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Clinical Oncology News Opko 4Kscore

ISSUE: APRIL 2015 | VOLUME: 10

4Kscore Can Reduce Need for Risky Prostate Biopsies

by Chase Doyle

Orlando, Fla.—Costly and invasive biopsies may soon be obsolete for most men screened for prostate cancer. According to results from a prospective clinical trial presented at the 2015 Genitourinary Cancers Symposium, a blood test called the 4Kscore can predict the personal risk of Gleason 3+4 or higher aggressive cancer with a 94% rate of accuracy (abstract 1).

“The role of the 4Kscore,” explained Sanoj Punnen, MD, an assistant professor in the Department of Urology at the University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, in Florida, “is to determine which patients are most likely to have an aggressive cancer and would, therefore, benefit from … biopsy. This allows us to forgo biopsies in men who are unlikely to ever suffer any serious consequences from a high-grade cancer.”

Although Dr. Punnen acknowledged the reduction in prostate cancer mortality shown in previous screening trials involving prostate-specific antigen (PSA), he was also quick to stress the costs of said reduction—namely, over-detection and overtreatment. “To save one man’s life,” Dr. Punnen said, “we need to screen over 1,000 men … ”

According to Dr. Punnen, much of this screening culminates in a prostate biopsy, which in addition to increased costs, can result in urinary complications, emotional stress and an increased trend for quinolone resistance. Additionally, he said, “75% of biopsies are either negative for cancer or show an indolent or low-grade cancer, which … is unlikely to ever affect the quantity or quality of anyone’s life.”

First Prospective Study Of Kallikrein Panel

The 4Kscore, a blood test based on the four-kallikrein panel, incorporates total PSA, free PSA, intact PSA and human kallikrein (hK2), as well as clinical information, including digital rectal exam results, prior biopsy status and the patient’s age. “When you take all of these factors together,” Dr. Punnen said, “you obtain a personalized risk prediction of a Gleason 3 or higher cancer of the prostate.”

Although a previous study, the European Randomized Study of Screening for Prostate Cancer, examined the kallikrein panel, it was a retrospective study (Lancet 2014.6;384[9959]:2027-2035, PMID: 25108889).

“This test has never been analyzed prospectively, and it’s never been performed in the United States,” Dr. Punnen said. “So that was the goal of this current study.”

From October 2013 to April 2014, Dr. Punnen and his co-investigators studied 1,012 patients from 26 different sites around the United States. All the men were referred by their urologists to undergo a biopsy of the prostate; there were no restrictions based on age or PSA values; all patients underwent a minimum of 10 core biopsies; and all patients gave samples of blood, which were tested for kallikrein levels.

Among the 1,012 men enrolled in the trial, the majority (77.2%) had either no prostate cancer or a Gleason 6 low-grade cancer; 231 men (22.8%) had a Gleason 3+4 or higher cancer.

“The idea of this test was to see how well we could predict the high-grade cancers using the 4Kscore,” said Dr. Punnen. “The calibration plot shows that the 4Kscore pretty much approximated the actual observed risk of a Gleason 3+4 cancer (area under the curve 0.82)” (Figure).

4Kscore Correlation Graph

The investigators also examined the clinical utility of the 4Kscore with a decision-curve analysis of the net benefit at various thresholds for performing a biopsy, which was useful in providing a personalized risk prediction to facilitate informed and shared decision making.

“For a very risk-averse person—a young person, for example—you may use a very low threshold in order to perform a biopsy,” he explained. “Anything 6% or higher may be your threshold. If you did that, you would avoid 30% of biopsies that you normally would [perform] and only about 1.3% of Gleason 3+4 or higher cancers would be missed. But, if you have an older man with more comorbidities, you may take a 15% threshold before you’re willing to undergo a biopsy. With this threshold, you’d avoid almost 60% of biopsies you would otherwise [perform].”

Although such a strategy carries some risk for missing high-grade cancers (4.7% with the aforementioned threshold), Dr. Punnen suggested that most of those cancers were Gleason 3+4 and unlikely to progress quickly and would probably be detected in subsequent screenings. “The likelihood of missing an actual high-grade Gleason 4+4 or higher cancer is less than 1% at all of those thresholds,” Dr. Punnen concluded.

Co-investigator Daniel W. Lin, MD, the chief of urologic oncology at the University of Washington Medical Center, in Seattle, underscored the value of the findings. He said, although “we can detect prostate cancer with PSA screening alone, the problem is it detects prostate cancers that might not need to be detected because they’re indolent. The value of the 4Kscore is to identify those men who have a higher likelihood of having high-grade prostate cancer. At the same time, it spares men the burden of having to get an unnecessary prostate biopsy.”

Oliver Sartor, MD, a professor of cancer research in the Departments of Medicine and Urology at Tulane School of Medicine, and the director of the Tulane Cancer Center, in New Orleans, commented on the study. “The study presented by Dr. Punnen helps to provide valuable new data,” Dr. Sartor said. “The 4Kscore test appears to correlate well with the presence of high-grade cancer on biopsy, much better than PSA. Though it is not perfect, it does represent a new step forward in the assessment of men at risk for prostate cancer.”