Lifestyle and Molecular Factors of Bone Health in Breast Cancer Survivors

乳腺癌幸存者的生活方式和骨骼健康的分子因素

• 批准号: 8688963
• 负责人: Marilyn L Kwan
• 金额: $ 61.56万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688963
• 关键词: 25-hydroxyvitamin D; Address; Adjuvant; Age; Alcohol consumption; Aromatase Inhibitors; Biological Assay; Biological Markers; Bone Density; Bone Resorption; Calcium; California; Cancer Patient; Cancer Prognosis; Cancer Survivor; Cancer Survivorship; Caring; Clinical; Clinical Trials; Cohort Studies; Coupled; Data; Diagnosis; Diet; Direct Costs; Early treatment; Enrollment; Environment; Epidemiology; Estrogen Metabolism; Estrogens; Facilities and Administrative Costs; Fracture; Future; General Population; Genes; Genetic Variation; Genotype; Guidelines; Health; Health Care Costs; High Risk Woman; Hip Fractures; Hormonal; Hormone Receptor; IL6 gene; Interleukin-1; Knowledge; Life; Life Style; Link; Managed Care; Medical; Modeling; Molecular; Molecular Genetics; Newly Diagnosed; Osteogenesis; Osteoporosis; Outcome; Pathway interactions; Patients; Performance; Pharmacy facility; Physical activity; Population; Positioning Attribute; Postmenopause; Predictive Value; Prevention; Prospective Studies; Public Health; Quality of life; Relative (related person); Request for Applications; Research; Risk; Risk Assessment; Risk Factors; Serum; Smoking; Spinal Fractures; Staging; Survivors; TNF gene; TNFSF11 gene; Tamoxifen; Time; Validation; Vitamin D; Woman; base; bone; bone health; bone metabolism; care systems; clinical risk; clinically significant; cytokine; design; disability; genome-wide; high risk; hormone therapy; improved; lifestyle factors; malignant breast neoplasm; mortality; osteoporosis with pathological fracture; primary outcome; programs; prospective; public health relevance; screening; secondary outcome; skeletal; tool

DESCRIPTION (provided by applicant): Aromatase inhibitors (AIs) have been rapidly replacing tamoxifen (TAM) as first-line adjuvant hormonal therapy for postmenopausal women diagnosed with hormone receptor (HR)-positive, early-stage breast cancer. The profound estrogen depletion triggered by AIs is responsible for improved outcomes compared to TAM, yet AI therapy can negatively impact bone health, elevating the already high risk of fractures in postmenopausal women. Osteoporotic fractures at older age can result in markedly increased mortality, poor quality of life, and staggering healthcare costs. Despite these outcomes, risk factors for fracture specific to postmenopausal breast cancer patients taking AIs remain surprisingly understudied. To date, no validated tools exist for fracture risk assessment specific to postmenopausal women prior to initiation of AI therapy. This application requests to conduct for the first time a prospective study on bone health in 2,062 postmenopausal breast cancer patients who received AI therapy in the Pathways Study, a prospective cohort study of breast cancer prognosis in the Kaiser Permanente Northern California (KPNC) Medical Care Program, enrolled from 2006-2013 and followed through 2016. The establishment of Pathways was concurrent with AIs widely replacing TAM as hormonal therapy for postmenopausal patients. By leveraging a rich body of epidemiologic, clinical and pharmacy data linked with high-quality biospecimens in Pathways, we have a unique opportunity to conduct one of the first in-depth studies of AI-associated fractures in breast cancer patients. Among postmenopausal women who received AI therapy for early-stage, HR-positive breast cancer, we will investigate the risk of fractures (primary outcome) and osteoporosis (secondary outcome) in association with 1) modifiable lifestyle factors such as physical activity, diet, vitamin D and calcium supplement use, smoking, and alcohol consumption; 2) germline genetic variations in estrogen and bone metabolism pathways with validation of findings using genome-wide assays; and 3) the associations of serum biomarkers, including BAP for bone formation and TRAP5b for resorption, six key regulatory cytokines (RANKL, OPG, IL1, IL6, TNF¿, CSF), and 25-hydroxyvitamin D. Finally, a prediction model for fracture risk in postmenopausal breast cancer patients on AI therapy will be developed based upon lifestyle factors, genetic variations, and serum biomarkers and compared with models intended for the general healthy population. Over 2.5 million women with breast cancer live in the U.S. today, with an estimated 230,000 newly diagnosed cases in 2011. An excess of 13,000 fractures per year has been estimated among postmenopausal survivors compared to their healthy counterparts. Therefore, understanding the health effects of AI therapy on risk of skeletal outcomes is of great public health importance. In the Pathways Study, we now have an exceptional opportunity to address an important gap in breast cancer survivorship research, and to reduce the burden of AI-induced osteoporotic fractures in a real-world clinical setting.

描述（由适用提供）：芳香酶抑制剂（AIS）已迅速替换了他莫昔芬（TAM）作为一线可调节激素治疗，用于诊断为骑马受体（HR）阳性的早期乳腺癌的绝经后妇女。与TAM相比，由AIS触发的深刻雌激素部署负责改善结果，但是AI疗法会对骨骼健康产生负面影响，从而提高了绝经后妇女骨折的高风险。骨质疏松性骨折的年龄较大可能会导致死亡率明显增加，生活质量差以及医疗费用惊人。尽管有这些结果，绝经后乳腺癌患者特异性骨折的危险因素仍然令人惊讶地理解。迄今为止，在开始AI治疗之前，尚无对绝经后妇女特异性骨折风险评估的验证工具。该申请要求首次进行对骨骼健康的前瞻性研究，对在途径研究中接受AI治疗的两,062例乳腺癌患者，这是一项针对北加州北加州北部北部永久性乳腺癌预后的前瞻性队列研究。绝经后患者的马疗治疗。通过利用与途径中高质量的生物测量有关的丰富的流行病学，临床和药房数据，我们有一个独特的机会，可以对乳腺癌患者进行AI相关骨折的第一个深入研究之一。在接受AI治疗的早期阶段HR阳性乳腺癌的绝经后妇女中，我们将研究骨折（主要结果）和骨质疏松症（次要结局）的风险（1）与1个相关性），例如身体活动，饮食，饮食，维生素D和钙补充剂的使用，例如 吸烟和饮酒； 2）使用全基因组刺激验证发现的雌激素和骨代谢途径的种系遗传变异；和3）血清生物标志物的关联，包括骨形成的BAP和用于分辨率的TRAP5B，六个关键调节性细胞因子（Rankl，OPG，IL1，IL1，IL6，IL6，TNF¿，CSF），CSF，CSF）和25-羟基伏胺D.最终，基于术后术后的遗传因素，是一种基于术后的遗传因素，是一种遗传疾病，是一种基于术后的遗传因素。变化和血清生物标志物，并将其与针对一般健康人群的模型进行了比较。如今，美国有超过250万乳腺癌的妇女居住在美国，2011年估计有230,000例新诊断的病例。与健康后的同伴相比，绝经后的生存中估计每年骨折超过13,000个骨折。因此，了解AI疗法对骨骼结局风险的健康影响至关重要。在途径研究中，我们现在有一个极好的机会来解决乳腺癌生存研究的重要差距，并在现实世界中临床环境中减少AI诱导的骨质疏松性骨折的燃烧。