cancers Article Comparative Analysis of PSA Density and an MRI-Based Predictive Model to Improve the Selection of Candidates for Prostate Biopsy Juan Morote 1,2, *,† , Angel Borque-Fernando 3,† , Marina Triquell 1 , Anna Celma 1 , Lucas Regis 1 , Richard Mast 4 , Inés M. de Torres 5,6 , María E. Semidey 5,6 , José M. Abascal 7 , Pol Servian 8 , Anna Santamaría 9 , Jacques Planas 1 , Luis M. Esteban 10,‡ and Enrique Trilla 1,2,‡ 1 Department of Urology, Vall d’Hebron Hospital, 08035 Barcelona, Spain; mtriquell@vhebron.net (M.T.); acelma@vhebron.net (A.C.); lregis@vhebron.net (L.R.); jplanas@vhebron.net (J.P.); etrilla@vhebron.net (E.T.) 2 Department of Surgery, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain 3 Department of Urology, Hospital Miguel Servet, IIS-Aragon, 50009 Zaragoza, Spain; aborque@comz.org 4 Department of Radiology, Vall d’Hebron Hospital, 08035 Barcelona, Spain; rmast@vhebron.net 5 Department of Pathology, Vall d´Hebron Hospital, 08035 Barcelona, Spain; itorres@vhebron.net (I.M.d.T.); mesemidey@vhebron.net (M.E.S.) 6 Department of Morphological Sciences, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain 7 Department of Urology, Parc de Salut Mar, Universitat Pompeu Fabra, 08003 Barcelona, Spain; jmabascalj@gmail.com 8 Department of Urology, Hospital Germans Trias i Pujol, 08035 Badalona, Spain; pservian.germantrias@gencat.cat 9 Vall d´Hebron Research Institute, 08035 Barcelona, Spain; anna.santamaria@vhir.org 10 Department of Applied Mathematics, Escuela Universitaria Politécnica La Almunia, Citation: Morote, J.; Universidad de Zaragoza, 50100 Zaragoza, Spain; lmeste@unizar.es * Correspondence: jmorote@vhebron.net; Tel.: +34-932746009 Borque-Fernando, A.; Triquell, M.; † These authors contribute equally as co-first authors. Celma, A.; Regis, L.; Mast, R.; de ‡ These authors contribute equally as co-last authors. Torres, I.M.; Semidey, M.E.; Abascal, J.M.; Servian, P.; et al. Comparative Simple Summary: Magnetic resonance imaging (MRI)-associated prostate-specific antigen density Analysis of PSA Density and an MRI-Based Predictive Model to (mPSAD) and MRI predictive models have been proposed for improving the selection of candidates Improve the Selection of Candidates for prostate biopsy among men with suspected prostate cancer (PCa). While the calculation of for Prostate Biopsy. Cancers 2022, 14, mPSAD only requires a simple division, the individual risk assessment of PCa using the available 2374. https://doi.org/10.3390/ risk calculators is also a swift process. We aim to compare the clinical usefulness of mPSAD and cancers14102374 an MRI predictive model that utilises the same predictors as the recently developed and externally validated Barcelona MRI predictive model (MRI-PMbdex). Academic Editor: David Wong Received: 6 April 2022 Abstract: This study is a head-to-head comparison between mPSAD and MRI-PMbdex. The MRI- Accepted: 9 May 2022 PMbdex was created from 2432 men with suspected PCa; this cohort comprised the development and Published: 11 May 2022 external validation cohorts of the Barcelona MRI predictive model. Pre-biopsy 3-Tesla multiparametric Publisher’s Note: MDPI stays neutral MRI (mpMRI) and 2 to 4-core transrectal ultrasound (TRUS)-guided biopsies for suspicious lesions with regard to jurisdictional claims in and/or 12-core TRUS systematic biopsies were scheduled. Clinically significant PCa (csPCa), defined published maps and institutional affil- as Gleason-based Grade Group 2 or higher, was detected in 934 men (38.4%). The area under the iations. curve