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National Institutes of Health: National Cancer Institute: Division of Cancer Control and Population Sciences
Grant Details

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
Fiscal Year: 2010
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Abstract

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.

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Publications

Prostate Cancer Risk-associated Variants Reported From Genome-wide Association Studies: Meta-analysis And Their Contribution To Genetic Variation
Authors: Kim S.T. , Cheng Y. , Hsu F.C. , Jin T. , Kader A.K. , Zheng S.L. , Isaacs W.B. , Xu J. , Sun J. .
Source: The Prostate, 2010-12-01 00:00:00.0; 70(16), p. 1729-38.
PMID: 20564319
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Effects Of Family History And Genetic Polymorphism On The Cost-effectiveness Of Chemoprevention With Finasteride For Prostate Cancer
Authors: Reed S.D. , Scales C.D. , Stewart S.B. , Sun J. , Moul J.W. , Schulman K.A. , Xu J. .
Source: The Journal Of Urology, 2011 Mar; 185(3), p. 841-7.
PMID: 21239023
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Functional Annotation Of Risk Loci Identified Through Genome-wide Association Studies For Prostate Cancer
Authors: Lu Y. , Zhang Z. , Yu H. , Zheng S.L. , Isaacs W.B. , Xu J. , Sun J. .
Source: The Prostate, 2011-06-15 00:00:00.0; 71(9), p. 955-63.
PMID: 21541972
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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 A.K. , Kim S.T. , Kim J.W. , Liu W. , Sun J. , Lu D. , Feng J. , Zhu Y. , et al. .
Source: The Prostate, 2012 Mar; 72(4), p. 376-85.
PMID: 21671247
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Utility Of Genome-wide Association Study Findings: Prostate Cancer As A Translational Research Paradigm
Authors: Turner A.R. , Kader A.K. , Xu J. .
Source: Journal Of Internal Medicine, 2012 Apr; 271(4), p. 344-52.
PMID: 22272820
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Changes In Initial Treatment For Prostate Cancer Among Medicare Beneficiaries, 1999-2007
Authors: Dinan M.A. , Robinson T.J. , Zagar T.M. , Scales C.D. , Curtis L.H. , Reed S.D. , Lee W.R. , Schulman K.A. .
Source: International Journal Of Radiation Oncology, Biology, Physics, 2012-04-01 00:00:00.0; 82(5), p. e781-6.
PMID: 22331001
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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 A.K. , Sun J. , Reck B.H. , Newcombe P.J. , Kim S.T. , Hsu F.C. , D'Agostino R.B. , Tao S. , Zhang Z. , Turner A.R. , et al. .
Source: European Urology, 2012 Dec; 62(6), p. 953-61.
PMID: 22652152
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Does Variation In Either Age At Start Of Therapy Or Duration Of Therapy Make Chemoprevention With Finasteride Cost-effective?
Authors: Stewart S.B. , Scales C.D. , Moul J.W. , Reed S.D. .
Source: Prostate Cancer And Prostatic Diseases, 2012 Dec; 15(4), p. 380-5.
PMID: 22777393
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A Comparison Of Bayesian And Frequentist Approaches To Incorporating External Information For The Prediction Of Prostate Cancer Risk
Authors: Newcombe P.J. , Reck B.H. , Sun J. , Platek G.T. , Verzilli C. , Kader A.K. , Kim S.T. , Hsu F.C. , Zhang Z. , Zheng S.L. , et al. .
Source: Genetic Epidemiology, 2012 Jan; 36(1), p. 71-83.
PMID: 22890972
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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 S.T. , Feng J. , Wang Z. , Tao S. , Chen Z. , Purcell L. , Smith S. , Isaacs W.B. , et al. .
Source: Human Molecular Genetics, 2012-12-01 00:00:00.0; 21(23), p. 5222-8.
PMID: 22936694
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Genetic Score Is An Objective And Better Measurement Of Inherited Risk Of Prostate Cancer Than Family History
Authors: Sun J. , Na R. , Hsu F.C. , Zheng S.L. , Wiklund F. , Condreay L.D. , Trent J.M. , Xu J. .
Source: European Urology, 2013 Mar; 63(3), p. 585-7.
PMID: 23245817
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The G84e Mutation Of Hoxb13 Is Associated With Increased Risk For Prostate Cancer: Results From The Reduce Trial
Authors: Chen Z. , Greenwood C. , Isaacs W.B. , Foulkes W.D. , Sun J. , Zheng S.L. , Condreay L.D. , Xu J. .
Source: Carcinogenesis, 2013 Jun; 34(6), p. 1260-4.
PMID: 23393222
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Genome-wide Association Study Identifies Genetic Determinants Of Urine Pca3 Levels In Men
Authors: Chen Z. , Sun J. , Kim S.T. , Groskopf J. , Feng J. , Isaacs W.B. , Rittmaster R.S. , Condreay L.D. , Zheng S.L. , Xu J. .
Source: Neoplasia (new York, N.y.), 2013 Apr; 15(4), p. 448-53.
PMID: 23555189
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Impact Of Prostate-specific Antigen On A Baseline Prostate Cancer Risk Assessment Including Genetic Risk
Authors: Kader A.K. , Liss M.A. , Trottier G. , Kim S.T. , Sun J. , Zheng S.L. , Chadwick K. , Lockwood G. , Xu J. , Fleshner N.E. .
Source: Urology, 2015 Jan; 85(1), p. 165-70.
PMID: 25530379
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Resource Use In The Last Year Of Life Among Patients Who Died With Versus Of Prostate Cancer
Authors: Dinan M.A. , Li Y. , Zhang Y. , Stewart S.B. , Curtis L.H. , George D.J. , Reed S.D. .
Source: Clinical Genitourinary Cancer, 2016 Feb; 14(1), p. 28-37.e2.
PMID: 26382223
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