Reducing Unnecessary Biopsies While Detecting Clinically Significant Prostate Cancer Including Cribriform Growth with the ERSPC Rotterdam Risk Calculator and 4Kscore - Beyond the Abstract

Population-wide screening with PSA reduces the mortality of prostate cancer (PCa), but with the downside of overdiagnosis and overtreatment 1, 2. To improve screening efforts further, a balance must be found between minimizing overdiagnosis and optimizing the timely detection of potentially deadly disease. Combining relevant clinical characteristics, biomarkers and new pathological insights into risk calculators can improve this balance. The latest International Society of Urological Pathology (ISUP) grading system and presence of a cribriform pattern (CR) and intraductal carcinoma (IDC) aids in the understanding of disease burden and could further reduce overdiagnosis when incorporated in a risk calculator 3.

Nowadays, there are many commercially available biomarkers offered by companies with often very active marketing strategies, pointing towards further improvement of risk-based patient selection for prostate biopsy. One of these novel biomarkers is the four-kallikrein panel, which is combined with age and DRE outcome into a prediction tool called the 4Kscore 4. In our study we compared the clinical impact of 4Kscore, the ERSPC Rotterdam Prostate Cancer Risk Calculator (RPCRC) and the combination of life both predicting clinical significant prostate cancer, defined by ISUP grade 2 PCa with CR/IDC plus all PCa with ISUP grade ≥3, on biopsy 5.

To assess the clinical utility of the RPCRC and the 4Kscore, it is important to independently compare them. We believe the dataset used in our study provides a fair comparison, as this cohort was used for the development of both the RPCRC and the 4Kscore. In addition, there is no other cohort available which has the advantage of a being a true population-based screening cohort and has the availability of both the 4Kscore and the pathologic evaluation of the prostate biopsy specimen including scoring of cribriform growth patterns. Finally, its population-based nature and the fact that men were systematically biopsied based on a fixed screening protocol (PSA≥3.0n/ml) avoiding selection bias (i.e. urologists decide who and when to biopsy) is a benefit in the assessment of the value of different risk prediction tools.

Our study showed that both RPCRC and 4Kscore have similar predictive performance and clinical utility. A reduction of two third of all biopsies can be achieved when compared to biopsy based solely on PSA. Adding new predictors and biomarkers into prediction models remains a tradeoff where, next to the clinical utility, aspects such as patient burden and costs are important considerations. It is perhaps human nature to assume that novel (often more expensive) biomarkers or models are better than existing more simple risk prediction tools. However, it is crucial that new developments like magnetic resonance imaging techniques, proteomics and/or genomics are extensively compared to existing methods to be sure that they indeed will provide more relevant pre-biopsy information and not overlooking aspects of costs and availability.

Written by:
Jan FM Verbeek, MD, and Professor Monique J. Roobol, Ph.D., MSc, Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands

1.  Schröder FH, Hugosson J, Roobol MJ, Tammela TLJ, 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. The Lancet. 2014;384:2027-35.
2. Loeb S, Bjurlin MA, Nicholson J, Tammela TL, Penson DF, Carter HB, et al. Overdiagnosis and overtreatment of prostate cancer. European Urology. 2014;65:1046-55.
3. Roobol MJ, Verbeek JFM, van der Kwast T, Kummerlin IP, Kweldam CF, van Leenders G. Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculator for Initial Prostate Biopsy by Incorporating the 2014 International Society of Urological Pathology Gleason Grading and Cribriform growth. European Urology. 2017;72:45-51.
4. Sjoberg DD, Vickers AJ, Assel M, Dahlin A, Poon BY, 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. European Urology. 2018;73:941-8.
5. Verbeek JFM, Bangma CH, Kweldam CF, van der Kwast TH, Kummerlin IP, van Leenders G, et al. Reducing unnecessary biopsies while detecting clinically significant prostate cancer including cribriform growth with the ERSPC Rotterdam risk calculator and 4Kscore. Urol Oncol. 2019;37:138-44.

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