Blood and urine biomarkers in prostate cancer: Are we ready for reflex testing in men with an elevated prostate-specific antigen?
Edward K. Changa,Adam J. Gadzinskia,Yaw A. Nyameab*()
a Department of Urology, University of Washington Medical Center, Seattle, WA, USA b Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Objective: There is no consensus on the role of biomarkers in determining the utility of prostate biopsy in men with elevated prostate-specific antigen (PSA). There are numerous biomarkers such as prostate health index, 4Kscore, prostate cancer antigen 3, ExoDX, SelectMDx, and Mi-Prostate Score that may be useful in this decision-making process. However, it is unclear whether any of these tests are accurate and cost-effective enough to warrant being a widespread reflex test following an elevated PSA. Our goal was to report on the clinical utility of these blood and urine biomarkers in prostate cancer screening. Methods: We performed a systematic review of studies published between January 2000 and October 2020 to report the available parameters and cost-effectiveness of the aforementioned diagnostic tests. We focus on the negative predictive value, the area under the curve, and the decision curve analysis in comparing reflexive tests due to their relevance in evaluating diagnostic screening tests. Results: Overall, the biomarkers are roughly equivalent in predictive accuracy. Each test has additional clinical utility to the current diagnostic standard of care, but the added benefit is not substantial to justify using the test reflexively after an elevated PSA. Conclusions: Our findings suggest these biomarkers should not be used in binary fashion and should be understood in the context of pre-existing risk predictors, patient's ethnicity, cost of the test, patient life-expectancy, and patient goals. There are more recent diagnostic tools such as multi-parametric magnetic resonance imaging, polygenic single-nucleotide panels, IsoPSA, and miR Sentinel tests that are promising in the realm of prostate cancer screening and need to be investigated further to be considered a consensus reflexive test in the setting of prostate cancer screening.
. [J]. Asian Journal of Urology, 2021, 8(4): 343-353.
Edward K. Chang,Adam J. Gadzinski,Yaw A. Nyame. Blood and urine biomarkers in prostate cancer: Are we ready for reflex testing in men with an elevated prostate-specific antigen?. Asian Journal of Urology, 2021, 8(4): 343-353.
Shoag JE, Nyame YA, Gulati R, Etzioni R, Hu JC. Reconsidering the trade-offs of prostate cancer screening. N Engl J Med 2020; 382:2465e8.
[2]
Welch HG, Albertsen PC. Reconsidering prostate cancer mor-talitydthe future of PSA screening. N Engl J Med 2020; 382:1557e62.
[3]
Loeb S, Bjurlin MA, Nicholson J, Tammela TL, Penson DF, Carter HB, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014; 65:1046e55.
[4]
Mahal BA, Butler S, Franco I, Spratt DE, Rebbeck TR, D’Amico AV, et al. Use of active surveillance or watchful waiting for low-risk prostate cancer and management trends across risk groups in the United States, 2010-2015. J Urol 2019; 202:451e2.
[5]
Cooperberg MR, Carroll PR. Trends in management for pa-tients with localized prostate cancer, 1990-2013. J Am Med Assoc 2015; 314:80e2.
[6]
Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, et al. Early detection of prostate cancer: AUA guideline. J Urol 2013; 190:419e26.
[7]
Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, Davidson KW, et al. Screening for prostate can-cer: US preventive Services Task Force recommendation statement. JAMA 2018; 319:1901e13.
[8]
Zhang K, Bangma CH, Roobol MJ. Prostate cancer screening in Europe and Asia. Asian J Urol 2017; 4:86e95.
[9]
Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol 2012; 61:1079e92.
[10]
Kimura T, Egawa S. Epidemiology of prostate cancer in Asian countries. Int J Urol 2018; 25:524e31.
[11]
Kitagawa Y, Namiki M. Prostate-specific antigen-based popula-tion screening for prostate cancer: Current status in Japan and future perspective in Asia. Asian J Androl 2015; 17:475e80.
[12]
Borghesi M, Ahmed H, Nam R, Schaeffer E, Schiavina R, Taneja S, et al. Complications after systematic, random, and image-guided prostate biopsy. Eur Urol 2017; 71:353e65.
[13]
Fawcett T. An introduction to ROC analysis. Pattern Recogn Lett 2006; 27:861e74.
[14]
Fitzgerald M, Saville BR, Lewis RJ. Decision curve analysis. JAMA 2015; 313:409e10.
