Lifestyle and Molecular Factors of Bone Health in Breast Cancer Survivors

描述（由申请人提供）：芳香酶抑制剂（AIs）已迅速取代他莫昔芬（TAM），成为诊断为激素受体（HR）阳性早期乳腺癌的绝经后妇女的一线辅助激素治疗。与TAM相比，人工智能引发的严重雌激素消耗是改善预后的原因，但人工智能治疗会对骨骼健康产生负面影响，增加绝经后妇女已经很高的骨折风险。老年骨质疏松性骨折可导致死亡率显著增加、生活质量下降和惊人的医疗费用。尽管有这些结果，服用AIs的绝经后乳腺癌患者发生骨折的危险因素仍未得到充分的研究。到目前为止，还没有有效的工具来评估绝经后妇女在开始人工智能治疗前的骨折风险。该申请首次要求对2062名接受人工智能治疗的绝经后乳腺癌患者的骨骼健康进行前瞻性研究，这是一项在Kaiser Permanente北加州（KPNC）医疗保健计划中进行的乳腺癌预后前瞻性队列研究，于2006-2013年入组，并随访至2016年。Pathways的建立与AIs广泛取代TAM作为绝经后患者的激素治疗同时进行。通过利用Pathways中丰富的流行病学、临床和药学数据，以及高质量的生物标本，我们有一个独特的机会，可以对乳腺癌患者的人工智能相关骨折进行首次深入研究。在接受人工智能治疗早期hr阳性乳腺癌的绝经后妇女中，我们将调查骨折（主要结局）和骨质疏松症（次要结局）的风险与1)可改变的生活方式因素（如体力活动、饮食、维生素D和钙补充剂的使用）的关系；

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.