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.

抽象的 乳房X线照片上乳房密集的妇女的乳腺癌风险增加了4-6倍。一个很大的 绝经前乳腺癌病例（39％）的比例归因于乳房致密。 观察性和临床试验数据表明，乳房密度的降低转化为减少 乳腺癌发病率。因此，减少乳房密度的干预措施可以预防乳腺癌。然而， 成人的饮食和生活方式修饰尚未证明可以降低乳房X线摄影密度。所以， 确定可以针对降低乳腺密度和乳腺癌发生率的途径至关重要。 核因子-κB（等级）途径的受体激活剂调节叶肺泡的发展 乳腺结构激活参与乳腺癌的下游信号级联反应，是主要的 乳腺干细胞孕酮驱动的膨胀介质。等级途径与 乳腺X线摄影密度和乳腺癌风险。这引起了人们对抑制等级配体的浓厚兴趣 （RANKL）预防乳腺癌的信号。然而，临床试验数据提供了明确的证据 将允许在减少乳房并预防乳腺癌的情况下采用RANKL抑制作用 可用的。因此，我们建议（i）执行一项随机临床试验以量化RANKL的影响 用denosumab抑制对高风险的乳房高风险乳房乳房X线摄影密度的抑制作用 （主要目的）； （ii）确定RANKL抑制对乳房组织等级的影响，孕酮调节 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分配给干预措施（n = 116）或安慰剂组（n = 116）。 干预措施：干预臂将接受两次皮下注射denosumab（60 mg），一个在 基线和6个月的第二个。安慰剂臂将在 基线和6个月。我们将使用Volpara软件评估基线乳房X线摄影密度，而12个 月份。 Volpara量化了密度的体积测量；容量百分比密度（VPD），使我们能够 分配给干预vs的妇女在12个月时乳房X线学密度变化的测试差异。 安慰剂。研究人群：232名女性在现场癌症中接受年度乳房X线摄影 中心（SCC），密苏里州圣路易斯。纳入标准：（i）绝经前； （ii）≥40岁； （iii）密集的乳房 （沃尔帕拉的体积百分比≥7.5％，相当于Bi-Rads类别C;（iv）的风险增加 乳腺癌（例如，一级亲戚，非BRCA敏感性中乳腺癌的阳性病史 基因）。目标人群：每年> 3,500次乳房的绝经前妇女≥40岁 在SCC上进行乳房X光检查，因此，我们有信心达到招聘目标。 影响：研究结果可以为预防原发性乳腺癌的其他治疗方法开放 乳房密集的高风险的乳房妇女，她们没有主要的遗传易感性。