[15]
Siddiqui MM, Rais-Bahrami S, Turkbey B, George AK, Rothwax J, Shakir N, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015; 313:390e7.
[16]
Vickers AJ, van Calster B, Steyerberg EW. A simple, step-by-step guide to interpreting decision curve analysis. Diagnostic Progn Res 2019;3:18. https://doi.org/10.1186/s41512-019-0064-7.
[17]
Van Calster B, Wynants L, Verbeek JFM, Verbakel JY, Christodoulou E, Vickers AJ, et al. Reporting and interpreting decision curve analysis: A guide for investigators. Eur Urol 2018; 74:796e804.
[18]
Vickers AJ, Elkin EB. Decision curve analysis: A novel method for evaluating prediction models. Med Decis Making 2006; 26:565e74.
[19]
Ankerst DP, Hoe?er J, Bock S, Goodman PJ, Vickers A, Hernandez J, et al. Prostate cancer prevention trial risk calculator 2.0 for the prediction of low- vs. high-grade pros-tate cancer. Urology 2014; 83:1362e8.
[20]
Foley RW, Maweni RM, Gorman L, Murphy K, Lundon DJ, Durkan G, et al. European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculators significantly outper-form the Prostate Cancer Prevention Trial (PCPT) 2.0 in the prediction of prostate cancer: A multi-institutional study. BJU Int 2016; 118:706e13.
[21]
Chen R, Xie L, Xue W, Ye Z, Ma L, Gao X, et al. Development and external multicenter validation of Chinese Prostate Can-cer Consortium prostate cancer risk calculator for initial prostate biopsy. Urol Oncol Semin Orig Investig 2016;34:416. e1e7. https://doi.org/10.1016/j.urolonc.2016.04.004.
[22]
Park JY, Yoon S, Park MS, Choi H, Bae JH, Moon DG, et al. Development and external validation of the Korean prostate cancer risk calculator for high-grade prostate cancer: Com-parison with two western risk calculators in an asian cohort. PloS One 2017; 12:1e11.
[23]
Center for Medicare and Medicaid Services. Medicare clinical laboratory fee Schedule 2021. 2021. https://www.cms.gov/medicaremedicare-fee-service-paymentclinicallabfeeschedclinical-laboratory-fee-schedule-files/21clabq1. [Accessed 12 January 2021].
[24]
He B-M, Chen R, Sun T-Q, Yang Y, Zhang C-L, Ren S-C, et al. Prostate cancer risk prediction models in Eastern Asian pop-ulations: Current status, racial difference, and future di-rections. Asian J Androl 2020; 22:158.
doi: 10.4103/aja.aja_55_19
[25]
Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/mL prostate specific antigen range. J Urol 2011; 185:1650e5.
[26]
Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, et al. The prostate health index selectively identifies clinically significant prostate cancer. J Urol 2015; 193:1163e9.
[27]
Boegemann M, Stephan C, Cammann H, Vincendeau S, Houlgatte A, Jung K, et al. The percentage of prostate-specific antigen (PSA) isoform [-2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men. BJU Int 2016; 117:72e9.
[28]
Le BV, Griffin CR, Loeb S, Carvalhal GF, Kan D, Baumann NA, et al. [-2]Proenzyme prostate specific antigen is more ac-curate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. J Urol 2010; 183:1355e9.
[29]
Loeb S, Shin SS, Broyles DL, Wei JT, Sanda M, Klee G, et al. Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU Int 2017; 120:61e8.
[30]
Foley RW, Gorman L, Sharifi N, Murphy K, Moore H, Tuzova AV, et al. Improving multivariable prostate cancer risk assessment using the Prostate Health Index. BJU Int 2016; 117:409e17.
[31]
Chiu PKF, Roobol MJ, Teoh JY, Lee WM, Yip SY, Hou SM, et al. Prostate health index (PHI) and prostate-specific antigen (PSA) predictive models for prostate cancer in the Chinese population and the role of digital rectal examination-estimated prostate volume. Int Urol Nephrol 2016; 48:1631e7.
[32]
Chiu PKF, Ng CF, Semjonow A, Zhu Y, Vincendeau S, Houlgatte A, et al. A multicentre evaluation of the role of the prostate health index (PHI) in regions with differing preva-lence of prostate cancer: Adjustment of PHI reference ranges is needed for European and asian settings (figure presented). Eur Urol 2019; 75:558e61.
[33]
Parekh DJ, Punnen S, Sjoberg DD, Asroff SW, Bailen JL, Cochran JS, et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol 2015; 68:464e70.