was 0.893 (95% confidence interval [CI]: 0.880–0.906) for MRI-PMbdex and 0.764 (95% CI: 0.774–0.783) for mPSAD, with p < 0.001. MRI-PMbdex showed net benefit over biopsy in all men when the probability of csPCa was greater than 2%, while mPSAD did the same when the probability of csPCa was greater than 18%. Thresholds of 13.5% for MRI-PMbdex and 0.628 ng/mL2 for mPSAD Copyright: © 2022 by the authors. had 95% sensitivity for csPCa and presented 51.1% specificity for MRI-PMbdex and 19.6% specificity Licensee MDPI, Basel, Switzerland. for mPSAD, with p < 0.001. MRI-PMbdex exhibited net benefit over mPSAD in men with prostate This article is an open access article distributed under the terms and imaging report and data system (PI-RADS) <4, while neither exhibited any benefit in men with conditions of the Creative Commons PI-RADS 5. Hence, we can conclude that MRI-PMbdex is more accurate than mPSAD for the proper Attribution (CC BY) license (https:// selection of candidates for prostate biopsy among men with suspected PCa, with the exception of creativecommons.org/licenses/by/ men with a PI-RAD S 5 score, for whom neither tool exhibited clinical guidance to determine the 4.0/). need for biopsy. Cancers 2022, 14, 2374. https://doi.org/10.3390/cancers14102374 https://www.mdpi.com/journal/cancers Cancers 2022, 14, 2374 2 of 22 Keywords: prostate-specific antigen density; predictive model; clinically significant prostate cancer 1. Introduction Early detection of clinically significant prostate cancer (csPCa) decreases the specific mortality of PCa [1]. The classic approach of PCa detection based on systematic biopsies after PCa suspicion, has been disapproved due to the high rates of unnecessary biopsies and the over detection of insignificant tumours (iPCa) [2–5]. While PCa suspicion continues to be based on serum prostate-specific antigen (PSA) elevation or abnormal digital rectal examination (DRE), the detection of csPCa has improved since the introduction of multi- parametric magnetic resonance imaging (mpMRI) and guided biopsies [6,7]. Nevertheless, there remain uncertain scenarios in which a high rate of unnecessary biopsies and over detection of iPCa occur [8,9]. The current high negative predictive value of mpMRI enables clinicians to avoid systematic biopsies in men with prostate imaging report and data system (PI-RADS) < 3; however, this approach may fail to detect 5–20% of existing csPCa in men with a negative mpMRI [10–12]. Contrarily, clinicians usually recommend prostate biopsy for men with PI-RADS > 3, as csPCa is usually detected approximately at a rate of 50–60% for men with PI-RADS 4, and up to 95% for men with PI-RADS 5 [13–15]. PI-RADS 3 re- mains the most uncertain scenario, in which csPCa usually does not reach 20% and in which more than 50% of the biopsied lesions reflect iPCa [9,15]. Prostate-specific antigen den- sity (PSAD), MRI-based predictive models (MRI-PM), and modern markers are currently recommended for improving the selection of candidates for prostate biopsy [6,7,16]. PSAD is a classic tool that improves the specificity of serum PSA [17]. However, PSAD can be strengthened by pre-biopsy MRI (mPSAD), which yields a more accurate prostate volume at no additional cost [18]. mPSAD has been analysed in overall popula- tions of men to enhance the detection of csPCa in relation to the PI-RADS score [19–22]. MRI-PMs are also effective tools. However, few MRI-PMs have been developed from the latest versions of PI-RADS; furthermore, external validation should be performed