Abstract 1099: Combination of bazedoxifene and lapatinib profoundly inhibits estrogen receptor positive (ER+) and Negative (ER-) mammary tumorigenesis
Authors: Mohammed Altaf , Sei Shizuko , Shoemakers Robert , Grubbs Clinton J. 
Published: September 2020

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&lt;0.0001). When the agents were started prior to dimethybenzanthracene (DMBA, 1.0 mg/gavage, Ix/week for 4 weeks) in MMTV/Neu mice (7 weeks age), cancer multiplicities at the end of the study (18 weeks after the initial DMBA treatment) were as follows: 1) Baz (5.0 mg/kg diet), 1.0; 2) Lap (625 mg/kg BW,1x/week), 2.1; 3) Lap (125 mg/kg BW, 5x/week), 2.65; 4) Baz + Lap as in Groups 1 and 2; 0.4; 5) Baz + Lap as in Groups 1 and 3, 0.2; and 6) none, 5.2, demonstrating similarly profound chemoprevention efficacy by the combination regimens with multiplicities reduced by 93-96% (p&lt;0.01). Of note, giving lap Ix/week either alone or in combination with Baz resulted in significant decreases in cancer incidence, multiplicities and weights in both models. In a 2-week biomarker study, female MMTV/Neu mice treated with the combinations had significantly decreased proliferation rate (Ki67) in mammary epithelial cells by 74% (p&lt;0.05). These findings indicate that the combination of low-dose daily Baz and weekly Lap is highly effective in preventing ER+ and ER- mammary cancers, and that treatment with the EGFR/HER2 inhibitor Lap once a week is similarly efficacious to daily treatment with divided doses in its cancer inhibitory activity without overt toxicity.

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.