Biomarker Test Could Reduce Unnecessary Biopsies to Detect Prostate Cancer

June 9, 2017, by NCI Staff

Testing for two biomarkers in urine may help some men avoid having to undergo an unnecessary biopsy to detect a suspected prostate cancer, findings from a new study show.

For many men referred for a prostate biopsy due to an abnormal prostate specific antigen (PSA) test or digital rectal exam (DRE), the biopsy reveals no cancer or a slow-growing cancer that in most cases doesn’t require treatment.

In the NCI-supported study, researchers tested urine samples from men referred for a prostate biopsy for elevated levels of two biomarkers (RNA biomarkers called PCA3 and T2:ERG) that studies have shown are associated with aggressive prostate cancer. Restricting biopsies to only those men with elevated levels of either of the biomarkers would have reduced the number of these unnecessary biopsies by an estimated one-third to one-half, the researchers reported May 18 in JAMA Oncology.

At the same time, this pre-biopsy screening approach would still “preserve the ability to detect the more aggressive cancers,” explained the study’s lead investigator, Martin Sanda, M.D., of the Emory University Winship Cancer Institute.

Currently, there are hurdles to implementing this testing in everyday care, Dr. Sanda cautioned. But the study findings “clearly demonstrate” that testing for these biomarkers could help to address some of the limitations of the current paradigm for prostate cancer screening and early detection, he said.

From Abnormal Result to Unnecessary Biopsy

With many organizations now recommending against routine screening for prostate cancer with the PSA test, its use has declined in recent years, as has the number of prostate biopsies and prostate cancer surgeries.

PSA testing can help identify men who may have prostate cancer. However, the test cannot help distinguish slow-growing, or indolent, cancers that are unlikely to ever cause a man harm from aggressive, potentially lethal cancers.

One of the biggest challenges for researchers has been identifying a way to screen for prostate cancer that can differentiate between indolent and potentially life-threatening cancers.

One approach being tested is to develop ways to better triage care decisions following an abnormal PSA test, including making more informed decisions about whether to pursue a biopsy. Prostate biopsies have risks, including pain, bleeding, and potentially serious infections. And the resulting overdiagnosis and overtreatment of indolent prostate cancers identified via biopsy have their own harms and costs.

“The risk of overtreatment remains a valid concern due to the impact of treatment on quality of life,” the American Urological Association noted in its most recent consensus statement on PSA screening. These effects can include “lasting impairment in urinary, bowl, and sexual function,” the statement explains, as well as potential and long-lasting psychological harms.

Adding Biomarkers, Reducing Unnecessary Biopsies

The study from Dr. Sanda and his colleagues was conducted through NCI’s Early Detection Research Network (EDRN). It involved two groups of men: a “developmental” cohort, which was used to assess the initial performance of the biomarkers, and a “validation” cohort, which was used to see if the findings would hold in an independent group of men, explained study co-author Sudhir Srivastava, Ph.D., chief of the Cancer Biomarkers Research Group in NCI’s Division of Cancer Prevention.

The 516 men in the study’s developmental cohort had not previously been diagnosed with prostate cancer and were being referred for a first-ever prostate biopsy following an abnormal PSA test or DRE. Urine samples from the men collected prior to their biopsy were tested for elevated levels of the two RNA biomarkers.

The PCA3 gene is expressed at high levels in prostate cancers, and a urine test for PCA3RNA is commonly used in clinical practice to monitor for potential disease in men who have a negative biopsy following an abnormal PSA test or DRE, Dr. Sanda explained.

There is also a urine test for T2:ERG, which is the result of a fusion, or translocation, of parts of two different genes, TMPRSS2 and ERG. This translocation is found in approximately half of advanced prostate cancers. Currently, the T2:ERG test is only available at a few academic cancer centers, Dr. Srivastava said.

Biopsy specimens from the men were analyzed by pathologists and grouped according to standard criteria: no cancer or a slow-growing cancer (indicated by a Gleason score of 6 or less), meaning the risk of the tumor progressing was low and the biopsy was likely unnecessary, or a potentially aggressive cancer (indicated by a Gleason score of 7 or greater) that required treatment.

The results of the urine tests were incorporated into an algorithm that would help to advise men to have a biopsy only if they had high levels of either PCA3 or T2:ERG. Compared with a PSA score that could suggest either indolent or aggressive tumors, adding the results of urine biomarker testing, they found, would have limited the need for biopsy to a smaller subset of men, among whom 39% would be found to have aggressive cancer on biopsy, versus only 18% of biopsies identifying aggressive cancers when prostate biopsy is done base on an elevated PSA alone.

The specimens for the validation group came from 561 men who had participated in an earlier prospective EDRN study of PCA3 testing , and for whom urine samples had been collected and stored. In this group, the specificity of detection of aggressive disease increased from 17% with PSA testing alone to 33% with PCA3/T2:ERG testing.

Overall, the research team wrote, “42% of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy.”

The results, Dr. Sanda acknowledged, “are not a home run.” Using the approach, many men with an indolent cancer would still undergo a biopsy. “Ultimately, there’s still room” to improve specificity, he said.

A Tough Path to the Clinic

Implementing this pre-biopsy testing in clinical practice may not yet be practical because of the limited availability of the T2:ERG test, Dr. Srivastava said.

But Dr. Sanda is hopeful that, based on the study’s findings, that may change. Nevertheless, the situation demonstrates that even well-conducted, definitive biomarker studies “are really just one step on the pathway to [the biomarkers’ use] in clinical practice,” he added.

This type of work “is a key next step to further enhance the utility of urinary markers to refine detection of aggressive prostate cancer,” Dr. Srivastava said.