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.
BACKGROUND
Several germline single nucleotide polymorphisms (SNPs) have been consistently associated with prostate cancer (PCa) risk.


OBJECTIVE
To determine whether there is an improvement in PCa risk prediction by adding these SNPs to existing predictors of PCa.


METHODS
Subjects included men in the placebo arm of the randomized Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in whom germline DNA was available. All men had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 yr and 4 yr. Predictive performance of baseline clinical parameters and/or a genetic score based on 33 established PCa risk-associated SNPs was evaluated.


METHODS
Area under the receiver operating characteristic curves (AUC) were used to compare different models with different predictors. Net reclassification improvement (NRI) and decision curve analysis (DCA) were used to assess changes in risk prediction by adding genetic markers.


CONCLUSIONS
Among 1654 men, genetic score was a significant predictor of positive biopsy, even after adjusting for known clinical variables and family history (p = 3.41 × 10(-8)). The AUC for the genetic score exceeded that of any other PCa predictor at 0.59. Adding the genetic score to the best clinical model improved the AUC from 0.62 to 0.66 (p<0.001), reclassified PCa risk in 33% of men (NRI: 0.10; p=0.002), resulted in higher net benefit from DCA, and decreased the number of biopsies needed to detect the same number of PCa instances. The benefit of adding the genetic score was greatest among men at intermediate risk (25th percentile to 75th percentile). Similar results were found for high-grade (Gleason score ≥ 7) PCa. A major limitation of this study was its focus on white patients only.


CONCLUSIONS
Adding genetic markers to current clinical parameters may improve PCa risk prediction. The improvement is modest but may be helpful for better determining the need for repeat prostate biopsy. The clinical impact of these results requires further study.
Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
A Karim
AK
Kader
Jielin
J
Sun
Brian H
BH
Reck
Paul J
PJ
Newcombe
Seong-Tae
ST
Kim
Fang-Chi
FC
Hsu
Ralph B
RB
D'Agostino
Sha
S
Tao
Zheng
Z
Zhang
Aubrey R
AR
Turner
Greg T
GT
Platek
Colin F
CF
Spraggs
John C
JC
Whittaker
Brian R
BR
Lane
William B
WB
Isaacs
Deborah A
DA
Meyers
Eugene R
ER
Bleecker
Frank M
FM
Torti
Jeffery M
JM
Trent
John D
JD
McConnell
S Lilly
SL
Zheng
Lynn D
LD
Condreay
Roger S
RS
Rittmaster
Jianfeng
J
Xu
D001706:Biopsy; D005188:False Negative Reactions; D005819:Genetic Markers; D006801:Humans; D008297:Male; D011237:Predictive Value of Tests; D011379:Prognosis; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment / Q000379:methods
D005819:Genetic Markers