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.
Subscribe to Journal
Get full journal access for 1 year
only $32.88 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schroder, F. H., Hugosson, J., Roobol, M. J., Tammela, T. L., Zappa, M., Nelen, V. et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 384, 2027–2035 (2014).
Ehdaie, B., Vertosick, E., Spaliviero, M., Giallo-Uvino, A., Taur, Y., O’Sullivan, M. et al. The impact of repeat biopsies on infectious complications in men with prostate cancer on active surveillance. J. Urol. 191, 660–664 (2014).
Loeb, S., Vellekoop, A., Ahmed, H. U., Catto, J., Emberton, M., Nam, R. et al. Systematic review of complications of prostate biopsy. Eur. Urol. 64, 876–892 (2013).
Klotz, L., Vesprini, D., Sethukavalan, P., Jethava, V., Zhang, L., Jain, S. et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J. Clin. Oncol. 33, 272–277 (2015).
Kinsella, N., Helleman, J., Bruinsma, S., Carlsson, S., Cahill, D., Brown, C. et al. Active surveillance for prostate cancer: a systematic review of contemporary worldwide practices. Transl. Androl. Urol. 7, 83–97 (2018).
Kaye, D. R., Qi, J., Morgan, T. M., Linsell, S., Ginsburg, K. B., Lane, B. R. et al. Pathological upgrading at radical prostatectomy for patients with Grade Group 1 prostate cancer: implications of confirmatory testing for patients considering active surveillance. BJU Int. 123, 846–853 (2018).
Epstein, J. I., Feng, Z., Trock, B. J. & Pierorazio, P. M. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur. Urol. 61, 1019–1024 (2012).
Chun, F. K., Briganti, A., Shariat, S. F., Graefen, M., Montorsi, F., Erbersdobler, A. et al. Significant upgrading affects a third of men diagnosed with prostate cancer: predictive nomogram and internal validation. BJU Int. 98, 329–334 (2006).
Reichard, C. A., Stephenson, A. J. & Klein, E. A. Applying precision medicine to the active surveillance of prostate cancer. Cancer 121, 3403–3411 (2015).
Sternberg, I. A., Vela, I. & Scardino, P. T. Molecular profiles of prostate cancer: to treat or not to treat. Annu Rev. Med. 67, 119–135 (2016).
Parekh, D. J., Punnen, S., Sjoberg, D. D., Asroff, S. W., Bailen, J. L., Cochran, J. S. et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur. Urol. 68, 464–470 (2015).
Punnen, S., Pavan, N. & Parekh, D. J. Finding the wolf in sheep’s clothing: the 4Kscore is a novel blood test that can accurately identify the risk of aggressive prostate cancer. Rev. Urol. 17, 3–13 (2015).
Punnen, S., Freedland, S. J., Polascik, T. J., Loeb, S., Risk, M. C., Savage, S. et al. A multi-institutional prospective trial confirms noninvasive blood test maintains predictive value in African American men. J. Urol. 199, 1459–1463 (2018).
Vickers, A. J., Vertosick, E. A. & Sjoberg, D. D. Value of a statistical model based on four kallikrein markers in blood, commercially available as 4Kscore, in all reasonable prostate biopsy subgroups. Eur. Urol. 74, 535–536 (2018).
Sjoberg, D. D., Vickers, A. J., Assel, M., Dahlin, A., Poon, B. Y., Ulmert, D. et al. Twenty-year risk of prostate cancer death by midlife prostate-specific antigen and a panel of four kallikrein markers in a large population-based cohort of healthy men. Eur. Urol. 73, 941–948 (2018).
Stattin, P., Vickers, A. J., Sjoberg, D. D., Johansson, R., Granfors, T., Johansson, M. et al. Improving the specificity of screening for lethal prostate cancer using prostate-specific antigen and a panel of kallikrein markers: a nested case-control study. Eur. Urol. 68, 207–213 (2015).
Vickers, A. J., Gupta, A., Savage, C. J., Pettersson, K., Dahlin, A., Bjartell, A. et al. A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol. Biomark. Prev. 20, 255–261 (2011).
Vaisanen, V., Peltola, M. T., Lilja, H., Nurmi, M. & Pettersson, K. Intact free prostate-specific antigen and free and total human glandular kallikrein 2. Elimination of assay interference by enzymatic digestion of antibodies to F(ab’)2 fragments. Anal. Chem. 78, 7809–7815 (2006).
Brand, T. C., Zhang, N., Crager, M. R., Maddala, T., Dee, A., Sesterhenn, I. A. et al. Patient-specific meta-analysis of 2 clinical validation studies to predict pathologic outcomes in prostate cancer using the 17-gene genomic prostate score. Urology 89, 69–75 (2016).
Bryant, R. J., Sjoberg, D. D., Vickers, A. J., Robinson, M. C., Kumar, R., Marsden L. et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J. Natl Cancer Inst. 107, djv095 (2015).
Vickers, A. J. & Elkin, E. B. Decision curve analysis: a novel method for evaluating prediction models. Med Decis. Mak. 26, 565–574 (2006).
Wenske, S., Korets, R., Cronin, A. M., Vickers, A. J., Fleisher, M., Scher, H. I. et al. Evaluation of molecular forms of prostate-specific antigen and human kallikrein 2 in predicting biochemical failure after radical prostatectomy. Int J. Cancer 124, 659–663 (2009).
Haese, A., Graefen, M., Becker, C., Noldus, J., Katz, J., Cagiannos, I. et al. The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer. Prostate 54, 181–186 (2003).
Haese, A., Graefen, M., Steuber, T., Becker, C., Pettersson, K., Piironen, T. et al. Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml. Prostate 49, 101–109 (2001).
Haese, A., Becker, C., Noldus, J., Graefen, M., Huland, E., Huland, H. et al. Human glandular kallikrein 2: a potential serum marker for predicting the organ confined versus non-organ confined growth of prostate cancer. J. Urol. 163, 1491–1497 (2000).
Carlsson, S., Maschino, A., Schroder, F., Bangma, C., Steyerberg, E. W., van der Kwast, T. et al. Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam. Eur. Urol. 64, 693–699 (2013).
Punnen, S., Nahar, B., Prakash, N. S., Sjoberg, D. D., Zappala, S. M. & Parekh, D. J. The 4Kscore predicts the grade and stage of prostate cancer in the radical prostatectomy specimen: results from a multi-institutional prospective trial. Eur. Urol. Focus 3, 94–99 (2017).
Lin, D. W., Newcomb, L. F., Brown, M. D., Sjoberg, D. D., Dong, Y., Brooks, J. D. et al. Evaluating the four kallikrein panel of the 4Kscore for prediction of high-grade prostate cancer in men in the canary prostate active surveillance study. Eur. Urol. 72, 448–454 (2017).
Borque-Fernando, A., Rubio-Briones, J., Esteban, L. M., Dong, Y., Calatrava, A., Gomez-Ferrer, A. et al. Role of the 4Kscore test as a predictor of reclassification in prostate cancer active surveillance. Prostate Cancer Prostatic Dis. 22, 84–90 (2018).
Sauter, G., Steurer, S., Clauditz, T. S., Krech, T., Wittmer, C., Lutz, F. et al. Clinical utility of quantitative gleason grading in prostate biopsies and prostatectomy specimens. Eur. Urol. 69, 592–598 (2016).
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.
Consent to publish
The data sets analysed for this study will be made available to researchers on reasonable request to the corresponding author.
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.
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.
Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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). https://doi.org/10.1038/s41416-020-0914-7