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Clinical Trial
. 2014 Oct;192(4):1081-7.
doi: 10.1016/j.juro.2014.04.013. Epub 2014 Apr 18.

Clinical Validation of an Epigenetic Assay to Predict Negative Histopathological Results in Repeat Prostate Biopsies

Free PMC article
Clinical Trial

Clinical Validation of an Epigenetic Assay to Predict Negative Histopathological Results in Repeat Prostate Biopsies

Alan W Partin et al. J Urol. .
Free PMC article


Purpose: The DOCUMENT multicenter trial in the United States validated the performance of an epigenetic test as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. Confirming an increased negative predictive value could help avoid unnecessary repeat biopsies.

Materials and methods: We evaluated the archived, cancer negative prostate biopsy core tissue samples of 350 subjects from a total of 5 urological centers in the United States. All subjects underwent repeat biopsy within 24 months with a negative (controls) or positive (cases) histopathological result. Centralized blinded pathology evaluation of the 2 biopsy series was performed in all available subjects from each site. Biopsies were epigenetically profiled for GSTP1, APC and RASSF1 relative to the ACTB reference gene using quantitative methylation specific polymerase chain reaction. Predetermined analytical marker cutoffs were used to determine assay performance. Multivariate logistic regression was used to evaluate all risk factors.

Results: The epigenetic assay resulted in a negative predictive value of 88% (95% CI 85-91). In multivariate models correcting for age, prostate specific antigen, digital rectal examination, first biopsy histopathological characteristics and race the test proved to be the most significant independent predictor of patient outcome (OR 2.69, 95% CI 1.60-4.51).

Conclusions: The DOCUMENT study validated that the epigenetic assay was a significant, independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result. Due to its 88% negative predictive value adding this epigenetic assay to other known risk factors may help decrease unnecessary repeat prostate biopsies.

Keywords: biopsy; epigenomics; methylation; prostate; prostatic neoplasms.

Conflict of interest statement

Financial interest and/or other relationship with MDxHealth.

Financial interest and/or other relationship with Provia Diagnostics and Provia Biologics.

Financial interest and/or other relationship with Healthtronics, Photocure and Cook.


Figure 1
Figure 1
Case prevalence trends as function of methylation characteristics. Detection of at least 1 methylated gene in at least 1 biopsy core resulted in significant detection of men with unsampled PCa. Using LOESS fit several trends indicated that likelihood of harboring unsampled cancer increased with increase in observed methylation relative to total amount of analyzable biopsy cores whether expressed as distinct genes (orange curve and circles), methylation positive biopsy cores (red curve and circles) or total number of epigenetic aberrations (green curve or circles). Of overall study population 29% were cases (horizontal line).
Figure 2
Figure 2
Multivariate analysis of potential predictors of cancer on repeat biopsy. OR and 95% CI were determined by logistic regression model. Final model OR (hatched bars) was obtained using only diagnostically important and significant (orange bars) parameters, ie DNA methylation and histopathology of biopsy 1 (atypia and HGPIN). Contribution of atypia in final model was further evaluated by determining ROC AUC. Model with only epigenetic assay had AUC of 0.628. When epigenetic assay was modeled simultaneously with atypia but not with HGPIN, AUC showed minor increase to 0.646.

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