Clinical validity and utility of genomic targeted chemoprevention of PCa

描述(由申请人提供)：前列腺癌(PCA)是美国男性中最常见的癌症。解决这一公共卫生问题的一个重要策略是预防这种疾病。两项大型随机临床试验，前列腺癌预防试验(PCPT)和度他雄胺减少前列腺癌事件(RECLE)，已经证明使用5种α还原酶抑制剂(5ARIs：非那雄胺和度他雄胺)可将前列腺癌风险降低23%-25%。然而，5ARIs没有被广泛采用，部分原因是成本效益不高。我们假设，基于1)总体遗传风险[家族史(FH)和与PCA风险相关的遗传变异]和2)与5ARI相互作用的基因多态，有针对性的化学预防可能更有效、更具成本效益，因此更有可能被医生和他们的患者采用。需要系统地评估这种以基因组为目标的方法的有效性，并将其与非基因组方法进行比较，使用基于证据的方法，如EGAPP(基因组应用于实践和预防评估)工作组推荐的方法。我们已经组建了一个多学科的研究团队来解决一个首要问题，即与非靶向方法相比，基因组靶向方法是否可以改善与使用5ARIs的PCa化学预防相关的结果。我们将在现有的两个大型随机临床试验(RECESS和PCPT)、两个新的前列腺癌风险男性研究人群以及对医生的调查中，评估和比较基因组和非基因组方法的有效性、知觉、决策和成本效益。REDUTE和PCPT的独特研究设计加上研究结束时的前列腺活检，使我们能够在这项研究中解决两个关键问题：PSA检测-PCa风险相关SNPs的偏倚以及使用5ARIs进行基因组靶向化学预防PCa的有效性。我们有以下具体目的：1)使用一组非PSA检测偏向的PCA风险相关单核苷酸多态性(SNPs)来评估PCA风险预测模型的临床有效性。2)识别和评估与5ARIs相互作用的新的多态在使用全基因组和候选基因方法减少PCa诊断方面的临床有效性；3)通过比较基因组靶向方法与非靶向化学预防方法的PCA发生率的降低来评估其临床实用性；4)比较医生和患者对基因组和非基因组靶向化学预防PCA的感知和决策；以及5)比较基因组靶向和非基因组靶向化学预防PCA的成本效益。这项研究的结果将为疾病控制中心的EGAPP工作组进行循证评估提供全面的数据，为比较有效性研究(CER)的原理研究提供证据，并将有助于构建21世纪未来基因组和个性化医学(GPM)的路线图。 公共卫生相关性：我们将评估基于遗传标记和前列腺癌家族史的男性目标群体是否可以提高前列腺癌化学预防的有效性。这将导致前列腺癌诊断的显著减少，并极大地减轻个人和社会的负担。

DESCRIPTION (Provided by the applicant): Prostate cancer (PCa) is the most common cancer among men in the U.S. One important strategy to address this public health concern is to prevent the disease. Two large randomized clinical trials, The Prostate Cancer Prevention Trial (PCPT) and The Reduction by Dutasteride of Prostate Cancer Events (REDUCE), have demonstrated a 23-25% reduction in PCa risk with the use of 5 alpha reductase inhibitors (5ARIs: finasteride and dutasteride). However, 5ARIs have not been widely adopted due, in part, to poor cost-effectiveness. We hypothesize that targeted chemoprevention, based on 1) overall genetic risk [family history (FH) and PCa risk associated genetic variants], and 2) polymorphisms that interact with 5ARIs, may be more efficacious and cost effective, and thus more likely to be employed by physicians and their patients. The effectiveness of this genomic-targeted approach needs to be systematically evaluated and compared to non-genomic approaches using evidence-based methods such as those recommended by the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) working group. We have assembled a multidisciplinary research team to address an overarching question of whether a genomic-targeted approach improves outcomes related to chemoprevention of PCa using 5ARIs compared to a non-targeted approach. We will evaluate and compare the efficacy, perception, decision making, and cost-effectiveness of genomic and non-genomic approaches in two existing large randomized clinical trials (REDUCE and PCPT), two new study populations of men at risk for PCa, and in a survey of physicians. The unique study design of REDUCE and PCPT, with end-of-study prostate biopsies, allows us to address two critical questions in this study: PSA detection-bias of PCa risk associated SNPs and efficacy of genomic-targeted chemoprevention of PCa using 5ARIs. We have the following specific aims: 1) assess the clinical validity of PCa risk prediction models using a panel of non PSA detection biased PCa risk-associated Single Nucleotide Polymorphisms (SNPs). 2) identify and assess the clinical validity of novel polymorphisms that interact with 5ARIs in reducing PCa diagnosis using both genome-wide and candidate gene approaches, 3) assess the clinical utility of a genomic-targeted approach by comparing its reduction in rates of PCa with non-targeted chemoprevention, 4) compare perception and decision making of physicians and patients for genomic and non-genomic-targeted chemoprevention of PCa, and 5) Compare the cost-effectiveness of genomic and non-genomic-targeted chemoprevention of PCa. Results from this study will provide comprehensive data for evidence-based evaluation by the Center for Disease Control's EGAPP working group, provide a proof of principle study of comparative effectiveness research (CER), and will help build a road map for future genomic and personalized medicine (GPM) in the 21st century. PUBLIC HEALTH RELEVANCE: We will evaluate whether targeting groups of men based on genetic markers and family history of prostate cancer may improve the effectiveness of chemoprevention for prostate cancer. This would lead to a significant decrease in prostate cancer diagnoses and greatly reduce the burden to the individual and society.