DOI: 10.1002/bco2.230 RESEARCH LETTER A risk-organised model for clinically significant prostate cancer early detection Juan Morote 1,2,3 | Ángel Borque-Fernando 3 | Marina Triquell 1,2 | José M. Abascal 4,5 | Pol Servian 6 | Jacques Planas 1,2 | Olga Mendez 7 | Luis M. Esteban 8 | Enrique Tilla 1,2 1 Department of Urology, Vall d’Hebron Hospital, Barcelona, Spain 2 Department of Surgery, Universitat Autònoma de Barcelona, Barcelona, Spain 3 Department of Urology, Hospital Miguel Servet, IIS-Aragon, Zaragoza, Spain 4 Department of Urology, Parc de Salut Mar, Barcelona, Spain 5 Department of Surgery, Universitat Pompeu Fabra, Barcelona, Spain 6 Department of Urology, Hospital Germans Trias i Pujol, Badalona, Spain 7 Urology Biomedical Research Unit, Vall d’Hebron Research Institute, Barcelona, Spain 8 Department of Applied Mathematics, Escuela Universitaria Politécnica La Almunia, Universidad de Zaragoza, Zaragoza, Spain Correspondence Juan Morote, Department of Urology, Vall d’Hebron Hospital, Barcelona, Spain. Email: juan.morote@vallhebron.cat Funding information Instituto de Salut Carlos III (SP), Grant/Award Number: PI20/01666; European Union K E Y W O R D S : clinically significant, mpMRI, prostate cancer, risk-organised model Evidence that specific mortality of PCa decrease when clinically signifi- reporting with an updated version of PI-RADS, obtain a negative pre- cant PCa (csPCa) is early detected has moved the focus of PCa screen- dictive value of mpMRI that reaches up to 95%, which makes it possi- ing towards csPCa.1 This paradigm shift has occurred since the spread ble to avoid prostate biopsies in men with suspected PCa with a PI- of multiparametric magnetic resonance imaging (mpMRI), which allows RADS <3. MRI-targeted biopsies of suspicious lesions (PI-RADS ≥3) to avoid unnecessary prostate biopsies and overdetection of insignifi- improve the sensitivity of systematic biopsies for csPCa. However, cant PCa (iPCa) in a cost-effective way.2,3 However, because suspicion uncertain scenarios after mpMRI, having high rates of unnecessary of PCa remains based on elevated serum prostate-specific antigen biopsies and/or overdetection of iPCa, remain, and then PSA density (PSA) and/or abnormal digital rectal examination (DRE), there has been (PSAD), new markers and predictive models are recommended to an increased demand for mpMRI that cannot always be performed. In improve the selection of candidates for prostate biopsy.4 The experienced centres, biparametric MR has replaced mpMRI, reducing European Association of Urology currently recommends the design of scan time by a quarter and maintaining the reproducibility and accu- csPCa risk-organised models (ROMs) by sequencing available tools to racy of the Prostate Imaging Reporting and Data System (PI-RADS).1 reduce the demand of mpMRI exams, and unnecessary prostate biop- The recommendation of prostate biopsy is currently made sies ones mpMRI is performed.1 Because prostate volume is a power- according to the PI-RADS category. Experienced radiologists, ful predictor of csPCa and usually transrectal ultrasound is not performed to assess prostate volume before mpMRI, its assessment Juan Morote and Ángel Borque-Fernando have equal contribution as first author. through DRE-prostate volume category is now recommended.5 There Luis M. Esteban and Enrique Tilla have equal contribution as last author. is also evidence that men with serum PSA higher than 10 ng/mL and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company. 420 wileyonlinelibrary.com/journal/bco2 BJUI Compass. 2023;4:420–422. MOROTE ET AL. 421 abnormal DRE do not benefit from MRI-targeted biopsies, since sys- A series of 946 men with serum PSA > 3.0 ng/mL and/or abnor- tematic biopsies can detect all existing csPCa.6 The Barcelona-risk cal- mal DRE was recruited prospectively in two academic centres of cities culator 1 (BCN RC-1) has been developed and externally validated to from the Barcelona metropolitan area (PSM and GTiP), between 7 individualise the risk of csPCa to avoid the demand of mpMRI exams, January 1 of 2018 and December 31 of 2021. This series was inde- as well as the BCN-RC 2 to predict the risk of csPCa after mpMRI and pendent from those for the development of BCN-RC 1 and BCN-RC avoid unnecessary biopsies.7 Both risk calculators are available at 2 recruited at VHH, between January 1 of 2016 and December 31 of https://mripcaprediction.shinyapps.io/MRIPCaPrediction/. 