Recent U.S. Preventive Services Task Force recommendations state that men age 55 to 65 should make personalized decisions about prostate specific antigen (PSA) screening for prostate cancer based on discussions with their clinicians about screening benefits and harms. Research demonstrates that PSA screening in this age group prevents 1.3 deaths per 1,000 men screened over 13 years. However, the tide of PSA screening has ebbed and flowed over the years, mostly because it has led to over-treatment of indolent conditions that likely wouldn’t have led to serious disease.

“The problem with PSA itself is that while it is specific for prostate disease, it’s not specific for prostate cancer,” said Eric Klein, MD, chairman of the Glickman Urological and Kidney Institute at Cleveland Clinic in Cleveland, Ohio. “PSA is made both by cancerous prostate cells and noncancerous prostate cells.”

This limitation has kept clinicians and researchers on the hunt for better ways to screen for prostate cancer using laboratory biomarkers directly associated with malignancy. Experts advise that imaging technologies also may fill in the gaps for PSA’s shortcomings.

Current Biomarkers

Ideally, physicians and patients would like biomarkers that discern better than PSA which men really need biopsies, to avoid the complications and imperfections associated with these invasive procedures, said Scott E. Eggener, MD, professor of surgery and radiology and director of the prostate cancer program at The University of Chicago Medicine. Secondary biomarkers help provide “nuanced information on the likelihood of whether the patient has a clinically meaningful cancer,” he said.

Doctors already use variants of PSA to decide whether patients with elevated PSA levels—typically greater than 3.0 or 4.0 ng/mL—need biopsies. Examples include: free PSA, or the percentage of PSA that is unbound to other proteins; PSA velocity, which is the rate of change in PSA over time; and PSA density, which is PSA divided by prostate volume measured by ultrasound or magnetic resonance imaging (MRI), said S. Adam Ramin, MD, urologist and medical director of Urology Cancer Specialists in Los Angeles.

Several commercially available biomarker tests are also available to help avoid biopsy, including Prostate Health Index (PHI), 4Kscore, SelectMDx, ExoDx Prostate, and Mi-Prostate Score (Box, right). For these tests to be adopted widely in clinical practice, however, they first need to demonstrate patient benefit, ease of use, and affordability, said Eggener.

The National Comprehensive Cancer Network recommends using free PSA, PHI, and 4Kscore in patients with PSA levels greater than 3 ng/mL who have not yet had a biopsy. The organization also recommends that doctors consider free PSA, PHI, 4Kscore, PCA3, and ConfirmMDx (MDxHealth), an epigenetic multiplex assay based on GSTP1, APC, and RASSF1, for men who have at least one prior benign biopsy but are still thought to be high risk.

Up and Coming Alternatives

Researchers continue to evaluate other laboratory screening tests for prostate cancer. For example, Stockholm 3 (STHLM3 model) assesses the plasma protein biomarkers PSA, free PSA, intact PSA—an uncleaved, enzymatically inactive form of PSA—human glandular kallikrein 2, microseminoprotein‐beta, and macrophage inhibitory cytokine-1. It also considers a genetic risk score based on 254 single-nucleotide polymorphisms (SNPs) and clinical variables. A recent study found this test reduced by 34% the number of biopsies needed in men with a PSA greater than 3ng/mL when compared to PSA screening alone (Eur Urol 2018; While the results are interesting, more research is needed, said Eggener.

Meanwhile, Klein is leading a research team studying IsoPSA, “a completely different way of looking at PSA in the blood,” he said.

IsoPSA measures all the different PSA protein isoforms in serum tightly linked to prostate cancer by partitioning these isoforms with an aqueous two-phase solution. “In cancer, PSA exists in multiple, maybe dozens of different isoforms,” said Klein. The presence, number, and nature of these isoforms is related to the disordered metabolism of cancer cells and glycosylation of proteins produced in these cells, he added.

Most prostate cancer patients’ blood contains multiple PSA isoforms that commercially available tests don’t measure, said Klein. In addition, a patient may have isoforms that change over time as his cancer changes, and IsoPSA measures these changes, while other existing assays don’t.

Klein presented data in May at the American Urological Association annual meeting suggesting that IsoPSA could eliminate up to 50% of unnecessary biopsies, especially when combined with MRI (J Urol 2018;199:e1147–8).

Another candidate tool, a polygenic hazard score, assesses 54 SNPs to determine patient risk of developing aggressive prostate cancer and age of onset (BMJ 2018;360:j5757). Promising early data should be followed up with more research, according to Howard L. Adler, MD, FACS, medical director of the prostate care program and clinical associate professor of urology at Stony Brook Medicine in Stony Brook, New York.

One issue to consider down the road with such a test is that if patients are found to be at increased risk of developing aggressive prostate cancer, insurance companies may consider this a pre-existing condition, said Adler, who is not associated with this line of research. However, one benefit could be that higher risk patients may undergo more frequent or earlier screening, while lower risk individuals may be able to delay screening.

The Imaging Angle

Multiparametric MRI is another ascending screening modality that clinical laboratory professionals should be aware of, Eggener suggested, since it, like supplemental laboratory tests, offers data to inform treatment decisions and is being used with and even compared to these tests. Multiparametric MRI provides a detailed view of the prostate, and radiologists score suspicious areas on a scale of 1 to 5, explained Mark Scholz, MD, medical director of Prostate Oncology Specialists in Marina del Rey, California. Scores above 4 in his clinic warrant a biopsy that specifically targets the suspicious area and requires only one or two core needle samples, resulting in fewer complications than traditional 12-core biopsy.

A recent study found that using multiparametric MRI enabled 38% of patients to avoid a biopsy (NEJM 2018;378:1767-77). Patients with a score above 3 proceeded to biopsy.

Another study found that multiparametric MRI was better than PCA3 and PHI for identifying malignancy in men whose biopsies were negative but who were still suspected of having cancer (J Urol 2014;192:60-6).

Whether urologists will value this screening modality more than blood-based biomarkers depends on how these technologies advance, said Adler. “We do know that a small percentage of patients who have a normal MRI may have prostate cancer,” he said. Notably, a handful of his patients with normal MRI and abnormal 4Kscores proceeded to biopsy only to find they had aggressive prostate cancer.

Clinical Practice Consults

While screening recommendations and evidence continue to evolve, clinical laboratories play an important role in educating clinicians about available prostate cancer screening tests, their performance characteristics, and what makes sense for screening in a given population, said Klein.

Ideally, laboratories could help simplify the testing process, suggested Ramin. “One of the problems we have is that if we perform a PSA test and it comes back as abnormal, we have to order more tests, which may require more blood draws or urine samples that need to be sent to different clinical labs,” he said.

Having some sort of collaboration or uniformity among laboratories could help to streamline the process, Ramin added. For example, having a testing algorithm so that if a PSA test was abnormal, supplemental tests would be performed automatically using blood or urine samples drawn during the initial visit. This would shorten the discovery cycle about a patient’s status while also avoiding repeat visits for him to provide more specimens. Ultimately, Scholz concluded, clinical laboratories can work together with urologists, oncologists, and imaging specialists to provide a screening program that helps men avoid unnecessary biopsies.


IsoPSA is being developed by Cleveland Diagnostics, partly owned by Cleveland Clinic. Dr. Klein has no financial interest in the company or test.

Dr. Eggener has been a consultant for Beckman Coulter and has served on an advisory board of and conducts research with MD Health. He is also involved in a clinical study with OPKO. He has no equity or stake in prostate cancer screening products or their companies.

Heather Lindsey is a freelance medical writer in Maplewood, New Jersey.+Email: [email protected]