Plasma Vitamin D Levels and Prostate Cancer Outcomes

描述(由申请人提供)：体外和体内研究中一致显示的抗癌作用，以及报告阳光照射与前列腺癌死亡率呈负相关的观察性研究支持了维生素D在前列腺癌幸存者中的有益作用。维生素D类似物在选定的患者中也显示出治疗效果。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。这项研究将调查前列腺癌患者血浆中25-羟基维生素D[25(OH)D]的浓度是否与疾病结局有关。这项研究有以下具体目的：1)测量前列腺癌人群中血浆25(OH)D的浓度；以及2)评估血浆25(OH)D浓度与前列腺癌特异性死亡风险和肿瘤复发或进展的关系。为了实现这些目标，我们将建立在现有人群队列的基础上，该队列包括1,477例经组织学证实的前列腺癌病例(随访6-18年)，已经收集或测量了广泛的流行病学数据、临床数据、诊断后血液样本以及维生素D代谢基因(VDR、CYP27B1和CYP24A1)的遗传变异。这一独特的队列正在持续跟踪，以确定疾病复发/进展、生命状况和潜在死亡原因(由另一笔赠款资助)。调整后的COX比例风险回归模型将被用来根据维生素D水平来确定危险比和结果的95%可信区间。我们还将探索这些危险比是否会受到体重指数、种族或维生素D代谢基因的影响。此外，还将根据临床参数(格里森评分、肿瘤分期、诊断PSA水平)和初步治疗来确定患者亚组中的相关性。此前只有一项小型流行病学研究报告了血清25(OH)D浓度与前列腺癌存活率之间的正相关关系。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水平的最大规模的研究，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水平与患者预后联系起来的创新和成本效益高的应用可以提供证据，支持使用维生素D水平作为生物标记物来确定有较高不良后果风险的男性，并支持努力开发一种维生素D类似物，作为维生素D可能对预后影响最大的适当患者的治疗剂。 公共卫生相关性：项目简介2009年，估计将有27,360人死于前列腺癌，在疾病发病率和医疗费用方面，美国将为192,280名被诊断患有前列腺癌的男性带来显著的额外负担。这项研究将测量前列腺癌男性患者血浆中的维生素D，这是一种已证明具有抗癌效果的可修饰因子，并通过维生素D水平来评估癌症复发/进展和前列腺癌特有死亡的风险。这项研究的结果可以用来设计临床试验，探索维生素D在治疗某些前列腺癌患者群体中的潜在益处，从而改善患者的预后，并开发维生素D作为更具侵袭性疾病患者的潜在生物标记物。

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.