2019.7,8 All men were scheduled to 3-T mpMRI and two- to four-core The present study aims to compare the current standard transrectal ultrasound (TRUS) cognitive MRI-targeted biopsies to PI- approach for early detection of csPCa, based on MRI-targeted biop- RADSv.2 ≥ 3 lesions and 12-core TRUS systematic biopsy; 12-core sies when PI-RADS lesions ≥3 and systematic biopsy,1 with a ROM TRUS systematic biopsy was performed when PI-RADSv.2 < 3. This designed to avoiding mpMRI exams in men with serum PSA over than project was approved by the institutional ethics committee of VHH 10.0 ng/mL and abnormal DRE, in addition to rule out mpMRI exams (PRAG-317/2017), and the analysis was performed on anonymised when the risk of csPCa from the BCN-RC 1 is lower than 12%.6,7 databases. CsPCa, defined as the International Society of Uro- Once mpMRI is performed, prostate biopsy will be scheduled in men pathology grade group 2 or higher, was detected in 386 men (40.8%). having a risk of csPCa from the BCN-RC 2 higher than 4%.8 The selec- The median age of participants was 67 years with an interquartile tion of proposed thresholds was made to avoid missing no more than range (IQR) between 61 and 75. The median serum PSA was 10% of csPCa detected. The 95% csPCa sensitivity thresholds of BCN 7.2 ng/mL (IQR: 5.5–10.9), 32.5% of participants had abnormal DRE, RC-1 and BCN RC-2, in those men in whom they were applied, were and 31% had previous negative prostate biopsy. CsPCa was detected selected. A probability analysis of avoiding mpMRI exams and pros- in 17.9% of the 235 men with PI-RADS <3 (24.8%); in 20.4% of the tate biopsies as well as missed csPCa has been performed. 301 men with PI-RADS 3 (21.2%); in 51.9% of the men with PI-RADS F I G U R E 1 Flow chart description of standard approach of csPCa, and the proposed risk-organised model, with intermediate and overall results according to rule out mpMRI exams, avoided prostate biopsies and missed csPCa detection. Data are expressed in number and (%) of all MRI exams and prostate biopsies performed and csPCa detected. Abbreviations: BCN, Barcelona; csPCa, clinically significant PCa; DRE, digital rectal examination; mpMRI, multiparametric magnetic resonance imaging; PB, prostate biopsies; PCa, prostate cancer; PI-RADS, Prostate Imaging Report and Data System; PSA, prostate-specific antigen; RC, risk calculator. aProposed thresholds. 422 MOROTE ET AL. 4 (12.6%); and 84% of those with PI-RADS 5 (12.6%). In the subset of CONFLIC T OF INTER E ST STATEMENT 124 men with serum PSA > 10.0 ng/mL and abnormal DRE, csPCa The authors have no conflict of interest to declare. was detected in 106 (85.6%). The probability analyses of the standard approach and the pro- ORCID posed ROM are presented in Figure 1. The standard approach Juan Morote https://orcid.org/0000-0002-2168-323X required mpMRI in all participants, 235 (24.8%) of prostate biopsies Ángel Borque-Fernando https://orcid.org/0000-0003-0178-4567 were avoided in those men with PI-RADS <3, and 42 (10.9%) of over- Enrique Tilla https://orcid.org/0000-0001-9401-0872 all csPCa detected were missed. Among the 711 participants biopsied (75.2%) csPCa was detected in 344 (48.4%). The proposed ROM ini- RE FE RE NCE S tially ruled out mpMRI in 124 men with serum PSA > 10.0 ng/mL and 1. Van Poppel H, Hogenhout R, Albers P, van den Bergh RCN, abnormal DRE (13.1% of all participants), in whom systematic biopsies Barentsz JO, Roobol MJ. A European model for an organised risk- stratified early detection Programme for prostate cancer. Eur Urol identified all 106 csPCa detected, which represented 27.5% of all Oncol. 2021;4(5):731–9. https://doi.org/10.1016/j.euo.2021.06.006 csPCa detected. The BCN-RC 1 ruled out mpMRI exams in 167 men 2. Schoots IG, Padhani AR, Rouvière O, Barentsz JO, Richenberg J. (17.7%), missing 13 csPCa (3.4%). After mpMRI, performed in Analysis of magnetic resonance imaging-directed biopsy strategies 655 men (69.2%), the BCN RC-2 ruled out prostate biopsy in for changing the paradigm of prostate cancer diagnosis. Eur Urol Oncol. 