Epigenetic profiling helps avoid unneeded repeat prostate biopsy

September 1, 2013

Epigenetic profiling of prostate biopsies significantly improved the accuracy of predicting cancer in men with negative results, according to a late-breaking abstract presented at the AUA annual meeting in San Diego.

San Diego-Epigenetic profiling of prostate biopsies significantly improved the accuracy of predicting cancer in men with negative results, according to a late-breaking abstract presented at the AUA annual meeting in San Diego.

The three-gene signature demonstrated more than a threefold increase in the odds of predicting the presence of cancer from a negative biopsy. The signature was the strongest predictor and one of only two predictors that achieved statistical significance, the other being the presence of atypical cells in the biopsy specimen.

Age, presence of high-grade prostatic intraepithelial neoplasia (HGPIN), suspicious digital rectal exam (DRE), and elevated PSA did not significantly improve predictive accuracy.

The combination of the epigenetic profile and histopathology results resulted in the best overall predictive capability.

“Results from clinical studies have demonstrated that [epigenetic profiling] can help urologists confirm negative biopsy results, reducing the need for repeat biopsies and ensuring that men with positive results are managed appropriately,” said first author Wim van Criekinge, PhD, head of the laboratory for computational genomics and bioinformatics at the University of Ghent in Ghent, Belgium.

“These results show that integrating multiple traditional risk factors with DNA methylation profiling increases the specificity of testing. Ultimately, this could decrease the risk of misdiagnosis and improve patient management.”

The findings came from examination of negative biopsy specimens from 391 men. Repeat biopsy within 30 months had revealed prostate cancer in 71 cases (18%). The negative initial specimens from the cases were evaluated histopathologically and by means of the ConfirmMDx epigenetic assay (MDxHealth, Inc., Irvine, CA) and compared with findings from noncancerous control specimens.

The assay was developed from evidence that DNA hypermethylation can result in silencing of tumor suppressor genes. The test evaluates tissue for changes in the DNA methylation profile of GSTP1, APC, and RASSF1. Collectively, the three genes are involved in DNA detoxification, apoptosis, cell migration and adhesion, and cell-cycle regulation. In previous studies involving residual prostate biopsy tissue, the gene test had demonstrated a negative predictive value of 90%.

Using the DNA methylation data and histopathologic findings, Dr. van Criekinge and colleagues developed and compared logistic regression models to determine the combination of factors that would produce the best overall accuracy for predicting the presence of cancer in negative biopsy specimens. Histopathology results were further categorized by presence or absence of HGPIN and atypia. Age, PSA ≥10.0 ng/mL, and abnormal DRE rounded out the parameters included in the models.

68% sensitivity, 64% specificity

The results showed that the epigenetic test had 68% sensitivity and 64% specificity. Investigators found that GSTP1 contributed 30% of the information in the test performance, APC contributed 42%, and RASSF1 contributed 28%.

Using patient age as the reference, the epigenetic test demonstrated the best accuracy for predicting the presence of cancer in the negative biopsy specimens (OR: 3.46, p<.001). The only other factor that proved to be significantly informative was the presence of atypia (but not HGPIN) by histopathology (OR: 3.28, p=.006).

Statistical modeling of various combinations of predictive factors showed that the best overall accuracy resulted from the combination of atypia and hypermethylation in at least one initial biopsy core. Those two factors resulted in a sensitivity of 74%, specificity of 63%, and negative predictive value of 91%.

The findings suggest that epigenetic profile can significantly improve the ability to identify men who can forego repeat biopsy following a negative initial prostate biopsy, Dr. van Criekinge concluded.

Dr. van Criekinge is a part-time consultant for and holds stock options in MDxHealth.UT

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