[34]
Benchikh A, Savage C, Cronin A, Salama G, Villers A, Lilja H, et al. A panel of kallikrein markers can predict outcome of prostate biopsy following clinical work-up: An independent validation study from the European Randomized Study of Prostate Cancer screening, France. BMC Cancer 2010;10:635. https://doi.org/10.1186/1471-2407-10-635.
[35]
Bryant RJ, Sjoberg DD, Vickers AJ, Robinson MC, 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 2015;107: djv095 https://doi.org/10.1093/jnci/djv095.
[36]
Darst BF, Chou A, Wan P, Pooler L, Sheng X, Vertosick EA, et al. The four-kallikrein panel is effective in identifying aggressive prostate cancer in a multiethnic population. Cancer Epidemiol Biomark Prev 2020; 29:1381e8.
[37]
Bussemakers MJG, Van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HFM, Schalken JA, et al. DD3: A new prostate-specific gene, highly overexpressed in prostate cancer. Can-cer Res 1999; 59:5975e9.
[38]
Tosoian JJ, Ross AE, Sokoll LJ, Partin AW, Pavlovich CP. Uri-nary biomarkers for prostate cancer. Urol Clin 2016; 43:17e38.
[39]
Crawford ED, Rove KO, Trabulsi EJ, Qian J, Drewnowska KP, Kaminetsky JC, et al. Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate spe-cific antigen: A prospective study of 1962 cases. J Urol 2012; 188:1726e31.
[40]
Gadzinski AJ, Cooperberg MR. Prostate cancer makers? Cancer Treat Res 2018; 175:55e86.
[41]
Scattoni V, Lazzeri M, Lughezzani G, De Luca S, Passera R, Bollito E, et al. Head-to-head comparison of prostate health index and urinary PCA3 for predicting cancer at initial or repeat biopsy. J Urol 2013; 190:496e501.
[42]
Hansen J, Auprich M, Ahyai SA, De La Taille A, Van Poppel H, Marberger M, et al. Initial prostate biopsy: Development and internal validation of a biopsy-specific nomogram based on the prostate-cancer antigen 3 assay. Eur Urol 2013; 63:201e9.
[43]
Ferro M, Bruzzese D, Perdona` S, Marino A, Mazzarella C, Perruolo G, et al. Prostate health index (PHI) and prostate cancer antigen 3 (PCA3) significantly improve prostate cancer detection at initial biopsy in a total PSA range of 2e10 ng/mL. PloS One 2013; 8:1e7.
[44]
Ruffion A, Devonec M, Champetier D, Decaussin-Petrucci M, Rodriguez-Lafrasse C, Paparel P, et al. PCA3 and PCA3-based nomograms improve diagnostic accuracy in patients under-going first prostate biopsy. Int J Mol Sci 2013; 14:17767e80.
[45]
Chevli KK, Duff M, Walter P, Yu C, Capuder B, Elshafei A, et al. Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy. J Urol 2014; 191:1743e8.
[46]
Wang FB, Chen R, Ren SC, Shi XL, Zhu YS, Zhang W, et al. Prostate cancer antigen 3 moderately improves diagnostic accuracy in Chinese patients undergoing first prostate biopsy. Asian J Androl 2017; 19:238e43.
[47]
Ochiai A, Okihara K, Kamoi K, Oikawa T, Shimazui T, Murayama SI, et al. Clinical utility of the prostate cancer gene 3 (PCA3) urine assay in Japanese men undergoing prostate biopsy. BJU Int 2013; 111:928e33.
[48]
Wei JT, Feng Z, Partin AW, Brown E, Thompson I, Sokoll L, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol 2014; 32:4066e72.
[49]
McKiernan J, Donovan MJ, O’Neill V, Bentink S, Noerholm M, Belzer S, et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol 2016; 2:882e9.
[50]
McKiernan J, Donovan MJ, Margolis E, Partin A, Carter B, Brown G, et al. A prospective adaptive utility trial to validate performance of a novel urine exosome gene expression assay to predict high-grade prostate cancer in patients with prostate-specific antigen 2e10 ng/mL at initial biopsy. Eur Urol 2018; 74:731e8.
[51]
Donovan MJ, Noerholm M, Bentink S, Belzer S, Skog J, O’Neill V, et al. A molecular signature of PCA3 and ERG exo-somal RNA from non-DRE urine is predictive of initial prostate biopsy result. Prostate Cancer Prostatic Dis 2015; 18:370e5.