before their use. Easily accessible risk calculators (RCs) are essential for avoiding nomograms, which are cumbersome and time-consuming [23–37]. Recently, the Barcelona MRI-PM was developed from the following independent predictors: PI-RADS score v.2.0, age, serum PSA, DRE, PCa family history, type of biopsy (initial vs. repeat), and MRI-derived prostate volume. External validation was carried out in the same metropolitan area, and a web-RC is freely available at https://mripcaprediction.shinyapps.io/MRIPCaPrediction/ (accessed on 5 March 2022). For the first time, the performance of an MRI-PM has been analysed with regard to PI-RADS categories, showing a net benefit over biopsy for all men in each PI-RADS < 4. The designed RC also incorporates the novel option of selecting the csPCa probability threshold [38], which may facilitate further external validation [15] and im- prove the model’s performance in specific PI-RADS categories [39]. Furthermore, modern markers can also be helpful; however, they are expensive and require the procurement of new samples of blood or urine, usually after prostate massage [40]. Four-Kallikrein test (4K) [41–45], the Prostate Health Index (PHI) [46–48], SelectMDx [49–52], Proclarix [52,53], and the combination of multiple markers have improved the prognostic performance of mpMRI [30]. This study aims to compare the clinical usefulness of mPSAD and MRI-PMbdex for the proper selection of candidates for prostate biopsy in a sizable, multicentre population of men with suspected PCa, according to PI-RADS categories. 2. Materials and Methods 2.1. Design, Setting and Participants A head-to-head comparison of mPSAD and MRI-PMbdex was designed from a multi- centre trial conducted in the metropolitan area of Barcelona. The trial involved 2432 men with suspected PCa due to a serum PSA > 3.0 ng/mL or an abnormal DRE. MRI-PMbdex Cancers 2022, 14, 2374 3 of 22 was created from the development cohort of 1486 men studied at Vall d’Hebron Hospital (VHH) and the external validation cohort of 946 men from Parc de Salut Mar (PSM) as well as Hospital Germans Trias i Pujol (GTiPH). This study was conducted between January 1, 2006, and 31 December 2019 [38]. Pre-biopsy 3-Tesla mpMRI and guided or system- atic prostate biopsies were always performed. Men undergoing 5-α reductase inhibitor treatment due to symptomatic benign prostatic hyperplasia, having a previous diagnosis of PCa, exhibiting isolated atypical small acinar proliferation, and exhibiting high-grade prostatic intraepithelial neoplasia with atypia were excluded. Furthermore, written consent for prostate biopsy was obtained from all participants, and the project was approved by the institutional review board of VHH (PRAG-317/2017). 2.2. Intervention The development of MRI-PMbdex and the individual generation of csPCa likelihood was expressed as percentages ranging from 0 to 100%. mPSAD (ng/mL2 ) was calculated from the pre-biopsy serum PSA and the prostate volume reported in the pre-biopsy MRI, and individual generation of csPCa likelihood was expressed as percentages ranging from 0 to 100%. 2.3. MRI Technique and Evaluation Magnetic resonance scans were acquired on 3-Tesla scanners with a standard surface phased-array coil. Magnetom Trio (Siemens Corp., Erlangen, Germany) equipment was used in VHH, Diamond Select Achieva (Phillips Corp., Eindoven, The Nederland) in PSM, and Nova Dual (Phillips Corp., Eindoven, Nederland) in GTiPH. The acquisition protocol included T2-weighted imaging (T2W), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) imaging, in accordance with the European Society of Urogenital Radiology guidelines [54]. In each institution, an expert radiologist, with over five years of experience and over 300 mpMRI reported per year, analysed the images and reported them according to PI-RADS v2.0, using a 5-point likelihood scale for csPCa [55]. Complex cases were reviewed by two expert radiologists. 