Next-Generation Prostate Cancer Biomarker Shows Promise

Diagnostic accuracy of novel PSA/SIA test appears robust

By Mark Stovsky, MD

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Patients and physicians face a challenging dilemma when addressing the controversial issues of prostate cancer screening and early detection. While screening and early detection strategies make intuitive sense, recently published data on the diagnostic and prognostic inaccuracy of the standard serum prostate specific antigen (PSA) test confound the discussion.

While recent U.S. Preventive Services Task Force recommendations against prostate cancer screening have been internalized by some physicians, most urologists and many primary care physicians will choose to follow the current American Urological Association guidelines, which indicate that screening and early detection strategies may be appropriate in high-risk patients (e.g., primary family history and African-American groups) and in men between the ages of 55 and 69 with an appropriate risk/benefit informed consent discussion.

Moreover, as long as competing guidelines exist, patients will continue to undergo screening and early detection either with their primary care physicians or in community-based health programs. To be sure, patients and their urologists have been placed between a rock and a diagnostic hard place.

Difficulties of Clinical Decision-Making

In perhaps the most common clinical scenario, a generation of patients has been evaluated with regular serum PSA tests and digital rectal examinations. Many of these patients have undergone prolonged periods of clinical surveillance for abnormal serum PSA or PSA analogue results (e.g., free PSA, complexed PSA, PSA velocity, PSA density, age-specific PSA). Further, a large subset of these patients also has undergone at least one transrectal ultrasound guided prostate biopsy (TRUS biopsy) procedure showing either benign prostate tissue or a noncancer deviation from normal, such as prostate intraepithelial neoplasia or atypical small acinar proliferation.

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Even if all screening and early detection programs ended today, these patients and their urologists would still be challenged through shared decision-making to determine the best course of action. In this clinical context, the management options are clearly defined. They include clinical observation, repeat prostate biopsy using either standard or extended/saturation techniques, state of the art imaging modalities such as prostate MRI, or the use of novel proteomic or genomic molecular biomarkers, to attempt to improve on the diagnostic precision, predictive value and prognostic accuracy of standard serum PSA testing.

In current practice, the prostate cancer antigen 3 (PCA3) biomarker can be used to help guide decision-making for initial and repeat TRUS biopsy in high-risk patients. PCA3 is an RNA transcription product of DNA that is overexpressed in the urine in a high percentage of prostate cancers. Peer-reviewed studies outlining the diagnostic performance of PCA3 indicate that PCA3 has greater sensitivity and specificity than standard total PSA, that PCA3 outperforms total PSA for initial and repeat biopsy decision-making, and that PCA3 provides independent diagnostic information compared with PSA testing.

The Promise of PSA/SIA

At Cleveland Clinic, urologists are playing leading roles in the use and development of promising next-generation prostate cancer biomarkers. One new test under investigation, PSA/solvent interaction analysis (PSA/SIA), shows promise in improving the diagnostic accuracy of screening and early detection strategies by differentiating PSA structural changes induced by cancer from those of benign glands.

In the initial multicenter validation trial published in Urology, PSA/SIA in urine displayed an area under the curve (AUC) of 0.90, sensitivity of 100 percent, specificity of 80.3 percent, positive predictive value of 80.6 percent and negative predictive value of 100 percent.

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A follow-up multi-institutional study of the PSA/SIA assay in serum showed similar performance with an AUC of 0.83, sensitivity range of 90 to 100 percent and specificity range of 48 to 60 percent for the complexed PSA fraction at various test cutoff values, as well as enhanced ability to separate structural cancer and non-cancer isoforms.  Additional data appears to show that the diagnostic accuracy of PSA/SIA is robust across a broad range of serum total PSA values – indicating that PSA/SIA may have clinical utility in patients with normal serum PSA values.

Future studies will aim to gauge the performance of PSA/SIA in other clinical settings, including the evaluation of patients after definitive treatment with radiation or cryotherapy.

Dr. Stovsky is a staff member of Cleveland Clinic Glickman Urological & Kidney Institute’s Department of Urology.