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（REDUCE），已经证明使用5种α还原酶抑制剂（5种ARI：非那雄胺和度他雄胺）可使PCa风险降低23-25%。然而，5ARI尚未被广泛采用，部分原因是成本效益差。我们假设，基于1）总体遗传风险[家族史（FH）和PCa风险相关的遗传变异]和2）与5ARI相互作用的多态性，靶向化学预防可能更有效，更具成本效益，因此更有可能被医生及其患者采用。这种基因组靶向方法的有效性需要进行系统的评估，并与非基因组方法进行比较，使用基于证据的方法，如EGAPP（评估基因组在实践和预防中的应用）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5ARI进行PCa化学预防相关的结果。我们将在两个现有的大型随机临床试验（REDUCE和PCPT）、两个新的前列腺癌风险男性研究人群和一项医生调查中评估和比较基因组和非基因组方法的疗效、感知、决策和成本效益。REDUCE和PCPT的独特研究设计，以及研究结束时的前列腺活检，使我们能够解决本研究中的两个关键问题：前列腺癌风险相关SNP的PSA检测偏倚和使用5ARI的基因组靶向化学预防前列腺癌的疗效。我们有以下具体目标：1）使用一组非PSA检测偏倚的PCa风险相关单核苷酸多态性（SNP）评估PCa风险预测模型的临床有效性。2)使用全基因组和候选基因方法鉴定和评估与5ARI相互作用的新多态性在减少PCa诊断中的临床有效性，3）通过比较基因组靶向方法与非靶向化学预防在PCa发生率方面的减少来评估基因组靶向方法的临床效用，4）比较医生和患者对PCa的基因组和非基因组靶向化学预防的感知和决策，比较PCa基因组和非基因组靶向化学预防的成本效益。这项研究的结果将为疾病控制中心EGAPP工作组的循证评估提供全面的数据，提供比较有效性研究（CER）的原理证明研究，并将有助于为21世纪的未来基因组和个性化医学（GPM）构建路线图。 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率的显著下降，并大大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.