2.4. Prostate Biopsy Procedure All men from the participant institutions underwent 2 to 4-core mpMRI-TRUS cog- nitive fusion-guided biopsies of suspicious lesions and 12-core TRUS systematic biopsies when the PI-RADS reported in the pre-biopsy mpMRI was 3 or higher, while 12-core TRUS systematic biopsies were performed when the PI-RADS was lower than 3 [56]. In each institution, the biopsies were performed by an experienced urologist, with over five years of experience and who had performed over 300 biopsies per year, using a BK Focus 400 ultrasound scanner (BK Medical Inc. Herlev, Denmark) in VHH, Siemens Acu- son 150 (Siemens Inc., Erlangen, Germany) in PSM, and a Sonolite Antares (Siemens Inc., Erlangen, Germany) in GTiPH. 2.5. Pathologic Analysis and csPCa Definition The biopsy samples were sent separately to each pathology department, where an expert uro-pathologist analysed the biopsy specimens and, after identifying the PCa, reported the International Society of Uro-Pathology (ISUP) Gleason-based Grade Group (GG) [57]. Complex cases were analysed by two expert uro-pathologists. Any ISUP-GGG ≥ 2 was defined as csPCa. 2.6. Endpoint Measurements The endpoint measurements were the rates of detected csPCa and missed csPCa, in addition to the frequency of avoided prostate biopsies and iPCa. Cancers 2022, 14, 2374 4 of 22 2.7. Statistical Analysis The reporting recommendations for tumour marker prognostic studies (REMARK) [58] and the update of standards for reporting diagnostic accuracy studies (STARD 2015) [59] were followed. Medians and interquartile ranges (25–75 percentiles) were used to describe the quantitative variables, and rates were used to describe the qualitative variables. The MRI-PMbdex individual likelihoods of csPCa were generated from the logistical regression analysis performed from the included independent predictors of the Barcelona MRI-PM [38]. The mPSAD individual likelihoods of csPCa were generated from the logistic regression analysis performed from the following independent predictors: PI-RADS score and mP- SAD. The chi-square and Mann–Whitney tests were used to find associations between the variables. Receiver operating characteristic curves (ROC) and areas under the curve (AUC) were used to analyse the efficacy of mPSAD and MRI-PMbdex for csPCa detection; the DeLong test was conducted to compare the AUCs [60,61]. Furthermore, decision curve analysis (DCA) was used to discern the net benefits of mPSAD and MRI-PMbdex over performing biopsies in all men [62]. The thresholds of mPSAD and MRI-PMbdex were se- lected from the 95% sensitivity for csPCa, and the specificities were analysed and compared. The performances were analysed based on sensitivity, specificity, negative and positive predictive values, accuracy, avoidable biopsies, and potentially missed csPCa. In addition, odds ratios and 95% confidence intervals (CI) were assessed. Tests with two-sided p < 0.05 were considered statistically significant. The statistical analyses were computed using the R programming language v.4.0.3 (The R Foundation for Statistical Computing, Vienna, Austria), and SPSS v.25 (IBM, Statistical Package for