Targeting RANK Pathway in Mammographic Density and Primary Breast Cancer Prevention

乳腺 X 光密度和乳腺癌初级预防中的靶向 RANK 通路

基本信息

批准号：
10217048
负责人：
Adetunji T Toriola
金额：
$ 62.41万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217048
关键词：
Address Adoption Adult Age-Years Alveolar Antibodies Biological Markers Blood Breast Breast Cancer Prevention Breast Cancer Risk Factor Breast biopsy Cancer Center Categories Chemoprevention Clinical Clinical Trials Computer software Data Development Diet Modification Dominant Genetic Conditions Enrollment Evaluation Fibroblast Growth Factor First Degree Relative Future Gene Expression Genes Genetic Predisposition to Disease Goals Incidence Injections International Intervention Intervention Studies Life Style Modification Ligands Malignant Neoplasms Mammary Gland Parenchyma Mammographic Density Mammographic screening Mammography Measures Mediator of activation protein Needles Nuclear Participant Pathway interactions Placebos Premenopause Progesterone Progesterone Receptors Randomized Randomized Clinical Trials Recording of previous events Risk Signal Transduction Structure Subcutaneous Injections Susceptibility Gene TRANCE protein Tamoxifen Target Populations Testing Therapeutic Time Transforming Growth Factors Translating Ultrasonography Woman aged arm biomarker signature breast density density high risk inclusion criteria indexing innovation interest malignant breast neoplasm mammary mammary epithelium predicting response predictive signature receptor receptor expression recruit routine screening screening side effect stem stem cells study population subcutaneous treatment arm

项目摘要

ABSTRACT Women with dense breasts on mammograpm have a 4-6-fold increased risk of breast cancer. A sizeable proportion of premenopausal breast cancer cases (39%) are attributable to having dense breasts. Observational and clinical trial data have shown that a decrease in breast density translates to a reduction in breast cancer incidence. Hence, interventions to reduce breast density could prevent breast cancer. However, adult dietary and lifestyle modifications have not been shown to reduce mammographic density. Therefore, identifying a pathway that can be targeted to reduce breast density and breast cancer incidence is crucial. The receptor activator of nuclear factor-κB (RANK) pathway regulates the development of the lobulo-alveolar mammary structures, activates downstream signaling cascades involved in breast cancer and is the major mediator of progesterone-driven expansion of mammary stem cells. The RANK pathway is associated with mammographic density and breast cancer risk. This has led to a strong interest in inhibiting RANK ligand (RANKL) signaling to prevent breast cancer. Nevertheless, clinical trial data providing definitive evidence that would allow the adoption of RANKL inhibition in reducing dense breasts and prevent breast cancer are not yet available. We, thereby, propose to (i) perform a randomized clinical trial to quantify the effect of RANKL inhibition with denosumab on mammographic density in high-risk premenopausal women with dense breasts (Primary Aim); (ii) determine the effect of RANKL inhibition on breast tissue RANK, progesterone-regulated pathway gene expression, and related biomarkers associated with breast cancer risk (Secondary Aim). Approach: Study participants will be randomized (1:1) to an intervention (N=116) or placebo arm (N=116). Intervention: The intervention arm will receive two subcutaneous injections of denosumab (60 mg), one at baseline, and a second at 6 months. The placebo arm will receive two subcutaneous placebo injections at baseline, and 6 months. We will use Volpara software to assess mammographic density at baseline, and 12 months. Volpara quantifies volumetric measures of density; volumetric percent density (VPD) allowing us to test differences in change in mammographic density at 12 months among women assigned to intervention vs. placebo. Study population: 232 women undergoing annual screening mammography at the Siteman Cancer Center (SCC), St. Louis, MO. Inclusion criteria: (i) premenopausal; (ii) ≥40 years of age; (iii) dense breasts (volumetric percent density ≥7.5% on Volpara, equivalent to BI-RADS Category C; (iv) have an increased risk of breast cancer (e.g. positive history of breast cancer in a first-degree relative, non-BRCA susceptibility genes). Target population: Annually, >3,500 premenopausal women with dense breasts aged ≥40 years undergo screening mammogram at the SCC, hence, we are confident of reaching our recruitment goals. Impact: Study findings could open up additional therapeutic approaches in primary breast cancer prevention for high-risk premenopausal women with dense breasts, who do not have dominant genetic predisposition.

抽象的乳房 X 光检查中乳房致密的女性患乳腺癌的风险增加 4-6 倍。绝经前乳腺癌病例的比例（39%）归因于乳房致密。观察和临床试验数据表明，乳腺密度的降低意味着乳腺密度的降低。因此，降低乳腺密度的干预措施可以预防乳腺癌。成人饮食和生活方式的改变尚未被证明可以降低乳房X线密度。确定可降低乳腺密度和乳腺癌发病率的途径至关重要。核因子-κB (RANK) 通路受体激活剂调节小叶-肺泡的发育乳腺结构，激活与乳腺癌相关的下游信号级联，是主要的黄体酮驱动的乳腺干细胞扩增的介质与 RANK 通路相关。乳腺X线密度和乳腺癌风险引起了人们对抑制RANK配体的浓厚兴趣。然而，临床试验数据提供了明确的证据表明。是否可以通过 RANKL 抑制来减少致密乳房并预防乳腺癌因此，我们建议 (i) 进行一项随机临床试验来量化 RANKL 的效果。狄诺塞麦对乳腺致密的高危绝经前妇女的乳腺 X 光密度的抑制作用（主要目标）；（ii）确定 RANKL 抑制对乳腺组织 RANK 的影响，孕激素调节途径基因表达以及与乳腺癌风险相关的相关生物标志物（次要目标）。方法：研究参与者将被随机 (1:1) 分配至干预组 (N=116) 或安慰剂组 (N=116)。干预：干预组将接受两次皮下注射狄诺塞麦（60 mg），一次在安慰剂组将在 6 个月时接受两次皮下安慰剂注射。我们将使用 Volpara 软件评估基线和 12 个月的乳房 X 光密度。 Volpara 量化了密度的体积测量值；体积百分比密度 (VPD)，使我们能够测试 12 个月时接受干预的女性与接受干预的女性的乳房 X 光密度变化的差异。安慰剂研究人群：232 名女性在 Siteman 癌症中心接受年度乳房 X 光检查。密苏里州圣路易斯中心 (SCC) 纳入标准：(i) 绝经前；(ii) 年龄≥40 岁；(iii) 乳房致密（Volpara 上的体积百分比密度≥7.5%，相当于 BI-RADS C 类；(iv) 风险增加乳腺癌（例如一级亲属的乳腺癌阳性病史、非 BRCA 易感性）目标人群：每年超过 3,500 名年龄≥40 岁、拥有致密乳房的绝经前女性。在 SCC 接受乳房 X 光检查，因此我们有信心实现我们的招募目标。影响：研究结果可能为乳腺癌的初级预防开辟更多的治疗方法乳房致密且不具有显性遗传倾向的高危绝经前女性。