Clinical validity and utility of genomic targeted chemoprevention of PCa

前列腺癌基因组靶向化学预防的临床有效性和实用性

基本信息

批准号：
7944011
负责人：
Jianfeng Xu
金额：
$ 200.64万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7944011
关键词：
5 Alpha-Reductase Inhibitor Address Adopted Affect Behavioral Biopsy CYP3A4 gene Calibration Candidate Disease Gene Centers for Disease Control and Prevention (U.S.)Chemoprevention Clinic Clinical Collaborations Cost Effectiveness Analysis Data Decision Making Detection Discrimination Disease Dutasteride Effectiveness Evaluation Event Family history of Finasteride Future Gene Family Gene Targeting Genetic Genetic Markers Genetic Polymorphism Genetic Risk Genetic screening method Genome Genomics Individual Intention Interdisciplinary Study Lead Malignant Neoplasms Malignant neoplasm of prostate Maps Medicine Methods Modeling Outcome PSA level Patients Perception Physicians Population Population Study Prevention Primary Care Physician Primary Health Care Prostate Prostate Cancer Prevention Trial Public Health Randomized Randomized Clinical Trials Recommendation Recruitment Activity Reporting Research Design Research Personnel Risk Risk Estimate Single Nucleotide Polymorphism Societies Staging Surveys Urologist Variant Work base cancer diagnosis cancer risk case control comparative effectiveness comparative efficacy cost cost effective cost effectiveness design effectiveness research ethical legal social implication evidence base follow-up genetic variant genome wide association study genome-wide high risk men improved men men&apos s group non-genomic novel practical application prevent prevention evaluation public health relevance response risk perception uptake willingness working group

项目摘要

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.

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项重要策略是预防这种疾病。前列腺癌预防试验 (PCPT) 和度他雄胺减少前列腺癌事件 (REDUCE) 两项大型随机临床试验表明，使用 5 α 还原酶抑制剂（5ARIs：非那雄胺）可将 PCa 风险降低 23-25%和度他雄胺）。然而，5ARIs 尚未得到广泛采用，部分原因是成本效益较差。我们假设基于 1) 总体遗传风险 [家族史 (FH) 和 PCa 风险相关遗传变异] 和 2) 与 5ARIs 相互作用的多态性的靶向化学预防可能更有效且更具成本效益，因此更有可能受雇于医生及其患者。这种基因组靶向方法的有效性需要使用基于证据的方法进行系统评估，并与非基因组方法进行比较，例如 EGAPP（基因组在实践和预防中的应用评估）工作组推荐的方法。我们组建了一个多学科研究团队来解决一个首要问题：与非靶向方法相比，基因组靶向方法是否可以改善使用 5ARIs 进行 PCa 化学预防相关的结果。我们将在两项现有的大型随机临床试验（REDUCE 和 PCPT）、两个针对 PCa 风险男性的新研究人群以及对医生的调查。 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：PCa 风险相关 SNP 的 PSA 检测偏倚以及使用 5ARIs 进行 PCa 基因组靶向化学预防的功效。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识别和评估与 5ARIs 相互作用的新型多态性在减少 PCa 诊断方面的临床有效性，3) 通过比较基因组靶向方法与 PCa 发生率的降低情况来评估基因组靶向方法的临床效用非靶向化学预防，4) 比较医生和患者对前列腺癌基因组和非基因组靶向化学预防的看法和决策，以及 5) 比较基因组和非基因组靶向化学预防的成本效益PCa 的非基因组靶向化学预防。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) 的原理研究证明，并将有助于构建未来基因组和个性化医学的路线图（GPM）在21世纪。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针对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大幅下降，并大大减轻个人和社会的负担。