Abstract 1099: Combination of bazedoxifene and lapatinib profoundly inhibits estrogen receptor positive (ER+) and Negative (ER-) mammary tumorigenesis

Bazedoxifene (Baz), a 3rd Gen SERM, is approved for prevention and treatment of osteoporosis as Duavee in the US. Baz downregulates ERα and inhibits growth of ER+ breast cancer (BC) cells, without stimulating the uterine endometrium. It also inhibits hormone-independent BC cell growth, presumably by inhibiting IL-6/GP130 interaction and downmodulating pSTAT3-cyclin D1 pathway, resulting in induction of apoptosis and reduction of tumor growth. Lapatinib (Lap), an FDA approved, small molecule dual inhibitor of both the EGFR/HER1 and HER2, is commonly used to treat patients with HER2-positive (HER2+) BC. We evaluated the efficacy of these two FDA-approved drugs, Baz and Lap, at lower doses, alone and in combination, for the prevention of BC in rodent models. Lap was given either daily or Ix/week by oral gavage while Baz was added directly to the diet. For ER+ mammary cancers, female Sprague-Dawley rats were given methylnitrosourea (MNU) at 50 days of age. The agents were started one week prior to MNU treatment in the following 6 groups: 1) Baz (5.0 mg/kg diet, 7x/week); 2) Lap (350 mg/kg BW, Ix/week); 3) Lap (50 mg/kg BW, 7x/week); 4) Baz + Lap as in Groups 1 and 2; 5) Baz + Lap as in Groups 1 and 3; and 6) none. At the end of the study (20 weeks after MNU), mammary cancer multiplicities in Groups 1 to 6 were: 0.75, 0.6, 0.2, 0.15, 0.1, and 4.25, respectively, demonstrating a profound (82-98%) inhibition of ER+ mammary cancers (p Citation Format: Altaf Mohammed, Shizuko Sei, Robert Shoemakers, Clinton J. Grubbs. Combination of bazedoxifene and lapatinib profoundly inhibits estrogen receptor positive (ER+) and Negative (ER-) mammary tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1099.