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

• 批准号: 9816472
• 负责人: Adetunji T Toriola
• 金额: $ 59.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/9816472
• 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; Epithelial; 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; Mammary gland; 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; Stem cells; Structure; Subcutaneous Injections; Susceptibility Gene; TRANCE protein; Tamoxifen; Target Populations; Testing; Therapeutic; Time; Transforming Growth Factors; Translating; Ultrasonography; Woman; aged; arm; breast density; density; high risk; inclusion criteria; indexing; innovation; interest; malignant breast neoplasm; predicting response; predictive signature; receptor; receptor expression; recruit; routine screening; screening; side effect; stem; study population; subcutaneous; treatment arm

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.

摘要 乳房X线摄影显示乳腺致密的女性患乳腺癌的风险增加4-6倍。相当大 绝经前乳腺癌病例的比例（39%）可归因于乳房致密。 观察性和临床试验数据表明，乳腺密度的降低意味着乳腺癌发病率的降低。 乳腺癌发病率。因此，降低乳腺密度的干预措施可以预防乳腺癌。然而，在这方面， 成年人饮食和生活方式的改变并没有显示出降低乳房X线摄影密度。因此，我们认为， 确定一种可用于降低乳腺密度和乳腺癌发病率的途径至关重要。的 核因子-κB受体激活剂（RANK）通路调节小叶-肺泡的发育 乳腺结构，激活下游信号级联参与乳腺癌，是主要的 雌激素驱动的乳腺干细胞扩增的介质。RANK通路与 乳腺密度和乳腺癌风险之间的关系。这导致了对抑制RANK配体的强烈兴趣 （RANKL）信号传导来预防乳腺癌。然而，临床试验数据提供了明确的证据， 将允许通过RANKL抑制来降低乳腺密度和预防乳腺癌， available.因此，我们建议（i）进行一项随机临床试验，以量化RANKL的作用 地舒单抗对高风险绝经前致密乳腺女性乳腺摄影密度的抑制作用 （主要目的）;（ii）确定RANKL抑制对乳腺组织RANK、孕酮调节的 通路基因表达和与乳腺癌风险相关的相关生物标志物（次要目的）。 方法：研究受试者将随机（1：1）分配至干预组（N=116）或安慰剂组（N=116）。 干预：干预组将接受两次地舒单抗（60 mg）皮下注射， 第一次是基线，第二次是6个月。安慰剂组将接受两次皮下安慰剂注射， 基线和6个月。我们将使用Volpara软件评估基线时的乳腺摄影密度， 个月Volpara量化了密度的体积测量;体积百分比密度（VPD）使我们能够 在12个月时，在分配到干预组的妇女与分配到对照组的妇女之间， 安慰剂研究人群：232名在Siteman Cancer接受年度筛查乳房X线摄影的女性 中心（SCC），圣路易斯，密苏里州。入选标准：（i）绝经前;（ii）≥40岁;（iii）致密乳腺 （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（例如一级亲属中有乳腺癌阳性病史，非BRCA易感性 基因）。目标人群：每年，> 3，500例年龄≥40岁的乳腺致密型绝经前女性 因此，我们有信心达到我们的招聘目标。 影响：研究结果可以为初级乳腺癌预防开辟额外的治疗方法， 乳腺致密的高危绝经前妇女，没有显性遗传倾向。