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