Plasma Vitamin D Levels and Prostate Cancer Outcomes

描述（由申请人提供）：维生素D在前列腺癌幸存者中的有益作用得到了体外和体内研究中一致显示的抗癌作用以及观察性研究报告阳光暴露与前列腺癌死亡率之间的负相关性的支持。维生素D类似物在选定的患者中也显示出治疗功效。然而，很少有流行病学研究专门评估循环维生素D水平与前列腺癌预后的关系。本研究将调查诊断为前列腺癌的男性血浆25-羟基维生素D [25（OH）D]浓度是否与疾病结局相关。该研究具有以下具体目的：1）测量基于人群的前列腺癌病例队列中25（OH）D的血浆浓度; 2）评价血浆25（OH）D浓度与前列腺癌特异性死亡和肿瘤复发或进展风险之间的相关性。为了实现这些目标，我们将建立在现有的1，477例组织学确诊的前列腺癌病例（随访6-18年）的人群队列基础上，这些病例已经收集或测量了广泛的流行病学数据，临床数据，诊断后血液样本和维生素D代谢基因（VDR，CYP 27 B1和CYP 24 A1）的遗传变异。这一独特的队列正在进行随访，以确定疾病复发/进展、生命状态和潜在死亡原因（由单独的拨款资助）。将使用调整后的考克斯比例风险回归模型根据维生素D水平确定结局的风险比和95%置信区间。我们还将探讨这些风险比是否受体重指数、种族或维生素D代谢基因型的影响。还将在根据已知影响前列腺癌结局的临床参数（Gleason评分、肿瘤分期、诊断PSA水平）和主要治疗定义的患者亚组中检查相关性。以前只有一项小型流行病学研究报告了血清25（OH）D浓度与前列腺癌生存率之间的正相关性。这项拟议的研究将是迄今为止评估前列腺癌幸存者维生素D水平的最大研究，并将包括对其他终点的分析和对相关亚组的评估。这种将血浆维生素D状态与患者预后联系起来的创新和具有成本效益的应用可以提供证据，支持使用维生素D水平作为生物标志物，用于识别不良结局风险较高的男性，并支持开发维生素D类似物作为治疗剂的努力，用于维生素D可能对预后影响最大的适当患者。 公共卫生相关性：在2009年，估计将有27，360人死于前列腺癌，并且在疾病发病率和192，280名被诊断患有前列腺癌的男性的医疗保健费用方面给美国带来显著的额外负担。本研究将测量前列腺癌男性血浆中的维生素D（一种具有抗癌作用的可变因素），并通过维生素D水平估计癌症复发/进展和前列腺癌特异性死亡的风险。这项研究的结果可用于设计临床试验，探索维生素D在治疗某些前列腺癌患者人群中的潜在有益作用，从而改善患者预后，并将维生素D开发为更具侵袭性疾病患者的潜在生物标志物。

DESCRIPTION (provided by applicant): A beneficial role for vitamin D in prostate cancer survivors is supported by anticancer effects consistently shown in both in vitro and in vivo studies, and by observational research reporting inverse associations between sunlight exposure and prostate cancer mortality. Vitamin D analogs have also shown therapeutic efficacy in selected patients. However, few epidemiological studies have specifically evaluated circulating vitamin D levels in relation to prostate cancer prognosis. This study will investigate whether plasma concentration of 25-hydroxyvitamin D [25(OH)D] in men diagnosed with prostate cancer is associated with disease outcomes. The study has the following specific aims: 1) To measure plasma concentration of 25(OH)D in a population-based cohort of prostate cancer cases; and, 2) To evaluate the association between plasma 25(OH)D concentrations with risks of prostate-cancer specific death and tumor recurrence or progression. To accomplish these aims we will build upon an existing population-based cohort of 1,477 histologically confirmed prostate cancer cases (with 6-18 years of follow-up) for which extensive epidemiological data, clinical data, post-diagnosis blood samples, and genetic variation in vitamin D metabolism genes (VDR, CYP27B1 and CYP24A1) have already been collected or measured. This unique cohort is under on-going follow-up for ascertainment of disease recurrence/progression, vital status and underlying cause of death (funded by a separate grant). Adjusted Cox proportional hazards regression models will be used to determine hazard ratios and 95% confidence intervals for the outcomes according to vitamin D level. We will also explore if these hazard ratios are modified by body mass index, race, or vitamin D metabolism genotypes. Associations also will be examined within patient subgroups defined by clinical parameters known to influence prostate cancer outcomes (Gleason score, tumor stage, diagnostic PSA level) and by primary treatment. Only one small epidemiological study has previously reported a positive association between serum concentration of 25(OH)D and prostate cancer survival. The proposed study will be the largest study to date to evaluate vitamin D level in prostate cancer survivors, and will include analyses of additional endpoints and evaluation of relevant subgroups. This innovative and cost-effective application to relate plasma vitamin D status with patient prognosis could provide evidence supporting the use of vitamin D level as a biomarker for identifying men at higher risk for adverse outcomes and bolster efforts to develop a vitamin D analog as a therapeutic agent for appropriate patients where vitamin D may have the greatest impact on prognosis. PUBLIC HEALTH RELEVANCE: Project Narrative In 2009 there will be an estimated 27,360 deaths from prostate cancer and a significant additional burden to the U.S. in terms of disease morbidity and health care costs for the 192,280 men diagnosed with prostate cancer. This study will measure vitamin D, a modifiable factor with demonstrated anti-cancer effects, in the plasma of men with prostate cancer and estimate the risks of cancer recurrence/progression and prostate cancer-specific death by vitamin D levels. Results from this study could be used to design clinical trials exploring the potentially beneficial effects of vitamin D in the treatment of certain patient populations with prostate cancer, thereby improving patient prognosis, and to develop vitamin D as a potential biomarker for patients with more aggressive disease.