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

Karen A. Corleto, Tara N. Mahmood, Danilo Landrock, S. Hursting, C. Fabian, B. Kimler, Erin D. Giles
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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 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.
摘要:Duavee®改善代谢健康而不增加癌症风险:来自肥胖和绝经后乳腺癌的临床前模型的发现
导论:由于担心副作用,尤其是血管舒缩症状,许多乳腺癌高危妇女不愿使用标准的选择性雌激素受体调节剂(SERMs)来预防癌症。Duavee®是一种SERM bazedoxifene (BZA;20mg) +共轭雌激素(CE;0.45毫克),被FDA批准用于缓解潮热。临床前和早期人类研究表明,Duavee®具有预防乳腺癌的潜力,有利于改变乳腺纤维腺的体积和增殖。鉴于绝经后妇女肥胖发生率>40%,肥胖增加乳腺癌风险,本研究旨在确定肥胖对Duavee®在肥胖和绝经后乳腺癌啮齿动物模型中的反应的影响。方法:本研究采用我们的特征良好的饮食性肥胖和绝经后雌激素受体阳性乳腺癌大鼠模型。7周龄大鼠注射n -甲基亚硝基脲(MNU, 50 mg/kg)诱导乳腺肿瘤,并饲喂高脂饲料(HF;46%卡路里脂肪),促进肥胖。16周时根据体脂百分比选择瘦鼠和肥鼠。每周用手触诊监测肿瘤,并用数字卡尺测量。当肿瘤达到0.7cm3时,切除荷瘤大鼠卵巢。然后,大鼠在8周内自由饲喂HF饲粮或HF饲粮加每日口服剂量的Duavee®(3mg BZA+ 0.07mg CE/kg体重)。每两周分析体成分(qMR),并在研究结束时称重脂肪垫,以确定区域脂肪分布。结果:与女性更年期一样,OVX在该模型中引起体重增加。结论:这些数据表明,Duavee®可能对肥胖OVX动物的身体组成和代谢有有益的影响,而不会促进肿瘤的生长。进一步的分析将包括研究Duavee®对绝经前和绝经后肥胖和乳腺癌大鼠模型中肿瘤、肿瘤微环境、胰岛素抵抗和乳腺癌风险的系统性标志物的直接影响。引文格式:Karen A. Corleto, Tara N. Mahmood, Danilo Landrock, Stephen D. Hursting, Carol J. Fabian, Bruce F. Kimler, Erin D. Giles。Duavee®改善代谢健康而不增加癌症风险:来自肥胖和绝经后乳腺癌的临床前模型的发现[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第2567期。
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