|Grant Number:||5UC2CA148463-02 Interpret this number|
|Primary Investigator:||Xu, Jianfeng|
|Organization:||Wake Forest University Health Sciences|
|Project Title:||Clinical Validity and Utility of Genomic Targeted Chemoprevention of PCA|
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.
Genome-wide association study identifies genetic determinants of urine PCA3 levels in men.
Authors: Chen Z, Sun J, Kim ST, Groskopf J, Feng J, Isaacs WB, Rittmaster RS, Condreay LD, Zheng SL, Xu J
Source: Neoplasia, 2013 Apr;15(4), p. 448-53.
The G84E mutation of HOXB13 is associated with increased risk for prostate cancer: results from the REDUCE trial.
Authors: Chen Z, Greenwood C, Isaacs WB, Foulkes WD, Sun J, Zheng SL, Condreay LD, Xu J
Source: Carcinogenesis, 2013 Jun;34(6), p. 1260-4.
EPub date: 2013 Feb 7.
Genetic score is an objective and better measurement of inherited risk of prostate cancer than family history.
Authors: Sun J, Na R, Hsu FC, Zheng SL, Wiklund F, Condreay LD, Trent JM, Xu J
Source: Eur Urol, 2013 Mar;63(3), p. 585-7.
EPub date: 2012 Dec 5.
Genome-wide association study identifies a new locus JMJD1C at 10q21 that may influence serum androgen levels in men.
Authors: Jin G, Sun J, Kim ST, Feng J, Wang Z, Tao S, Chen Z, Purcell L, Smith S, Isaacs WB, Rittmaster RS, Zheng SL, Condreay LD, Xu J
Source: Hum Mol Genet, 2012 Dec 1;21(23), p. 5222-8.
EPub date: 2012 Aug 30.
A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.
Authors: Newcombe PJ, Reck BH, Sun J, Platek GT, Verzilli C, Kader AK, Kim ST, Hsu FC, Zhang Z, Zheng SL, Mooser VE, Condreay LD, Spraggs CF, Whittaker JC, Rittmaster RS, Xu J
Source: Genet Epidemiol, 2012 Jan;36(1), p. 71-83.
Does variation in either age at start of therapy or duration of therapy make chemoprevention with finasteride cost-effective?
Authors: Stewart SB, Scales CD Jr, Moul JW, Reed SD
Source: Prostate Cancer Prostatic Dis, 2012 Dec;15(4), p. 380-5.
EPub date: 2012 Jul 10.
Potential impact of adding genetic markers to clinical parameters in predicting prostate biopsy outcomes in men following an initial negative biopsy: findings from the REDUCE trial.
Authors: Kader AK, Sun J, Reck BH, Newcombe PJ, Kim ST, Hsu FC, D'Agostino RB Jr, Tao S, Zhang Z, Turner AR, Platek GT, Spraggs CF, Whittaker JC, Lane BR, Isaacs WB, Meyers DA, Bleecker ER, Torti FM, Trent JM, McConnell JD, Zheng SL, Condreay LD, Rittmaster RS, Xu J
Source: Eur Urol, 2012 Dec;62(6), p. 953-61.
EPub date: 2012 May 12.
Changes in initial treatment for prostate cancer among Medicare beneficiaries, 1999-2007.
Authors: Dinan MA, Robinson TJ, Zagar TM, Scales CD Jr, Curtis LH, Reed SD, Lee WR, Schulman KA
Source: Int J Radiat Oncol Biol Phys, 2012 Apr 1;82(5), p. e781-6.
EPub date: 2012 Feb 11.
Utility of genome-wide association study findings: prostate cancer as a translational research paradigm.
Authors: Turner AR, Kader AK, Xu J
Source: J Intern Med, 2012 Apr;271(4), p. 344-52.
Association of prostate cancer risk with SNPs in regions containing androgen receptor binding sites captured by ChIP-On-chip analyses.
Authors: Lu Y, Sun J, Kader AK, Kim ST, Kim JW, Liu W, Sun J, Lu D, Feng J, Zhu Y, Jin T, Zhang Z, Dimitrov L, Lowey J, Campbell K, Suh E, Duggan D, Carpten J, Trent JM, Gronberg H, Zheng SL, Isaacs WB, Xu J
Source: Prostate, 2012 Mar;72(4), p. 376-85.
EPub date: 2011 Jun 10.
Functional annotation of risk loci identified through genome-wide association studies for prostate cancer.
Authors: Lu Y, Zhang Z, Yu H, Zheng SL, Isaacs WB, Xu J, Sun J
Source: Prostate, 2011 Jun 15;71(9), p. 955-63.
EPub date: 2010 Dec 6.
Effects of family history and genetic polymorphism on the cost-effectiveness of chemoprevention with finasteride for prostate cancer.
Authors: Reed SD, Scales CD Jr, Stewart SB, Sun J, Moul JW, Schulman KA, Xu J
Source: J Urol, 2011 Mar;185(3), p. 841-7.
EPub date: 2011 Jan 15.
Prostate cancer risk-associated variants reported from genome-wide association studies: meta-analysis and their contribution to genetic Variation.
Authors: Kim ST, Cheng Y, Hsu FC, Jin T, Kader AK, Zheng SL, Isaacs WB, Xu J, Sun J
Source: Prostate, 2010 Dec 1;70(16), p. 1729-38.