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Blood-based assay superior to PSA for prostate cancer diagnosis

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May 30, 2017

The IsoPSA assay better identified prostate cancer and benign disease than a PSA test, according to results of a prospective study.

These results suggest the novel assay may reduce the need for biopsy, thus leading to a reduction in the overtreatment and overdiagnosis of prostate cancer.

Eric L. Klein

“The methodology used in the IsoPSA assay represents a significant departure from conventional ways to define biomarkers in blood, and may be applicable to improving other cancer biomarkers,” Eric L. Klein, MD, chair of the Glickman Urological & Kidney Institute at Cleveland Clinic, said in a press release.

PSA has changed the detection, screening and management of prostate cancer. However, since it is not cancer specific, overdiagnosis and overtreatment of less detrimental cancers has called its clinical usefulness into question.

IsoPSA (Cleveland Diagnostics) is a blood- and structure-based assay that agnostically interrogates the entire spectrum of structural changes of complex PSA. It is used to predict prostate cancer risk by partitioning isoforms of PSA with an aqueous two-phase reagent.

Klein and colleagues enrolled 261 men scheduled for prostate biopsy — due to increased PSA level or abnormal digital rectal examination — from five urology centers. Researchers collected heparin plasma for IsoPSA between August 2015 and December 2016.

Efficacy of IsoPSA assay compared with a standard concentration–based assay for the detection of any prostate cancer compared with no cancer, as well as high-grade prostate cancer compared with low-grade cancer or benign disease, served as the primary endpoints.

Prostate cancer occurred in 53% of patients, and high-grade prostate cancer occurred in 34%.

Researchers used receiver-operating characteristic analysis to determine discrimination power and decision curve analysis to compare the net benefit of IsoPSA against other methods.

For cancer vs. no cancer, the area under the receiver-operating characteristic curve was 0.79 (95% CI, 0.73-0.84) for IsoPSA vs. 0.61 (95% CI, 0.54-0.67) for total PSA (P < .001). IsoPSA also outperformed total PSA in this measure for distinguishing high-grade cancer from low-grade cancer/benign disease (0.81; 95% CI, 0.74-0.86 vs. 0.69; 95% CI, 0.61-0.75; P < .005).

The decision curve analysis showed IsoPSA had a superior net benefit compared with no biopsy, all biopsy and the modified Prostate Cancer Prevention Trial Risk Calculator 2.0.

With the goal of detecting cancer vs. no cancer, the IsoPSA assay led to a 48% reduction in unneeded biopsies using a 35% cutoff for the assay compared with 4 ng/ml cutoff for PSA.


Further, for detecting high-grade prostate cancer vs. low-grade prostate cancer/benign disease, the assay led to a 45% reduction in unneeded biopsies at a 17% cutoff.

“Due to its inherent simplicity, requiring only a blood draw and presenting information to the physicians in familiar contest using a single number — just like PSA itself — we are quite hopeful in IsoPSA’s future utility after further validation studies,” study researcher Mark Stovsky, MD, MBA FACS, staff urologist at the Glickman Urological & Kidney Institute at Cleveland Clinic, said in the release.

While IsoPSA is an “intriguing” new option, more studies are needed to identify additional biomarkers, Devin N. Patel, MD, from the division of urology at Cedars-Sinai Medical Center, and Stephen J. Freeland, MD, director of the Center for Integrated Research in Cancer at Cedars-Sinai Medical Center, wrote in a related editorial.

“Until well-conducted comparative effectiveness studies are carried out, the field of prostate cancer biology will continue in the unfettered pursuit of more novel biomarkers and the medicine of diagnosing prostate cancer will be unmethodical in its use of these new tests,” Patel and Freeland wrote. – by Melinda Stevens

Disclosures: Klein reports no relevant financial disclosures. Stovsky is the chief medical officer of Cleveland Diagnostics and reports investment interest in the company. Other researcher report employment with Cleveland Diagnostics. Freeland reports a consultant role with and stock ownership in Armune BioScience, the manufacturer of the APIFINY blood test. Patel reports no relevant financial disclosures.

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Peter E. Clark

The development of PSA as a biomarker for screening and managing prostate cancer has revolutionized how we approach this disease. Since the advent of PSA screening in the United States in the early 1990s, there has been a general decline in prostate cancer mortality rates and a migration toward lower stage disease at the time of diagnosis. However, there have been significant controversies surrounding PSA’s use, particularly as a screening tool.

Two large prospective randomized trials that tested whether PSA-based screening would reduce prostate cancer mortality have produced controversial results, and there has been significant debate in the health care community regarding the appropriateness of PSA as a screening tool. In large measure, this has to do with some of the performance characteristics of the test. Although PSA is produced almost exclusively by the prostate and is highly specific to that organ, it is not specific to prostate cancer. Therefore, PSA as currently measured in whole serum can change due to any disease process related to the prostate, whether benign or malignant. Further, it is not specific for high-grade disease, and therefore can lead to the detection of low-volume, low-grade cancers that we increasingly understand do not require therapy. The challenge has been to find a superior “PSA test.”

Klein and colleagues have shown in a preliminary report a modified way to detect PSA in serum based on its varying structural forms as opposed to its total concentration. This so-called IsoPSA test outperformed total PSA in a cohort of men already due to undergo prostate biopsy in terms of both detecting cancer and in detecting higher grade cancer. The improved performance characteristics included a high sensitivity while maintaining a reasonably high specificity for cancer or high-grade cancer. If verified in independent cohorts — in particular, a larger population that is more representative of a screening population — this could have profound implications for the debate around serum biomarker-based screening for prostate cancer.

The study itself was well designed as a preliminary study and as a proof of concept.

However, this study will require validation and will need to address certain weaknesses in this preliminary report including: a more standardized approach to biopsy rather than a mix of ultrasound and MRI fusion-based approaches; centralized pathologic review of the biopsies; and testing a population with a lower prevalence of prostate cancer, such as the general population that would be the subject of any future screening efforts.

Nevertheless, this preliminary report shows impressive performance characteristics for the IsoPSA assay that may allow us to offer a more robust screening tool for prostate cancer in the future.

Peter E. Clark, MD

Carolinas HealthCare System

Levine Cancer Institute

Disclosure: Clark reports he has no relevant financial disclosures.