Results from the U.S. validation study of a test that combines plasma levels of four prostate-specific kallikreins with clinical data demonstrated it accurately predicts high-grade prostate cancer and is superior to a validated clinical variable-based risk calculator.
Seattle-Results from the U.S. validation study of a test that combines plasma levels of four prostate-specific kallikreins with clinical data demonstrated it accurately predicts high-grade prostate cancer and is superior to a validated clinical variable-based risk calculator.
The elements of the test, known as the 4Kscore Test (OPKO Diagnostics, Miami), include total PSA, intact PSA, free PSA, human kallikrein 2, age, digital rectal exam status, and prior biopsy status. An algorithm uses all of these data to generate a final score that identifies the individual patient’s precise risk of having high-grade disease across a spectrum ranging from <1% to 95%.
Findings from the trial were originally presented at the AUA annual meeting in Orlando, FL and are currently in press in European Urology.
Separately, at the American Society of Clinical Oncology annual meeting in Chicago, researchers reported that the biomarkers used in the 4Kscore Test were shown to predict the probability of distant metastasis within 20 years.
“This test essentially gives the positive predictive value of finding high-grade disease on biopsy, and is optimized to detect clinically relevant and actionable high-grade disease,” said Daniel W. Lin, MD, professor of urology and chief of urologic oncology at the University of Washington, Seattle, who presented the study findings in Orlando.
“By reducing over-diagnosis of indolent disease and allowing us to focus our efforts around treatment of high-grade cancer, it certainly addresses the current controversy about PSA screening and the concerns of policymakers who question prostate cancer screening in general.”
The U.S. trial by Dr. Lin and colleagues prospectively enrolled 1,367 patients who underwent transrectal ultrasound biopsy (≥10 cores) at 26 participating urology centers. All assays were performed at the OPKO CLIA-certified laboratory, and histopathology was done at the clinical site.
The first 300 men enrolled were used for a calibration cohort, 55 men had samples excluded, and 1,012 men comprised the validation cohort. Patients were eligible regardless of PSA, age, DRE status, and prior biopsy, but were excluded if they were receiving any treatment known to influence PSA levels. There were no significant differences in the clinical variables or total PSA levels comparing the calibration and validation cohorts, and the characteristics of the population were typical of men who would be referred for prostate cancer biopsy in the community practice setting.
In the validation cohort, 54% of men had a negative biopsy result, 23% had low-grade disease (Gleason grade 6), and 23% had high-grade cancer (Gleason 7 or higher). The ability of the test to discriminate men with high-grade disease from those with no or low-grade cancer was evaluated in an area under the curve (AUC) analysis. The results showed a statistically significant difference favoring the 4Kscore test compared to use of PCPT 2.0 (a risk calculator based on the Prostate Cancer Prevention Trial) (AUC, 0.82 vs. 0.74) in the overall population as well as for the subgroup of men who would be considered “in the diagnostic gray zone,” ie, those with high-grade disease and PSA levels of 2.0 to 10.0 ng/mL (AUC, 0.77 vs. 0.66).
Dr. Lin also presented data demonstrating that the test performed nearly perfectly at the individual patient level in predicting risk of high-grade cancer and showing that across a range of test cut-off scores, use of the test would greatly reduce the number of unnecessary biopsies while minimizing delay in diagnosis of high-grade prostate cancer for nearly all affected men.
For example, using a test score threshold of ≥6% to select patients for biopsy, the test would avoid 30% of unnecessary biopsies and identify 98.7% of men with high-grade cancer. Using a cutoff of ≥15%, the test would avoid 58.4% of unnecessary biopsies and still identify 95.3% of men with high-grade cancer.
At ASCO, authors from four European centers and Memorial Sloan Kettering Cancer Center in New York showed that among men with PSA levels above median, the 4KScore Test biomarkers improved prediction of distant metastasis at 10 to 20 years versus PSA alone. In a decision analysis, using a biopsy cutoff of PSA ≥3.0 ng/mL would have resulted in biopsies performed on 15.5% of men with blood drawn at age 60. This rate would have been reduced by 38% if biopsy were restricted to those with ≥7.5% risk of high-grade cancer according to the 4KScore Test biomarkers. “However, 10- to 15-year risk of distant metastases was 0.18%-1.16% in this group, a 15-year risk of metastases less than an eighth of that for those with PSA ≥3.0 ng/ml and ≥7.5% risk score,” the researchers wrote.
“As opposed to other assays that might give a threshold on which to recommend biopsy or not, this test allows for a unique personalization of risk and the opportunity to individualize recommendations for biopsy,” Dr. Lin said. “The test score together with clinical factors such as comorbidities, family history, age, and patient preference can be used by the patient and physician to inform shared decision making.”
Funding for the study by Dr. Lin et al was provided by OPKO Diagnostics. Two of the ASCO study authors have stock ownership in the company.
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