a standard (Teklad, 4% fat) diet, while letrozole was gavaged 7x/week (vehicle was ethanol: PEG 400, 10:90, v/v). When evaluated alone in rats receiving MNU at 50 days of age, bazedoxifene (started one week after MNU) at doses of 100 and 30 mg/kg diet decreased mammary cancer multiplicity by 93 and 88%, respectively. In a similar protocol, letrozole at a dose of 0.1 mg/kg BW/day reduced cancer multiplicity by 89%, while a dose of 0.05 mg/kg BW/day reduced the number by 47%. In a separate study evaluating lower doses of bazedoxifene (5 mg/kg diet) and letrozole (0.04 mg/kg BW/day), mammary cancer multiplicity was decreased by 73% by both agents. When the agents were given in combination at these lower dose levels, cancer number was reduced by 91%. It is obvious that bazedoxifene is as effective as letrozole in the prevention of ER+ mammary cancers. Furthermore, administration of the agents in combination suggests an additive effect. The large increase in body weight gain generally noted in letrozole treated rats was not observed in rats receiving bazedoxifene; of interest, rats receiving the combination also had no increase in body weights. Several published invitro studies suggested that bazedoxifene might also be effective in preventing ER- mammary cancers; e.g., the agent is a novel inhibitor of IL-6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches that result in apoptosis. In an initial study using MMTV/Neu mice (N=21/group) that received dimethylbenzanthracene (DMBA), we showed that administering bazedoxifene (15 mg/kg diet) would reduce the mammary tumor multiplicity from 5.4/mouse in controls to 1.1/mouse (an 80% decrease). These studies suggested that bazedozxifene is superior to other similar agents in that both ER+ and ER- mammary cancers are prevented at non-toxic doses. Supported by NCI contract HHSN261201200021I, Task Order HHSN26100007. Citation Format: Dunn BK, Grubbs CJ. Effects of bazedoxifene and/or letrozole in the prevention of chemically-induced mammary cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-14-02.