Abstract 2567: Duavee® improves metabolic health without increasing cancer risk: findings from a preclinical model of obesity and postmenopausal breast cancer

Abstract

Abstract Introduction: Many women at high risk for breast cancer will not take standard selective estrogen receptor modulators (SERMs) for cancer prevention due to concern of side effects, especially vasomotor symptoms. Duavee®, a tissue selective complex of the SERM bazedoxifene (BZA; 20mg) + conjugated estrogen (CE; 0.45mg), is FDA approved for relief of hot-flashes. Preclinical and early phase human studies suggest Duavee® has potential for breast cancer prevention, with favorable change in mammographic fibroglandular volume and proliferation. Given the >40% incidence of obesity in postmenopausal women, and that obesity increases breast cancer risk, the current study was aimed at identifying the effects of obesity on response to Duavee® in a rodent model of obesity and postmenopausal breast cancer. Methods: This study used our well-characterized rat model of diet-induced obesity and postmenopausal ER-positive breast cancer. Rats were injected with N-methylnitrosourea (MNU, 50 mg/kg) at 7 weeks of age to induce mammary tumors and fed a high fat diet (HF; 46% kcal fat) to promote obesity. Lean and obese rat were selected based on % body fat at 16 weeks. Tumors were monitored by manual palpation weekly and measured using digital calipers. Tumor-bearing rats were ovariectomized (OVX) when a tumor reached 0.7cm3. Rats were then maintained on ad libitum HF diet or HF diet plus a daily oral dose of Duavee® (3mg BZA+ 0.07mg CE/kg body weight) for 8 weeks. Body composition was analyzed biweekly (qMR) and fat pads weighed at study end to determine regional fat distribution. Results: Like menopause in women, OVX induces weight gain in this model. Duavee® significantly blunted the OVX-induced weight gain in both lean (-65%, p<0.001) and obese (-88%, p<0.001) rats compared to controls. Similarly, Duavee®-treated rats gained less body fat after OVX vs controls (-50% lean; -97% obese, p<0.001). Duavee® administration was associated with reduction in glucose in obese rats after 2 weeks and in lean and obese rats after 8 weeks (-11% vs controls, p=0.03). The effects of Duavee® on regional fat deposition varied by adiposity. Obese Duavee®-treated rats had significantly lower pericardial fat (-17%, p<0.05) and tended to have lower mammary fat (-19%, p=0.08); lean rats had less gonadal fat (-20%, p<0.05), while deposition in this region was not altered by Duavee® in obese rats. At 8 weeks there was no evidence that Duavee® promoted tumor development or growth in lean or obese OVX rats. Conclusions: These data suggest that Duavee® may provide beneficial effects on body composition and metabolism in obese OVX animals without promotion of tumor growth. Further analyses will include study of direct effects of Duavee® on tumors, the tumor microenvironment, and systemic markers of insulin resistance and mammary cancer risk in our rat model of pre-and postmenopausal obesity and breast cancer. Citation Format: Karen A. Corleto, Tara N. Mahmood, Danilo Landrock, Stephen D. Hursting, Carol J. Fabian, Bruce F. Kimler, Erin D. Giles. Duavee® improves metabolic health without increasing cancer risk: findings from a preclinical model of obesity and postmenopausal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2567.