Abstract 648: Effects of bazedoxifene and lapatinib in the prevention of estrogen receptor positive (ER+) and negative (ER-) 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. Our research previously showed that this agent (at a dose of 5 mg/kg diet) would decrease ER+ mammary cancers in rats by 73%. Lapatinib, an epidermal growth factor receptor (EGFR) inhibitor, is commonly used to treat patients with HER2+ breast cancer. We have also shown that the compound inhibits the development of ER+ mammary cancers in rats and ER- mammary cancers in mice at a dose of 75 mg/kg BW/day. The present studies were done to determine if lower doses and different treatment regimens designed to reduce possible toxicity would also be effective in preventing mammary cancers. Bazeodxifene was added directly to the diet (Teklad, 4% fat), while lapatinib was given by oral gavage. When evaluated in rats receiving methylnitrosourea (MNU), lapatinib given daily at doses of 75, 50 and 25 mg/kg BW/day reduced mammary cancer multiplicity by 93, 84 and 67%, respectively. Equivalent doses given 1x/week caused reductions of 87, 56, and 40%. When lapatinib was given to dimethylbenzanthracene (DMBA) treated MMTV/Neu mice at dose levels of 250, 125, and 63 mg/kg BW, 5x/week, mammary cancer multiplicity was reduced by 89, 60 and 80%, respectively. When equivalent doses were given 1x/week, the number of cancers were reduced by 82, 61, and 70%. Bazedoxifene given at 5.0 and 2.5 mg/kg diet to female MMTV/Neu mice also receiving DMBA caused reduction of mammary cancers by 73 and 51%. In a biomarker study lasting two weeks, bazedoxifene at the 5.0 mg/kg BW/day dose decreased the proliferation rate of normal mammary epithelial cells in MMTV/Neu mice by 60%. Additional studies to determine why this SERM is having a preventive effect against ER- mammary cancers are warranted. Studies to evaluate the efficacy of the combination of low doses of bazedoxifene and lapatinib in prevention of ER+ and ER- mammary cancers are in progress and will be presented. Supported by the NCI contract number HHSN261201500036I, Task Order HHSN26100005. Citation Format: Clinton J. Grubbs, Altaf Mohammed, Shizuko Sei, Robert H. Shoemaker. Effects of bazedoxifene and lapatinib in the prevention of estrogen receptor positive (ER+) and negative (ER-) mammary cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 648.