Epigenetic Assay Identifies Biopsy-Negative Prostate Cancer

Emma Hitt, PhD

May 29, 2012

May 29, 2012 (Atlanta, Georgia) — A multicenter study has confirmed the clinical utility of an epigenetic multiplex gene assay (ConfirmMDx, MDxHealth Inc.) in the identification of prostate cancer.

The assay correctly identified the presence of cancer in two thirds of patients with prostate cancer who had initial false-negative formalin-fixed paraffin-embedded (FFPE) biopsies, researchers found.

Grant D. Stewart, BSc, MB ChB, PhD, from the University of Edinburgh, Western General Hospital, in the United Kingdom, and colleagues presented the findings during a late-breaking oral podium poster session here at the American Urological Association 2012 Annual Scientific Meeting.

The assay also correctly confirmed negative biopsies in approximately two thirds of men without prostate cancer. According to the researchers, the high (90%) negative predictive value (NPV) suggests that this assay could prevent unnecessary repeat prostate biopsies.

"We wanted to improve on the negative predictive value...using surplus tissue from that same biopsy to prevent the need for further unnecessary negative prostate biopsies, which have the potential to cause patient morbidity," Dr. Stewart told Medscape Medical News.

"The study results show that the NPV of pathology can be improved upon using this methylation assay, and that a proportion of unnecessary further prostate biopsies will be avoided," he explained. "A negative result from the ConfirmMDx assay gives reassurance to the clinician and patient that they are very unlikely to harbor occult prostate cancer and that standard clinical follow-up can be performed," he added.

According to the researchers, concern about false-negative prostate biopsy results frequently leads to a subsequent biopsy. The Methylation Events to Locate Occult Cancer (MATLOC) study evaluated the clinical effectiveness of an epigenetic test using quantitative methylation-specific polymerase chain reaction (PCR) to measure epigenetic changes. These changes can indicate the presence of prostate cancer despite a negative biopsy; in addition, they can increase the NPV (preventing unnecessary repeat biopsies).

Dr. Stewart's team compared initially negative FFPE biopsies with subsequent biopsies conducted within 30 months. The researchers defined cases as those with second biopsies that indicated prostate cancer. On average, individual prostate biopsies consisted of approximately 10 separate cores, each processed using quantitative methylation-specific PCR technology with two 10-micron sections. The assay is a proprietary multiplexed methylated gene panel that contains GSTP1, APC, and RASSF1. A positive result was defined as a methylated value above the analytical cutoff in at least 1 core.

The researchers tested 4625 prostate biopsy cores in a blinded fashion, collected from 483 men tested at 3 sites in Belgium and the United Kingdom.

The prevalence of prostate cancer in the repeat biopsy cohort was 18%. The methylation panel was a significant predictor of eventual prostate cancer diagnosis; findings were confirmed with logistic regression analysis corrected for prostate-specific antigen (PSA) and digital rectal examination results prior to first biopsy. The assay had an NPV of 90% and a sensitivity of 68%.

According to Dr. Stewart, the assay needs to be validated in the United States because of the slightly different diagnostic pathway that exists in Europe, where the study was conducted.

"This work is almost complete, as part of the DOCUMENT study, which involves 5 urology centers and 360 men," he said.

"This test will add to the armamentarium of the clinician diagnosing men with prostate cancer," he added. "The man with a negative biopsy and persistently elevated PSA is a diagnostic quandary for the urologist. ConfirmMDx will provide information on the need for another immediate prostate biopsy."

Independent commentator David I. Lee, MD, assistant professor of surgery/urology at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, pointed out that there is a need to improve the performance of the prostate biopsy.

"There are many more negative biopsies than positive, but then many repeat biopsies are needed when the PSA rises or the rectal exam changes," he told Medscape Medical News. "If there was a way to examine the normal tissue that could prove that a particular patient had an even lower risk of developing prostate cancer, this could certainly reduce the number of repeat biopsies," he said.

Dr. Lee added that this is "quite novel test in the realm of prostate cancer diagnosis. There is no other way that I am aware of in which examination of the normal tissue removed from biopsy can lead to a better prediction of whether a patient will later develop prostate cancer."

According to Dr. Lee, if the results in the United States confirm what has been seen already, this should provide a better method for ruling out occult prostate cancer. "This test probably doesn't help us to determine potential aggressiveness, but it can better help with detection," he added.

The study was supported by MDxHealth. Dr. Lee has disclosed no relevant financial relationships.

American Urological Association (AUA) 2012 Annual Scientific Meeting: Abstract LBA6. Presented May 22, 2012.

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