Background: Prostate biopsy is the gold standard test for diagnosing prostate cancer. However, due to the sampling error involved, it has low accuracy. Using markers associated with DNA damage and the concept of field effect, this study attempts to improve the diagnostic accuracy of prostate biopsies in men at high risk for this disease.
Methods: Data were obtained from men participating in the Negative Biopsy Trial, a randomized multicenter phase 3 chemoprevention trial designed to investigate the effects of selenium supplementation on prostate cancer incidence in men who were at high risk for prostate cancer (PSA (prostate specific antigen) > 4ng/ml &/or PSA velocity (rate of PSA change over time) > 0.75ng/ml/yr &/or positive digital rectal examination) and had a negative prostate biopsy. 699 men were randomized to three treatment arms (placebo, 200ug Se/d, 400ug Se/d) and were followed every 6 months for up to five years. During the course of the study, 73 subjects were diagnosed with prostate cancer on repeat biopsy. For the current study, prostate biopsy samples from 73 subjects and 144 matched controls were stained for RAD51 and H2AX, markers of DNA repair, using immunohistochemistry techniques. Image analysis was conducted using ScanScope and Spectrum software from Aperio Technologies (Vista, California), which provided percentage of positive nuclei. Statistical analysis was conducted using Stata12 statistical software (Statacorp, College station, Texas).
Results: Subjects diagnosed with prostate cancer, as compared to controls, demonstrated higher expression levels of both H2AX (mean(SD), 33.8(17.7) and 19.4(14.5)) as well as RAD51 (55.8(24.1) and (44.7(26.5)). As compared to the model containing baseline PSA, age and race (k1), the model containing RAD51 and H2AX data in addition to the data included in k1 showed improved positive predictive value, negative predictive value and area under the curve (70%, 78.9%, 0.77 and 80%, 87.06%, 0.90 respectively, p= 0.025). The above also holds true when data from subjects diagnosed with low grade disease are compared with those having high grade disease (100%, 80%, 0.72 and 100%, 85%, 0.82, p=0.07).
Conclusions: Results of this study indicate that DNA damage markers may improve diagnostic accuracy for prostate cancer and also for aggressive disease in both men at high risk, and men diagnosed with prostate cancer.
Citation Format: Amit M. Algotar, Anne E. Cress, Raymond B. Nagle, Dan Drinkwitz, Naran S. Lodhia, Patricia A. Thompson, Steven P. Stratton. DNA damage and repair markers (H2AX and RAD51) improve accuracy of prostate cancer diagnosis and improve identification of aggressive disease. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1856. doi:10.1158/1538-7445.AM2014-1856