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SAN FRANCISCO -- An assay that identifies abnormal PSA proteins showed promise as an aid to avoid unnecessary prostate biopsies triggered by worrisome PSA test results, according to data reported here.

In two separate studies involving comparisons with biopsy findings, the IsoPSA assay results could have eliminated the need for biopsy in almost half of the 532 patients included in the studies. The assay's ability to distinguish intermediate- and high-grade disease from low-grade and benign disease improved when paired with MRI fusion biopsy, as opposed to standard transrectal ultrasound (TRUS)-guided biopsy, reported Mark Stovsky, MD, of the Cleveland Clinic, and colleagues, at the American Urological Association meeting.

"When you pair up novel biomarkers that have superior diagnostic accuracy with better templates for biopsy, you can really do a lot to change the algorithm for evaluating a patient, either in the early detection [of prostate cancer] or for use as a reflex test or, theoretically, for use in active surveillance, when you're trying to define a patient group that's at high risk for grade migration," he said.

The IsoPSA was developed (with the recognition that PSA is a nonspecific test that can be influenced by both malignant and benign conditions. As prostate cancer evolves, abnormal PSA isoforms emerge. IsoPSA detects any malignancy-associated proteins, not a specific type of abnormality, Stovsky said. A key characteristic of the assay is its ability to distinguish intermediate and high-risk prostate cancer from low-risk and benign disease.

Using a predefined cutoff value (17% likelihood of high-grade cancer) to recommend biopsy, an of the assay in 261 patients had a receiver operating characteristic area under the curve (AUC) of 0.79 for any cancer and 0.81 for high-grade versus low-grade prostate cancer or benign pathology. A comparison of assay and biopsy results showed a 48% reduction in false-positive biopsies, 45% when the cutoff was set to distinguish men with a low risk of high-grade disease.

Stovsky presented data from a 271-patient multicenter validation study, involving patients scheduled for prostate biopsy because of abnormal PSA tests. Eligible patients had a PSA ≥2 ng/mL, and the 17% cutoff value for high-grade disease was used. A higher proportion of patients underwent MRI fusion biopsies as compared with the initial study, Stovsky said.

In both studies, a third of the patients had high-grade prostate cancer at pathology. The results showed an AUC of 0.79 for recognition of high-grade cancer. Combined results from the two studies yielded an AUC of 0.80. The negative predictive value was 93%-94% in both studies.

A statistical model that included IsoPSA results and patient age slightly improved the assay's performance. Combining the assay with prostate volume, patient race, and total PSA value did not significantly improve results.

Separate analyses by type of pathologic assessment showed that the assay performed improved with "superior" pathology, said Stovsky. Overall, the assay had an AUC of 0.80 for all biopsies, 0.79 with TRUS-guided biopsy and 0.83 with MRI fusion biopsy. AUC improved to 0.84, 0.83, and 0.87 when the three analyses excluded patients with Gleason grade 6 pathology, which proves to be erroneous (upgrade to Gleason ≥7) in about 30% of cases, said Stovsky.

As currently envisioned for clinical practice, the IsoPSA would come into play whenever a patient has a "worrisome" PSA value. If the assay proved negative, a patient would be offered active surveillance. If the IsoPSA result suggested high-grade disease, MRI evaluation would follow. If negative, the patient would undergo conventional TRUS-guided biopsy, but if MRI supported the IsoPSA finding of high-grade disease, the patient would undergo .

"The question is, what is the new training paradigm going to look like," said Eric Klein, MD, also of the Cleveland Clinic and first author of the initial study of IsoPSA. "We know that PSA alone is only accurate about 60% of the time in terms of diagnosing prostate cancer and leads to overdiagnosis of low-grade prostate cancer."

The new paradigm in England is for men with a worrisome PSA to have MRI. If the imaging study is negative, the patient doesn't have a biopsy, but if the MRI also is worrisome, a biopsy follows, said Klein. The development of new types of assays, such as IsoPSA, has introduced the possibility of a clinical paradigm that follows a worrisome PSA with a "reflex" test, as described by Stovsky.

"MRI misses about 20% of biologically significant prostate cancers," said Klein. "My thought is that if you combine MRI with one of these newer assays, you'll probably find those patients who have negative MRIs but still harbor biologically significant prostate cancers."

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