2020;3(1):32–41. https://doi.org/10.1016/j.euo.2019.10.001 100 men, in whom 13 detected csPCa were missed (3.4%). Among the 3. Donato P, Morton A, Yaxley J, Teloken PE, Coughlin G, Esler R, et al. 555 men finally biopsied (63.3%), csPCa was detected in 254 (45.8%). Improved detection and reduced biopsies: The effect of a multipara- The ROM would rule out 30.8% of mpMRI exams, and 28.2% of pros- metric magnetic resonance imaging-based triage prostate cancer tate biopsies, whereas 6.7% of overall csPCa would be undetected. pathway in a public teaching hospital. World J Urol. 2020;38(2): 371–9. https://doi.org/10.1007/s00345-019-02774-y The proposed ROM was able to rule out almost one-third of 4. Osses DF, Roobol MJ, Schoots IG. Prediction medicine: Biomarkers, mpMRI exams and the percentage of saved biopsies increased from risk calculators and magnetic resonance imaging as risk stratification the 24.8% observed with the standard approach to the 28.2%, tools in prostate cancer diagnosis. Int J Mol Sci. 2019;20(7):1637. whereas the percentage of undetected csPCa decreased from 10.9 to https://doi.org/10.3390/ijms20071637 6.7 respectively. Remmers et al. have recently reported the results 5. Roobol MJ, van Vugt HA, Loeb S, Zhu X, Bul M, Bangma CH, et al. Prediction of prostate cancer risk: The role of prostate volume and with an ROM based on sequencing the Rotterdam RC-3 and the Rot- digital rectal examination in the ERSPC risk calculators. Eur Urol. terdam MRI-RC in the MRI arm of the PRECISION trial, which was 2012;61(3):577–83. https://doi.org/10.1016/j.eururo.2011.11.012 carried out in biopsy-naïve men. After recalibration and adjustment of 6. Morote J, Celma A, Roche S, de Torres IM, Mast R, Semedey ME, csPCa thresholds in both predictive models, this ROM was able to rule et al. Who benefits from multiparametric magnetic resonance imag- ing after suspicion of prostate cancer. Eur Urol Oncol. 2019;2(6): out 13% of mpMRI exams, decreasing the number of prostate biopsies 664–9. https://doi.org/10.1016/j.euo.2018.11.009 in 9% and missing 8.5% of csPCa detected in the 134 men with PI- 7. Morote J, Borque-Fernando Á, Triquell M, Campistol M, Celma A, RADS ≥3 in whom MRI-targeted biopsies of suspicious lesions and Regis L, et al. A clinically significant prostate cancer predictive model systematic biopsy were performed.9 using digital rectal examination prostate volume category to stratify initial prostate cancer suspicion and reduce magnetic resonance The present study confirms the effectiveness of the proposed imaging demand. Cancers (Basel). 2022;14(20):5100. https://doi.org/ ROM to improve the early detection of csPCa by reducing the 10.3390/cancers14205100 demand of mpMRI exams and unnecessary prostate biopsies. The 8. Morote J, Borque-Fernando A, Triquell M, Celma A, Regis L, missing rate of csPCa of the standard approach that avoids systematic Escobar M, et al. The Barcelona predictive model of clinically signifi- cant prostate cancer. Cancers (Basel). 2022;14(6):1589. https://doi. biopsy in men with negative mpMRI also decreased. The main limita- org/10.3390/cancers14061589 tion for the use of the proposed ROM is the need of validation in the 9. Remmers S, Kasivisvanathan V, Verbeek JFM, Moore CM, populations where it will be implemented. Now, following the recom- Roobol MJ, ERSPC RSGPRECISIONIG. Reducing biopsies and mag- mendation of EAU, this ROM is ready to be used in the metropolitan netic resonance imaging scans during the diagnostic pathway of prostate cancer: Applying the Rotterdam prostate cancer risk calcula- area of Barcelona, and validation in Catalonia (Spain), a country with tor to the PRECISION trial data. Eur Urol Open Sci. 2022;36:1–8. seven and half million inhabitants, is ongoing. Ideally, a randomised https://doi.org/10.1016/j.euros.2021.11.002 trial would be necessary to generate high evidence level. AUTHOR CONTRIBUTIONS Juan Morote, Ángel Borque-Fernando and Luis M. Esteban conceptua- How to cite this article: Morote J, Borque-Fernando Á, lised the idea. Marina Triquell, José M. Abascal, Pol Servian, Jacques Triquell M, Abascal JM, Servian P, Planas J, et al. A risk- Planas, Olga Mendez and Enrique Tilla developed the concept. Juan organised model for clinically significant prostate cancer early Morote wrote the first draft of the manuscript. All authors were detection. BJUI Compass. 2023;4(4):420–2. https://doi.org/ involved in editing, critical review and final approval of the manuscript. 10.1002/bco2.230 ACKNOWLEDGEMEN TS The Instituto de Salut Carlos III (SP) and European Union financed this project, ref. PI20/01666.