Predicting Prostate Biopsy Result in Men With Prostate Specific Antigen 2.0 to 10.0 ng/ml Using an Investigational Prostate Cancer Methylation Assay
Abstract
Purpose:
The inadequacies of prostate specific antigen testing have created a need for novel markers for prostate cancer screening. The investigational ProCaM™ prostate cancer methylation assay detects aberrant methylation of DNA in cells associated with prostate cancer. We describe a large, prospective, multicenter study done to verify the performance of this assay.
Materials and Methods:
The assay is designed to detect epigenetic modifications in the 3 markers GSTP1, RARβ2 and APC, which are indicative of prostate cancer. A total of 232 men with cancer and 283 without cancer from 18 clinical sites were evaluated by trained operators at central testing laboratories. Study inclusion criteria were age 40 to 75 years, total prostate specific antigen between 2.0 and 10.0 ng/ml, and a digital rectal examination result. All participants signed an informed consent form and underwent transrectal ultrasound guided needle biopsy with 10 or more cores.
Results:
Assay sensitivity was 60%, specificity was 80% and the informative rate was 97%. Assay predictive accuracy was higher than that of age, digital rectal examination, family history, prostate specific antigen, prior negative biopsy and prostate volume (AUC 0.73 vs 0.52 to 0.66, p <0.038). Risk factors plus the assay improved overall predictive power (AUC 0.79, p = 0.001). A man with a positive prostate cancer methylation result was 7.7 times more likely to have high grade cancer.
Conclusions:
The prostate cancer methylation assay correlated with positive biopsy and with Gleason score. This assay has the potential to add value to the biopsy decision making process by improving current prostate cancer screening algorithms to more accurately identify men with prostate cancer.
References
- 1 Cancer Facts and Figures. Atlanta: American Cancer Society2009: 4. Google Scholar
- 2 : Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol1990; 143: 1146. Link, Google Scholar
- 3 : Predictors of cancer in repeat extended multisite prostate biopsy in men with previous negative extended multisite biopsy. Urology2002; 60: 836. Google Scholar
- 4 : Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination: Enhancement of specificity with free PSA measurements. JAMA1997; 277: 1452. Google Scholar
- 5 : Screening and prostate-cancer mortality in a randomized European study. N Engl J Med2009; 360: 1320. Google Scholar
- 6 : Mortality results from a randomized prostate-cancer screening trial: PLCO Project Team. N Engl J Med2009; 360: 1310. Google Scholar
- 7 : Prostate-Specific Antigen Best Practice Statement: 2009 Update. Linthicum: American Urological Association Education and Research2009. Google Scholar
- 8 : In vitro stability of free prostate-specific antigen (PSA) and prostate-specific antigen (PSA) complexed to alpha 1-antichymotrypsin in blood samples. Urology1996; 48: 81. Google Scholar
- 9 : Significance and metabolism of complexed and noncomplexed prostate specific antigen forms and human glandular kallikrein 2 in clinically localized prostate cancer before and after radical prostatectomy. J Urol1999; 162: 2029. Link, Google Scholar
- 10 : Biological variation of prostate specific antigen levels in serum: an evaluation of day-to-day physiological fluctuations in a well-defined cohort of 24 patients. J Urol1997; 157: 2183. Link, Google Scholar
- 11 : Human glandular kallikrein as a tool to improve discrimination of poorly differentiated and non-organ-confined prostate cancer compared with prostate-specific antigen. Urology2000; 55: 481. Google Scholar
- 12 : The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer. Prostate2003; 54: 181. Google Scholar
- 13 : PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol2008; 179: 1587. Link, Google Scholar
- 14 : PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. J Urol2007; 69: 532. Google Scholar
- 15 : Epigenetic markers for molecular detection of prostate cancer. Dis Markers2007; 23: 31. Google Scholar
- 16 : Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following radical prostatectomy. Clin Cancer Res2005; 11: 4037. Google Scholar
- 17 : Quantitative methylation-specific polymerase chain reaction gene patterns in urine sediment distinguish prostate cancer patients from control subjects. J Clin Oncol2005; 23: 6569. Google Scholar
- 18 : Development of a multiplexed urine assay for prostate cancer diagnosis. Clin Chem2008; 54: 874. Google Scholar
- 19 : A multicenter evaluation of an investigational prostate cancer methylation assay. J Urol2009; 182: 825. Google Scholar
- 20 : Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst2006; 98: 529. Google Scholar
- 21 : Biomarkers for prostate cancer. Annu Rev Med2009; 60: 139. Google Scholar
- 22 : High-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice. Am J Surg Pathol2005; 29: 1548. Google Scholar
- 23 : Statistical methods to correct for verification bias in diagnostic studies are inadequate when there are few false negatives: a simulation study. BMC Med Res Methodol2008; 8: 75. Google Scholar
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