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: 10675080
• 负责人: Adetunji T Toriola
• 金额: $ 59.54万
• 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/10675080
• 关键词: Address; Adoption; Adult; Age Years; 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; 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; Needles; Nuclear; Participant; Pathway interactions; Placebos; Premenopause; Progesterone; Progesterone Receptors; Proliferating; Randomized; Receptor Inhibition; Recording of previous events; Signal Transduction; Structure; Subcutaneous Injections; Susceptibility Gene; Tamoxifen; Target Populations; Testing; Therapeutic; Time; Transforming Growth Factors; Translating; Woman; aged; arm; biomarker signature; breast density; density; high risk; inclusion criteria; indexing; innovation; interest; malignant breast neoplasm; mammary; mammary epithelium; participant enrollment; predicting response; predictive signature; randomized, clinical trials; receptor; receptor expression; recruit; routine screening; screening; side effect; stem cells; study population; subcutaneous; treatment arm; ultrasound

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 乳房致密的女性患乳腺癌的风险是乳房X光检查的4-6倍。一个相当大的 绝经前乳腺癌的比例(39%)可归因于乳房致密。 观察和临床试验数据表明，乳房密度的下降转化为 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， 成人饮食和生活方式的改变并没有显示出降低乳房X光照相密度。因此， 确定一条可以有针对性地降低乳房密度和乳腺癌发病率的途径至关重要。这个 核因子受体激活剂-κB(RANK)通路对肺泡发育的调控作用 乳腺结构，激活下游信号级联反应，参与乳腺癌，是主要的 孕酮驱动的乳腺干细胞扩增的中介物。等级路径与以下各项相关 乳房X光照相密度与乳腺癌风险。这导致了人们对抑制RANK配体的强烈兴趣 (RANKL)发出预防乳腺癌的信号。然而，临床试验数据提供了确凿的证据 是否会通过RANKL抑制在减少致密乳房和预防乳腺癌方面尚不成熟 可用。因此，我们建议(I)进行一项随机临床试验来量化RANKL的效果 地诺舒单抗对绝经前密乳高危妇女钼靶密度的抑制作用 (主要目的)；(Ii)确定RANKL抑制对乳腺组织等级、孕酮调节的影响 途径基因表达，以及与乳腺癌风险相关的生物标记物(次级目标)。 研究方法：研究参与者将被随机(1：1)分为干预组(N=116)或安慰剂组(N=116)。 干预：干预组将接受两次皮下注射地诺舒单抗(60毫克)，一次是在 基线，第二次在6个月时。安慰剂手臂将接受两次皮下安慰剂注射 基线，6个月。我们将使用Volpara软件评估基线和12个月的乳腺X光检查密度 月份。Volpara将密度的体积测量量化；体积百分比密度(VPD)使我们能够 在12个月后，接受干预的妇女与 安慰剂。研究人群：在Siteman癌症中心接受年度乳房X光检查的232名妇女 中心(SCC)，密苏里州圣路易斯纳入标准：(I)绝经前；(Ii)≥40岁；(Iii)丰满乳房 (VOLPAR上的体积百分比密度≥为7.5%，相当于BI-RADS C类；(Iv)风险增加 乳腺癌(例如，一级亲属中的乳腺癌阳性病史，非BRCA易感性 基因)。目标人群：≥40岁，每年3,500名乳房丰满的绝经前妇女 在SCC接受筛查X光检查，因此，我们有信心实现我们的招聘目标。 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 高危绝经前女性，乳房致密，没有显性遗传倾向。