[52]
Leyten GHJM, Hessels D, Smit FP, Jannink SA, De Jong H, Melchers WJG, et al. Identification of a candidate gene panel for the early diagnosis of prostate cancer. Clin Cancer Res 2015; 21:3061e70.
[53]
Haese A, Trooskens G, Steyaert S, Hessels D, Brawer M, Vlaeminck-Guillem V, et al. Multicenter optimization and validation of a 2-gene mRNA urine test for detection of clin-ically significant prostate cancer before initial prostate bi-opsy. J Urol 2019; 202:256e62.
[54]
Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol 2016; 70:740e8.
[55]
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun X, et al. Recurrent fusion of TMPRSS2 and ETS transcrip-tion factor genes in prostate cancer. Science 2005; 310:644e8.
[56]
Salami SS, Schmidt F, Laxman B, Regan MM, Rickman DS, Scherr D, et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol Oncol Semin Orig Investig 2013; 31:566e71.
[57]
Tomlins SA, Day JR, Lonigro RJ, Hovelson DH, Siddiqui J, Kunju LP, et al. Urine TMPRSS2:ERG plus PCA3 for individual-ized prostate cancer risk assessment. Eur Urol 2016; 70:45e53.
[58]
Leyten GHJM, Hessels D, Jannink SA, Smit FP, De Jong H, Cornel EB, et al. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol 2014; 65:534e42.
[59]
Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, et al. TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Cauca-sian, African-American and Japanese patients. Prostate 2011; 71:489e97.
[60]
Nordström T, Vickers A, Assel M, Lilja H, Grönberg H, Eklund M. Comparison between the four-kallikrein panel and prostate health index for predicting prostate cancer. Eur Urol 2015; 68:139e46.
[61]
Seisen T, Rouprêt M, Brault D, Léon P, Cancel-Tassin G, Compérat E, et al. Accuracy of the prostate health index versus the urinary prostate-cancer antigen 3 score to predict overall and significant prostate cancer at initial biopsy. Pros-tate 2015; 75:103e11.
[62]
Wysock JS, Becher E, Persily J, Loeb S, Lepor H. Concordance and performance of 4Kscore and SelectMDx for informing de-cision to perform prostate biopsy and detection of prostate cancer. Urology 2020; 141:119e24.
[63]
Teoh JY-C, Leung C-H, Wang MH, Chiu PK-F, Yee C-H, Ng C-F, et al. The cost-effectiveness of prostate health index for prostate cancer detection in Chinese men. Prostate Cancer Prostatic Dis 2020; 23:615e21.
[64]
Nichol MB, Wu J, Huang J, DenHam D, Frencher SK, Jacobsen SJ. Cost-effectiveness of prostate health index for prostate cancer detection. BJU Int 2012; 110:353e62.
[65]
Voigt JD, Dong Y, Linder V, Zappala S. Use of the 4Kscore test to predict the risk of aggressive prostate cancer prior to prostate biopsy: Overall cost savings and improved quality of care to the us healthcare system. Rev Urol 2017; 19:1e10.
[66]
Govers TM, Caba L, Resnick MJ. Cost-effectiveness of urinary biomarker panel in prostate cancer risk assessment. J Urol 2018; 200:1221e6.
[67]
Sathianathen NJ, Kuntz KM, Alarid-Escudero F, Lawrentschuk NL, Bolton DM, Murphy DG, et al. Incorporating biomarkers into the primary prostate biopsy setting: A cost-effectiveness analysis. J Urol 2018; 200:1215e20.
[68]
National Comprehensive Cancer Network. Prostate Cancer Early Detection (Version 2.2020). https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. [Accessed 28 October 2020].
[69]
Elkhoury FF, Felker ER, Kwan L, Sisk AE, Delfin M, Natarajan S, et al. Comparison of targeted vs. systematic prostate biopsy in men who are biopsy naive: The prospective assessment of image registration in the diagnosis of prostate cancer (PAIR-EDCAP) study. JAMA Surg 2019; 154:811e8.
[70]
Sonn GA, Chang E, Natarajan S, Margolis DJ, Macairan M, Lieu P, et al. Value of targeted prostate biopsy using magnetic resonanceeultrasound fusion in men with prior negative bi-opsy and elevated prostate-specific antigen. Eur Urol 2014; 65:809e15.
[71]
Filson CP, Natarajan S, Margolis DJA, Huang J, Lieu P, Dorey FJ, et al. Prostate cancer detection with magnetic resonanceeultrasound fusion biopsy: The role of systematic and targeted biopsies. Cancer 2016; 122:884e92.
