Emerging Tests: New Genetic Tests May Be Better than PSA Screening in Assessing Prostate Cancer Risk

The U.S. Preventive Services Task Force (USPTF) recommends that men age 55 to 65 consider prostate cancer screening based on their specific circumstances. The reason that the USPTF does not directly recommend testing for every man in this age group is that current prostate specific antigen (PSA) screening methods are notoriously unreliable. But things may be changing thanks to the emergence of new genetic tests that rely on more sophisticated biomarker detection and algorithmic analysis to assess prostate cancer risk. In addition to the urine testing products currently on the market, last month, the U.S. Food and Drug Administration (FDA) cleared the way for final approval of a new blood-based assay shown to be more accurate than traditional PSA tests.

Problems with PSA Screening

The current PSA test can detect high levels of the prostate-specific antigen protein in the blood. The problem is in interpreting the results. Stated simply, PSA is not a reliable biomarker. High levels of PSA could be a sign of not only prostate cancer but infection, inflammation or other disease. In some cases, high PSA is caused not by disease but just the common age-related condition of an enlarged prostate gland. But given the risks involved, when screening tests show high PSA levels, biopsies are ordered to rule out cancer. Not surprisingly, a large percentage of these biopsies prove unnecessary.

Another problem with PSA testing is that it over-detects for low-grade cancer that does not pose a threat to the patient. This can result in treatment that leads to erectile dysfunction, urinary incontinence, and other side effects that do more harm than the cancer.

The New Blood-Based PSA Test

On Oct. 17, 2019, Cleveland Diagnostics, Inc., a company partly owned by the Cleveland Clinic dedicated to developing next-generation diagnostic tests for early cancer detection, announced it has received FDA breakthrough device designation for a test that uses a new and more accurate methodology for detecting prostate cancer risk: The so-called IsoPSA test does not simply measure PSA levels but evaluates structural changes to the PSA protein. Specifically, the test accounts for the fact that not all PSA is created equal. The protein comes in different isoforms, i.e., similar but non-identical amino acid sequences. The presence, number, and nature of these isoforms is related to the disordered metabolism of cancer cells.

What distinguishes IsoPSA from other commercially available tests is its ability to measure all the different PSA isoforms in a serum tightly linked to prostate cancer. As a result, it allows for more accurate differentiation between cancer and non-cancerous conditions; it is also capable of identifying whether cancer detected is serious and needs to be treated or is benign enough to be left under what the urology community describes as “active surveillance” without biopsy or treatment.

The early results suggest that the test is effective in reducing both unnecessary biopsies and false positives. In a 2018 study of 271 men published in the Journal of Urology, use of IsoPSA was associated with a 43% reduction in the number of unnecessary biopsies. This study followed an earlier one linking IsoPSA to either a 45% or 48% reduction in false-positive rates, depending on whether the cutoff was selected to recommend biopsy or identify people at low risk of high-grade disease.

Commercialization of IsoPSA

These studies and other evidence were instrumental in the FDA’s decision to grant breakthrough designation to IsoPSA. “We are very grateful that FDA recognizes the potential of IsoPSA,” noted Cleveland Diagnostics CEO Arnon Chait. Securing FDA breakthrough designation expedites the approval process and brings the company significantly close to its goal of getting final approval to market the test in the U.S. in 2020. “We look forward to working closely with FDA to expedite the appropriate approvals and get this important new test into the hands of physicians,” Dr. Chait said.

Other Genetic Early Prostate Cancer Detection Tests on the Market

Of course, when and if it reaches the market, IsoPSA would not be the only commercially available biomarker prostate cancer test designed to help patients avoid unnecessary biopsies. Others include:

• Prostate Health Index (PHI) (Beckman Coulter), which uses a mathematical formula calculating prostate cancer probability by combining PSA, free PSA and p2PSA tests into a single score;
• 4Kscore (OPKO Health), which calculates a patient’s percentage risk for aggressive prostate cancer by combining four prostate-specific kallikrein assay results with clinical information in an algorithm;
• SelectMDx (MDxHealth), a urine test that measures the expression of two mRNA cancer-related biomarkers that, when combined with the patient’s clinical risk factors, provides a score assessing whether patient needs a biopsy or active surveillance;
• ExoDx Prostate (IntelliScore), aka, The EPI Test (Exosome Diagnostics), which analyzes a urine sample for three biomarkers of aggressive prostate cancer and uses an algorithm to assess the results and generate a score for use in determining whether a biopsy is necessary; and
• Mi-Prostate Score (MiPS) (Michigan Medicine), which combines the amount of serum PSA with the amounts of two genes for prostate cancer in the patient’s urine for early prostate cancer detection.