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（由申请人提供）：芳香酶抑制剂（AI）已迅速取代他莫昔芬（TAM），作为诊断患有激素受体（HR）阳性的早期乳腺癌的绝经后妇女的一线辅助激素疗法。与 TAM 相比，AI 引发的治疗效果更好，但 AI 治疗会对骨骼健康产生负面影响，增加绝经后女性本来就很高的骨折风险。尽管存在这些结果，但老年骨质疏松性骨折可能会导致死亡率显着增加、生活质量下降和医疗费用惊人，但迄今为止，尚无针对服用 AI 的绝经后乳腺癌患者的骨折风险因素进行充分的研究。在开始 AI 治疗之前对绝经后女性进行骨折风险评估 该申请要求首次对 2,062 名接受 AI 治疗的绝经后乳腺癌患者进行骨骼健康前瞻性研究。 Pathways 研究是北加州 Kaiser Permanente (KPNC) 医疗保健计划中乳腺癌预后的一项前瞻性队列研究，于 2006 年至 2013 年入组并跟踪至 2016 年。 Pathways 的建立与 AI 广泛取代 TAM 作为激素疗法同时发生。通过利用 Pathways 中与高质量生物样本相关的丰富的流行病学、临床和药学数据，我们有独特的机会进行研究。这是对乳腺癌患者 AI 相关骨折的首批深入研究之一，在接受 AI 治疗的早期 HR 阳性乳腺癌的绝经后女性中，我们将调查骨折（主要结果）和骨质疏松症的风险。次要结果）与 1）可改变的生活方式因素相关，例如体力活动、饮食、维生素 D 和钙补充剂的使用， 吸烟和饮酒；2) 雌激素和骨代谢途径的种系遗传变异，并使用全基因组测定验证结果；3) 血清生物标志物的关联，包括用于骨形成的 BAP 和用于吸收的 TRAP5b，六种关键的调节细胞因子（RANKL、OPG、IL1、IL6、TNF¿、CSF）和 25-羟基维生素 D。最后，采用 AI 治疗的绝经后乳腺癌患者骨折风险的预测模型将是该模型是根据生活方式因素、遗传变异和血清生物标志物开发的，并与针对一般健康人群的模型进行了比较。目前，美国有超过 250 万患有乳腺癌的女性，估计 2011 年有 230,000 例新诊断病例。超过 13,000 例。与健康骨骼相比，估计绝经后幸存者每年骨折的数量。因此，了解人工智能治疗对骨骼结果风险的健康影响具有重要的公共卫生意义。在途径研究中，我们现在有一个难得的机会来解决乳腺癌生存研究中的重要差距，并减轻现实临床环境中人工智能引起的骨质疏松性骨折的负担。