The 4Kscore (OPKO Health Inc.), a pre-specified model based on 4 kallikrein markers in blood, may help guide clinical decisions about whether additional risk assessment, such as confirmatory biopsy, is warranted when deciding between active surveillance (AS) and curative therapy, according to a new retrospective study.

The findings, published in the British Journal of Cancer, demonstrated that the 4Kscore can strongly predict adverse pathology and biochemical recurrence (BCR) in men with low-grade cancer on biopsy.

The study showed the 4Kscore, along with findings from additional tests such as magnetic resonance imaging (MRI), may help assist urologists and their patients with Gleason 3 + 3 cancers decide whether additional risk assessment may be necessary before initiating AS.

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“We were now interested to understand whether a 4Kscore test in pretreatment blood could improve assessment of risk of adverse pathology features above and beyond the established predictors, such as age, PSA, tumor grade and stage at diagnosis,” said corresponding author Hans Lilja, MD, PhD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York.

The 4Kscore was measured in cryopreserved blood from 2330 men and was obtained before radical prostatectomy (RP) between 2002 and 2010. The study included only men with localized PCa undergoing RP at a tertiary referral center in Hamburg, German. All men had undergone 10-12-core transrectal ultrasound-guided biopsy using a standard template. The rate of AS at the time was very low, and almost all men were treated shortly after diagnosis.

The median age at blood draw was 64 years and approximately two-thirds of men who had undergone RP had Gleason 3 + 3 cancer at biopsy. Of the 2330 men, 709 (30%) had adverse pathology, and the estimated rate of adjuvant treatment was 21%. After adjusting for established clinical predictors, 4Kscore was significantly associated with nearly 1.5-fold increased odds of adverse pathology. Adding 4Kscore to other predictors improved the area under the curve from 0.672 to 0.718 within biopsy Gleason 3 + 3 cancer and from 0.644 to 0.659 within biopsy Gleason 3 + 4 cancer. A higher 4Kscore was significantly associated with a 16% greater risk of BCR.

“The 4Kscore strongly predicts adverse pathology and biochemical recurrence in men with low-grade cancer on biopsy,” Dr Lilja told Renal & Urology News. “The 4Kscore, along with additional tests such as MRI, could assist physicians and their patients in making critical clinical decision for Gleason 3+3 cancers. Evidence that the 4Kscore improves decision-making among men with Gleason 3+4 at biopsy is less strong and worthy of further study.”

The 4Kscore test combines 4 prostate-specific biomarkers (total PSA, free PSA, intact PSA, and human kallikrein 2 [hK2]) with clinical factors (age, prior biopsy status, and optional digital rectal examination [DRE]) to provide a man’s risk of high-grade PCa (Gleason 7 or higher). It is indicated after an abnormal PSA and/or DRE, prior to the first biopsy or after a negative biopsy to help reach a prostate biopsy decision. The 4Kscore test has been included in testing guidelines from the National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA). “In reference to men with Gleason grade 3+3 at biopsy the effect size is considerable and could possibly change clinical practice,” said Dr Lilja.

The 4Kscore is among the tests than the NCCN Guidelines for Prostate Early Detection can be considered. NCCN’s treatment guidelines do not mention 4Kscore. Edward Schaeffer, MD, PhD,  Chair of the NCCN Guidelines Panel for Prostate Cancer and is affiliated with the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, said the current investigation was nicely done and provides information on the role of the 4kscore in helping to discriminate between men with aggressive cancer from men with less disease. “So, it gives us another tool in our armamentarium that helps us better decide treatment,” Dr Schaeffer said.

Jeffrey J. Tosoian, MD, MPH, a clinical lecturer and fellow in urologic oncology at the University of Michigan in Ann Arbor, said the new study demonstrates that 4Kscore adds incremental information regarding outcomes after surgery, particularly in men with Gleason score 6 cancer diagnosed on biopsy. “The authors reasonably suggest that the test could assist in decision-making prior to initiating AS,” Dr Tosoian said. “Whether there is a practical, definable role for 4Kscore in this clinical setting is less clear, because in current practice the overwhelming majority of men with GS 6 cancer initiate AS, which at most centers begins after a confirmatory biopsy.”

Urologic oncologist Andres Felipe Correa, MD, Assistant Professor at Fox Chase Cancer Center in Philadelphia, said the 4KScore was initially developed as a pre-biopsy test to assess the risk of clinically significant PCa in patients presenting with an elevated PSA. Although the current study is novel in its use of the 4KScore in the post-biopsy setting, there are several limitations that would prevent its applicability in the clinical setting. The clinical model is simplistic compared with currently available clinical models, such as the Cancer of the Prostate Risk Assessment (CAPRA) Score and MSKCC prostate cancer nomogram.

Dr Correa said the current study can only be considered exploratory, as it fails to address how it would improve on the currently available tools, especially prostate MRI. MRI, he explained, confers the added benefits of identifying potentially under-sampled cancers and adverse pathologic findings, such as seminal vesical invasion and extra-prostatic extension. MRI also can provide accurate gland volume measurements. “It would be interesting to evaluate if the addition of 4Kscore may improve on the negative predictive value of MRI as to potentially avoid unnecessary diagnostic prostate biopsies in those screened with MRI, or confirmatory biopsies in the AS setting,” he said.

Disclosure: Hans Lilja holds patents on assays for intact PSA and is named on a patent for a statistical method to detect prostate cancer (the 4KScore test) that has been commercialized by OPKO Health. Hans Lilja receives royalties from sales of the test and has stock in OPKO Health.


Haese A, Tin AL, Carlsson SV, et al. A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy [published online May 29, 2020]. Br J Cancer 2020. doi: 10.1038/s41416-020-0914-7