Study Verifies IsoPSA’s Utility as a Prostate Cancer Biomarker

A new validation study has confirmed the novel IsoPSA™ prostate-specific antigen assay’s superiority over conventional tests to detect high-grade, clinically significant prostate cancers.

If used in a clinical setting, the IsoPSA test could reduce unnecessary prostate biopsies by more than 40% while reliably differentiating among high-grade, low-grade and benign disease, the multi-center study found.

Its false-negative rate was acceptably low, and its enhanced ability to identify high-grade tumors when used in concert with multiparametric magnetic resonance imaging (mpMRI)-guided biopsy could one day establish a new diagnostic regimen for prostate cancer, the study’s authors conclude.

“The validation study verifies the clinical utility of this marker to help correctly identify those men at highest risk of prostate cancer, and to avoid biopsy in those at lower risk,” says Eric Klein, MD, Chair of Cleveland Clinic’s Glickman Urological & Kidney Institute and the study’s lead author.

Why a better test is needed

Cleveland Clinic and the biotechnology company Cleveland Diagnostics, Inc., co-developed* the IsoPSA test in response to a vexing problem with the current gold standard for prostate cancer diagnosis, the prostate-specific antigen (PSA) assay.

The PSA biomarker protein is tissue-specific, but not cancer-specific. Its expression and serum concentration may be elevated due to prostate cancer, but also by non-cancerous conditions such as benign prostatic hyperplasia or prostatitis.

Thus, concentration-based PSA tests — which constitute the majority of currently available assays — are vulnerable to false positives. In the event of legitimate cancer detection, the standard PSA tests’ inability to discriminate between biologically insignificant tumors and aggressive malignancies requiring intervention results in unnecessary biopsies, overdiagnosis of low-grade cancers, and overtreatment of tumors that are not life-threatening.

The advantage of conformational tests

Many cancer-related proteins such as PSA undergo structural modifications caused by cancer cells’ altered metabolism, including alterations in the primary sequence and post-translational modifications such as glycosylation. Next-generation conformation-based PSA assays have improved diagnostic accuracy compared with concentration-based tests.

However, currently available next-generation assays have limitations. Cancer biomarkers’ conformational changes vary from patient to patient, and within an individual patient over time, as the disease evolves molecularly. Current conformation-based assays detect only a few of the multiple PSA isoforms that may or may not be present in a particular patient at a particular point in cancer progression.

The IsoPSA test is capable of interrogating a serum sample for the entire spectrum of PSA isoforms, using an aqueous biphasic solvent system that causes any extant isoform to distribute unequally between the two liquids based on its structure and interaction with other proteins. This process is called solvent interaction analysis. A conventional enzyme-linked immunosorbent assay then quantifies the biomarker concentration in each phase. The ratio of the PSA isoform concentrations in the two phases yields the test value, K, which can be used as a clinical parameter and generally increases with the presence of cancer.

A preliminary trial published in 2017 found that IsoPSA outperformed standard concentration-based PSA assays for cancer detection and detection of high-grade (Gleason score ≥ 7) disease.

What the validation study found

The latest prospective validation study assessed IsoPSA’s ability to differentiate between high-grade and low-grade prostate cancers in a new patient cohort. Participants were 271 men with elevated or rising total PSA and/or suspicious digital rectal exam results who were referred for prostate biopsy at Cleveland Clinic and six other medical centers in the U.S. and Israel in 2017 and 2018.

Heparin plasma samples for assay were collected prior to biopsy, which was performed using either trans-rectal ultrasound (TRUS) alone or in combination with mpMRI for guidance. Biopsies identified high-grade cancer in 80 of the 271 subjects in the study cohort.

Statistical analysis of the assay results showed that:

• With all assays set at 93% specificity, IsoPSA outperformed conventional PSA tests (total PSA [tPSA], % free PSA [%fPSA] and a model that combined tPSA and %f PSA) in detecting clinically significant cancers. IsoPSA’s positive predictive value was 43%, compared with 35% for tPSA, 32% for %fPSA and 37% for tPSA+%fPSA.
• In the same head-to-head comparison, all of the assays had a similarly small (~2%) false-negative rate, but IsoPSA performed significantly better than its counterparts in reducing unnecessary biopsies — a 46% decrease compared with 16% for tPSA, 21% for %fPSA and 19% for tPSA+%fPSA.
• In a theoretical cohort of 1,000 men undergoing prostate biopsy, IsoPSA testing would decrease the number of unnecessary procedures from 705 to 402 (a 43% reduction). The assay would miss only 22 high-grade cancers, 7 of those with Gleason scores ≥4+3.
• IsoPSA’s sensitivity for high-grade cancers was better in patients who underwent TRUS/mpMRI-guided biopsies than in those who received only TRUS-guided ones. Since mpMRI is more accurate than TRUS alone at identifying high-grade tumors, IsoPSA’s improved performance in the mpMRI-biopsied subset “adds confidence that the [assay] accurately identifies those at highest risk of high-grade disease,” the researchers wrote.

A new paradigm

The U.S. Food and Drug Administration has not yet approved IsoPSA for commercial use.

“The results suggest that IsoPSA could improve the current screening paradigm when used as a reflex test in someone with a worrisome PSA, before jumping immediately to biopsy,” Dr. Klein says. “That could reduce the overall biopsy rate and, in conjunction with MRI, improve diagnostic yield.”

* Cleveland Clinic has an equity position in Cleveland Diagnostics. Dr. Klein has no direct or indirect personal financial interests in the company.