Social Sciences, San Francisco, CA, USA) was used. 3. Results 3.1. Characteristics of the Study Population The characteristics of the entire population are summarised in Table 1. A median age of 68 years, serum PSA of 6.5 ng/mL, and prostate volume of 55 cm3 can be observed. The DRE was abnormal in 25% of the men; 28% were scheduled to repeat prostate biopsies, and 6.6% had PCa family history. PCa was diagnosed in 1214 men (49.9%), csPCa in 934 men (38.4%), and iPCa in 280 men (11.5%). The characteristics of the men according to PI-RADS categories as well as comparisons between each pair of consecutive PI-RADS are presented in Table 2. All characteristics showed differences regarding all PI-RADS categories (p < 0.001), with the exception of PCa family history, which showed a non-significant trend that ranged from 4.7% in men with PI-RADS 1 to 8.3% in men with PI-RADS 5 (p = 0.287). On comparing the characteristics of men with PI-RADS 1 and those with PI-RADS 2, it was found that only the frequency of repeat biopsies was significantly higher among the latter (19.4% vs. 34.1%; p < 0.001); all other characteristics were similar between the two categories. Between PI-RADS 2 and PI-RADS 3, the frequency of PCa detection increased from 20.3% to 30.5% (p = 0.028), while the frequency of csPCa and iPCa exhibited no significant increase. Men with PI-RADS 4 were significantly older than those with PI-RADS 3, had a higher PSA and mPSAD, had a lower prostate volume, and exhibited an abnormal DRE more often. The frequency of repeat biopsies, PCa family history, and iPCa detection was similar in both PI-RADS 3 and PI-RADS 4 categories; however, a significant increase in csPCa frequency was observed (p < 0.001). Moreover, in PI-RADS 5 compared with PI-RADS 4, the frequency of repeat biopsies and iPCa was low, while the frequency of csPCa and overall PCa increased significantly (p < 0.001). The frequency of repeat biopsies as well as iPCa also decreased, while the frequency of all PCa and csPCa increased significantly (p < 0.001). Cancers 2022, 14, 2374 5 of 22 Table 1. Characteristics of study population. Characteristic Measurement Number of cases 2432 Median age, years (IQR) 68 (62–73) Median total PSA, ng/mL (IQR) 6.5 (4.7–10.0) Abnormal DRE, n (%) 612 (25.2) Median prostate volume, ml (IQR) 55 (40–77) Median PSA density, ng/mL2 (IQR) 0.12 (0.08–0.20) Repeat biopsy, n (%) 681 (28.0) Family history of PCa, n (%) 161 (6.6%) PI-RADS, n (%) 1–2 550 (22.6) 3 645 (26.5) 4 841 (34.6) 5 396 (16.3) Overall PCa detection, n (%) 1214 (49.9) csPCa detection, n (%) 934 (38.4) iPCa detection, n (%) 280 (11.5) Table 2. Characteristics of study population according to the PI-RADS category. p p p Characteristic PI-RADS 1 Value PI-RADS 2 Value PI-RADS 3 p Value PI-RADS 4 Value PI-RADS 5 Number of cases 427 - 123 - 645 - 841 - 396 Median age, years 66 (60–72) =0.633 66 (60–71) =0.901 66 (60–71) <0.001 69 (63–74) <0.001 72 (66–76) (IQR) Median total PSA, =0.323 =0.644 <0.001 <0.001 9.4 ng/mL (IQR) 6.2 (4.5–8.7) 5.8 (4.4–8.4) 6.0 (4.4–8.4) 6.6 (4.8–9.5) (5.8–18.0) Abnormal DRE, n 59 (13.8) =0.818 18 (14.6) =0.497 80 (12.4) <0.001 216 (25.7) <0.001 239 (60.4) (%) Median PV, mL 63 (43–90) =0.666 60 (45–84) =0.833 63 (45–82) <0.001 50 (37–74) <0.001 46 (35–60) (IQR) Median PSAD, 0.10 0.11 0.10 0.13 0.21 =0.960 =0.797 <0.001 <0.001 ng/mL2 (IQR) (0.07–0.15) (0.07–0.15) (0.07–0.15) (0.08–0.20) (0.13–0.37) Repeat biopsy, n 83 (19.4) <0.001 42 (34.1) =0.631 206 (31.9) =0.860 271 (32.3) <0.001 78 (19.7) (%) Family history of 20 (4.7) =0.649 