Abstract 5246: Effects of bazedoxifene either alone or in combination with letrozole in the prevention of chemically induced mammary cancers

Abstract

Abstract Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) that has been clinically 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 is currently evaluating bazedoxifene for chemopreventive efficacy when given alone or in combination with the aromatase inhibitor (AI) 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 number (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 (MNU also given to rats at 50 days of age), bazedoxifene at a dose of 5 mg/kg diet and letrozole at a dose of 0.04 mg/kg BW/day both decreased mammary tumor multiplicity by 73%. When the agents were given in combination at these lower dose levels, cancer number was reduced by 91%. An additional study was done in which the agents were given to rats receiving MNU at an older age (100 days). Rats receiving the agents at the original doses beginning one week after MNU (bazedoxifene at 30 mg/kg diet; letrozole at 0.1 mg/kg BW/day) had identical decreases in mammary tumor development (96%). It is obvious that bazedoxifene is as effective as letrozole in the prevention of mammary cancers even when initiated in older rats. 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. These studies indicate that bazedoxifene may be superior to other SERMs in that chemopreventive efficacy is achieved at low doses, which may be associated with less toxicity. Supported by NCI contract HHSN261201200021I, Task Order HHSN26100007. Citation Format: Barbara K. Dunn, Chen Suen, Ronald A. Lubet, Vernon E. Steele, Clinton J. Grubbs. Effects of bazedoxifene either alone or in combination with letrozole in the prevention of chemically induced mammary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5246. doi:10.1158/1538-7445.AM2017-5246