[72]
Alberts AR, Roobol MJ, Verbeek JFM, Schoots IG, Chiu PK, Osses DF, et al. Prediction of high-grade prostate cancer following multiparametric magnetic resonance imaging: Improving the rotterdam European randomized study of screening for prostate cancer risk calculators. Eur Urol 2019; 75:310e8.
[73]
Ahmed HU, Bosaily AE, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): A paired vali-dating confi rmatory study. Lancet 2017; 389:815e22.
[74]
Hsieh PF, Li WJ, Lin WC, Chang H, Chang CH, Huang CP, et al. Combining prostate health index and multiparametric mag-netic resonance imaging in the diagnosis of clinically significant prostate cancer in an Asian population. World J Urol 2020; 38:1207e14.
[75]
Druskin SC, Tosoian JJ, Young A, Collica S, Srivastava A, Ghabili K, et al. Combining Prostate Health Index density, magnetic resonance imaging and prior negative biopsy status to improve the detection of clinically significant prostate cancer. BJU Int 2018; 121:619e26.
[76]
Kim SJ, Vickers AJ, Hu JC. Challenges in adopting level 1 ev-idence for multiparametric magnetic resonance imaging as a biomarker for prostate cancer screening. JAMA Oncol 2018; 4:1663e4.
[77]
Westphalen AC, McCulloch CE, Anaokar JM, Arora S, Barashi NS, Barentsz JO, et al. Variability of the positive predictive value of PI-RADS for prostate MRI across 26 cen-ters: Experience of the society of abdominal radiology prostate cancer disease-focused panel. Radiology 2020; 296:76e84.
[78]
Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al. Association analyses of more than 140 000 men identify 63 new prostate cancer susceptibility loci. Nat Genet 2018; 50:928e36.
[79]
Fredsøe J, Koetsenruyter J, Vedsted P, Kirkegaard P, Væth M, Edwards A, et al. The effect of assessing genetic risk of prostate cancer on the use of PSA tests in primary care: A cluster randomized controlled trial. PLoS Med 2020;17: e1003033 https://doi.org/10.1371/journal.pmed.1003033.
[80]
Amos CI, Dennis J, Wang Z, Byun J, Schumacher FR, Gayther SA, et al. The oncoarray consortium: A network for understanding the genetic architecture of common cancers. Cancer Epidemiol Biomark Prev 2017; 26:126e35.
[81]
Conran C, Na R, Chen H, Jiang D, Lin X, Zheng S, et al. Popu-lation-standardized genetic risk score: The SNP-based method of choice for inherited risk assessment of prostate cancer. Asian J Androl 2016; 18:520e4.
[82]
Chen H, Liu X, Brendler CB, Ankerst DP, Leach RJ, Goodman PJ, et al. Adding genetic risk score to family history identifies twice as many high-risk men for prostate cancer: Results from the prostate cancer prevention trial. Prostate 2016; 76:1120e9.
[83]
Na R, Labbate C, Yu H, Shi Z, Fantus RJ, Wang CH, et al. Sin-gle-nucleotide polymorphism-based genetic risk score and patient age at prostate cancer diagnosis. JAMA Netw Open 2019;2:e1918145. https://doi.org/10.1001/jamanetworkopen.2019.18145.
[84]
Callender T, Emberton M, Morris S, Eeles R, Kote-Jarai Z, Pharoah PDP, et al. Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study. PLoS Med 2019;16:e1002998. https://doi.org/10.1371/journal.pmed.1002998.
[85]
Klein EA, Chait A, Hafron JM, Kernen KM, Manickam K, Stephenson AJ, et al. The single-parameter, structure-based IsoPSA assay demonstrates improved diagnostic accuracy for detection of any prostate cancer and high-grade prostate cancer compared to a concentration-based assay of total prostate-specific antigen: A preliminary repo. Eur Urol 2017; 72:942e9.
[86]
Stovsky M, Klein EA, Chait A, Manickam K, Stephenson AJ, Wagner M, et al. Clinical validation of IsoPSATM,a single parameter, structure based assay for improved detection of high grade prostate cancer. J Urol 2019; 201:1115e20.
[87]
Wang WLW, Sorokin I, Aleksic I, Fisher H, Kaufman RP, Winer A, et al. Expression of small noncoding RNAs in urinary exosomes classifies prostate cancer into indolent and aggres-sive disease. J Urol 2020; 204:466e75.
