This peer reviewed publication describes the findings of a prospective multicenter clinical validation study of the novel IsoPSA prostate cancer (CaP) early detection test performed at 10 sites in the United States and Israel including the Cleveland Clinic Glickman Urological and Kidney Institute, the Johns Hopkins James Buchanan Brady Urological Institute, UT Southwestern Medical Center Department of Urology, Rabin Medical Center Department of Urology, Michigan Institute of Urology, Chesapeake Urology Associates, The Urology Group, and Kaiser Permanente Northwest.
The objectives of this pivotal study were: 1) to describe the diagnostic performance and predictive characteristics of IsoPSA, based on the Solvent Interaction Analysis aqueous 2-phase physicochemical method, for the detection of high-grade CaP (Gleason Score ≥ 7) and any CaP (Gleason Score ≥ 6) in men ≥ 50 years of age with a pre-biopsy total PSA ≥ 4 ng/ml, 2) to compare the diagnostic accuracy of IsoPSA to both total PSA and % free PSA, and 3) to assess the performance of IsoPSA in clinically relevant sub-groups with total PSA 4-10 ng/ml, total PSA > 10 ng/ml, and in relation to biopsy status (biopsy naïve vs prior negative biopsy).
IsoPSA is a structure-based assay that is designed to categorize patients by risk based on the expression of particular protein isoforms linked to cancer biology. In practice, IsoPSA is in essence a liquid biopsy filter that selectively partitions PSA structural variants based on certain physicochemical properties that are inherently connected to the underlying cancer biology, prior to standard immunoassay quantification, to derive the reportable IsoPSA Index. IsoPSA is unique in that it is agnostic to the particular PSA structural forms expressed by a given patient and that it measures changes to PSA related to the disordered cellular metabolism of malignancy without the need for a priori biomarker assumptions, complex algorithms, or interdependent clinical elements required by other CaP early detection assays.
In this authoritative study, IsoPSA outperformed total PSA and % free PSA on overall accuracy, specificity, and predictive value with similar sensitivity for both high-grade CaP and any CaP using biopsy as the common pathologic comparator. IsoPSA also outperformed % free PSA on overall accuracy when the total PSA was 4-10 ng/ml (range of total PSA for which % free PSA has statistical accuracy) for both biopsy outcomes. Based on the improved overall accuracy and specificity of the assay, IsoPSA should predictably reduce unnecessary biopsies performed in low-risk patients compared to both total and % free PSA.
Importantly, IsoPSA displayed statistically informative negative and positive predictive characteristics based on likelihood ratio analysis of pre- and post-test risk to yield clinically actionable results in the majority of patients, demonstrated robust performance independent of biopsy technique (i.e., TRUS vs MRI fusion vs perineal), and maintained diagnostic accuracy across a broad range of total PSA values (i.e., 4-100 ng/ml) seen in practice - making the test demonstrably more clinically useful than assays that assess more limited histopathologic outcomes (i.e., any CaP or high-grade CaP only), exhibit only negative predictive value, or that are constrained to a narrow total PSA range. The diagnostic performance of IsoPSA was also consistent regardless of prior biopsy status, suggesting that IsoPSA could exhibit particular utility over time in the management of clinically challenging patients with persistently elevated total PSA levels who may have undergone one or more biopsies and helping to break the cycle of repeat biopsy and imaging procedures while focusing early detection strategies on patients properly classified by risk. And, the use of medications for symptomatic BPH (e.g., 5 ARIs and alpha blockers) did not interfere with the analytic performance of the assay - providing a test that can help to distinguish active benign prostate disease from clinically significant malignancy.
On balance, IsoPSA is the first prostate cancer diagnostic test to combine biology-based physicochemical partitioning of different structural variants of the same protein with standard immunoassays. IsoPSA interrogates the PSA distribution of structural variants in blood and thereby assesses cancer risk more accurately than existing concentration-based PSA assays. IsoPSA provides actionable results for the majority of patients tested and is validated to discriminate the risk of both high-grade CaP and any CaP - differentiating the assay in the prostate cancer early detection space. For urology specialists, IsoPSA should improve shared decision-making for or against prostate biopsy irrespective of the use of advanced imaging techniques. For primary care and medical oncology providers, IsoPSA should provide a mechanism to manage clinically complex, low-risk patients in their practices and allow for more effective specialist referral decisions for those at increased CaP risk.
Written by: Eric A. Klein, Alan Partin, Yair Lotan, Jack Baniel, Martin Dineen, Jason Hafron, Kannan Manickam, Marc Pliskin, Matthew Wagner, Aimee Kestranek, Mark Stovsky
Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, OH; Stanford University Distinguished Careers Institute, Stanford, CA., Johns Hopkins James Buchanan Brady Urological Institute, Baltimore, MD., University of Texas Southwestern Medical Center Department of Urology, Dallas TX., Rabin Medical Center Department of Urology, Petah Tikvah, Israel., Advanced Urology Institute, Daytona Beach, FL., Michigan Institute of Urology, West Bloomfield, MI., Chesapeake Urology Associates, Baltimore, MD., The Urology Group, Cincinnati, OH., Kaiser Permanente Northwest, Clackamas, OR., Cleveland Diagnostics, Inc., Cleveland, OH.
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