Molecular Diagnostics

A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy



A pre-specified model based on four kallikrein markers in blood, commercially available as 4Kscore, predicts Gleason Grade (GG) 3 + 4 or higher prostate cancer on biopsy. However, sampling error and variation in pathology reporting may miss aggressive disease.


The 4Kscore was measured in cryopreserved blood from 2330 men obtained before prostatectomy at a single institution between 2002 and 2010. Adverse surgical pathology and biochemical recurrence (BCR) were pre-specified to be assessed in all men, biopsy GG 3 + 3, and 3 + 4.


Adjusted for established clinical predictors, the 4Kscore was significantly associated with adverse pathology (OR 1.49; 95% CI 1.32, 1.67; p < 0.0001). Adding 4Kscore increased discrimination from (AUC) 0.672 to 0.718 and 0.644 to 0.659 within biopsy GG 3 + 3 and 3 + 4, respectively. Higher 4Kscore was associated with higher risk of BCR (HR 1.16, 95% CI 1.06, 1.26; p = 0.001). Adding 4Kscore improved the prediction of BCR (C-index 0.630–0.660) within GG 3 + 3, but not GG 3 + 4.


The 4Kscore can help guide the clinical decision whether additional risk assessment—such as confirmatory biopsy—is needed to decide between active surveillance versus curative therapy. Evidence that the panel could influence management in biopsy GG 3 + 4 is less strong and requires further investigation.

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Fig. 1: Decision curve analysis based on Gleason Grade.
Fig. 2: Risk of adverse pathology and distribution of 4Kscore based on Gleason Grade.


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Author information




A.H. conceived the idea, acquired the data and revised the paper. A.T. analysed and interpreted the data, carried out the statistical analysis, drafted and revised the paper. S.C. interpreted the data and drafted the paper. D.S. interpreted the results and revised the paper. D.P. acquired data and revised the paper. T. Steuber conceived the idea and revised the paper. H.H. conceived the idea and revised the paper. M.G. conceived the idea and revised the paper. P.S. conceived the idea and revised the paper. T. Schlomm conceived the idea and revised the paper. A.V. conceived and designed the idea, analysed and interpreted the data and revised the paper. H.L. conceived and designed the idea, interpreted the data and revised the paper. G.S. conceived the idea and revised the paper.

Corresponding author

Correspondence to Hans Lilja.

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Ethics approval and consent to participate

Ethical approval was obtained from the MSKCC IRB. Consent was not sought from participants for this retrospective biomarker study as this was waived by the IRB. The study was performed in accordance with the Declaration of Helsinki.

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Not applicable.

Data availability

The data sets analysed for this study will be made available to researchers on reasonable request to the corresponding author.

Competing interests

Hans Lilja holds patents on assays for free PSA, intact PSA and hK2. Andrew Vickers, Hans Lilja, and Peter Scardino are named on a patent for a statistical method to detect prostate cancer (the 4KScore test) that has been commercialised by OPKO Health. Andrew Vickers, Hans Lilja and Peter Scardino receive royalties from sales of the test. Hans Lilja and Peter Scardino have stock, and Andrew Vickers has stock options in OPKO Health. Sigrid Carlsson has received a lecture honorarium and travel support from Astellas Pharma (unrelated to the current study). The other authors declare no other competing interests.

Funding information

This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], a SPORE grant in Prostate Cancer to Dr. H. Scher [P50 CA092629], the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation. This work was also supported in part by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program in the United Kingdom, the Swedish Cancer Society (CAN 2017/559), the Swedish Research Council (VR-MH project no. 2016-02974) and General Hospital in Malmö Foundation for Combating Cancer.

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Haese, A., Tin, A.L., Carlsson, S.V. et al. A pre-specified model based on four kallikrein markers in blood improves predictions of adverse pathology and biochemical recurrence after radical prostatectomy. Br J Cancer (2020).

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