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，解决这种公共卫生问题的一种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）和前列腺癌事件的杜甲酰胺的减少（减少），证明PCA风险降低了23-25％，使用了5种α还原酶抑制剂（5aris：finasteride：finasteride和dutasteride和dutasteride）。但是，5ARI并未被广泛采用，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）和与PCA风险相关的遗传变异剂]和2）与5ARI相互作用的多态性可能更有效，更具成本效益，因此更有可能被医师及其患者使用更可能更有可能使用。使用基于证据的方法，例如EGAPP建议的方法（对实践和预防中的基因组应用评估）工作组，需要系统地评估这种基因组靶向方法的有效性。我们已经组建了一个多学科研究团队，以解决一个总体问题，即与非目标方法相比，使用5ARI相比，使用5ARIS的基因组靶向方法是否可以改善与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（Repard and PCPT），两个有PCA风险的男性以及对医师的调查中评估和比较基因组和非基因组方法的疗效，看法，决策以及基因组和非基因组方法的成本效益。 Reald和PCPT的独特研究设计，具有研究终止前列腺活检，使我们能够在本研究中解决两个关键问题：PCA风险相关SNP的PSA检测偏置以及使用5ARIS PCA的PCA化学预防的功效。我们具有以下具体目的：1）使用一组非PSA检测偏置PCA风险相关的单核苷酸多态性（SNP）评估PCA风险预测模型的临床有效性。 2）确定和评估与5ARI相互作用在使用全基因组和候选基因方法降低PCA诊断方面相互作用的新型多态性的临床有效性，3）评估基因组靶向方法的临床实用性，通过比较其对PCA的降低速度的临床效用，并将其与非针对性的化学疗法和不可识别的化学疗法进行比较，4） PCA的化学预防和5）比较了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的EGAPP工作组提供全面的数据，用于基于证据的评估，提供了比较有效性研究（CER）的主要研究证明，并将帮助建立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的男性和前列腺癌家族史是否可以提高化学预防对前列腺癌的有效性。这将导致前列腺癌诊断的大幅减少，并大大减轻了个人和社会的负担。