7 (5.7) =0.733 42 (6.5) =0.702 59 (7.0) =0.410 33 (8.3) PCa, n (%) Overall PCa 97 (22.7) =0.574 25 (20.3) =0.028 194 (30.5) <0.001 548 (65.2) <0.001 350 (88.4) detection, n (%) csPCa detection, n 42 (9.8) =0.865 13 (10.6) =0.081 109 (16.9) <0.001 439 (52.2) <0.001 331 (83.6) (%) iPCa detection, n 55 (12.9) =0.351 12 (9.8) =0.295 85 (13.2) =0.902 109 (13.0) <0.001 19 (4.8) (%) 3.2. Performance of mPSAD and MRI-PMbdex in the Entire Population The efficacy of MRI-PMbdex in detecting csPCa was higher than that of mPSAD. The AUC was 0.893 (95% CI: 0.880–0.906) for MRI-PMbdex and 0.763 (95% CI: 0.774–0.783) for mPSAD, with p < 0.001 (Figure 1A). The MRI-PMbdex exhibited net benefit over mPSAD and over biopsy of all men from a csPCa probability threshold of 2%, while mPSAD exhibited net benefit over biopsy of all men from a csPCa probability threshold of 18% (Figure 1B). Cancers 2022, 14, 2374 6 of 22 The thresholds of MRI-PMbdex and mPSAD with 95% sensitivity for csPCa were 13.5% and 0.628 ng/mL2 , respectively, and their corresponding specificities were 51.1% and 19.6%, respectively, with p < 0.001 (Table 3). MRI-PMbdex and mPSAD were able to avoid 33.4% and 14.0% of prostate biopsies, respectively, while missing 5% of csPCa (p < 0.001). In relation to the aggressiveness of missed csPCa, both mPSAD and MRI-PMbdex missed 2.4% of PCa with ISUP-GG ≥ 3 (22/934). Furthermore, mPSAD missed 1% of csPCa with ISUP-GG ≥ 4 (9/934), while MRI-PMbdex did not miss any of them. Table 3. Performance of mPSAD and MRI-PMbdex, with respective thresholds of 0.628 ng/mL2 and 13.5%, in the entire study population and grade groups of detected tumours. Parameter mPSAD MRI-PMbdex Sensitivity 887/934 (95.0) 887/934 (95.0) Specificity 294/2091 (19.6) 765/1498 (51.1) Negative predictive value 294/341 (86.2) 765/812 (94.2) Positive predictive value 887/2091 (42.4) 887/1620 (54.8) Accuracy 1181/2432 (48.6) 1652/2432 (67.9) Avoided biopsies 341/2432 (14.0) 812/2432 (33.4) Missed csPCa 47/934 (5%) 47/934 (5%) Odds ratios (95% CI) 4.61 (3.35–6.35) 19.70 (14.44–26.86) p Value <0.001 <0.001 GG 2 25 25 GG 3 13 22 GG 4 8 0 Cancers 2022, 14, x FOR PEER REVIEW 7 of 24 GG 5 1 0 Figure 1. Cont. Cancers 2022, 14, 2374 7 of 22 Cancers 2022, 14, x FOR PEER REVIEW 8 of 24 Figure 1. The ROC curves and AUCs show the efficacy of mPSAD (PSAD in the graphic) and MRI- Figure 1. ThePMbdex ROC curves and (model in the AUCs graphic)show the efficacy in detecting ofThe csPCa (A). mPSAD (PSAD DCAs show in the the net graphic) benefit of mPSADand MRI- PMbdex (model in the graphic) and MRI-PMbdex in detecting compared csPCa to performing (A).onThe biopsies DCAs all men showtothe according thenet benefit csPCa of mPSAD probability threshold (B). and MRI-PMbdex compared to performing biopsies on all men according to the csPCa probability threshold (B). The thresholds of MRI-PMbdex and mPSAD with 95% sensitivity for csPCa were 13.5% and 0.628 ng/mL2, respectively, and their corresponding specificities were 51.1% 3.3. Performance of mPSAD and 19.6%, and MRI-PMbdex respectively, According with p < 0.001 (Table to the PI-RADS 3). MRI-PMbdex Categories and mPSAD were able to Amongavoid 33.4%men the 550 and with 14.0% negative of prostate mpMRI biopsies, respectively, (PI-RADS < while missing 3), the 5% of csPCa (p MRI-PMbdex < exhibited 0.001). In relation to the aggressiveness of missed csPCa, both mPSAD and MRI-PMbdex an AUC of 0.824 (95% CI: 0.756–0.892), while mPSAD exhibited an AUC of 0.685 (95% CI: missed 2.4% of PCa with ISUP-GG ≥ 3 (22/934). Furthermore, mPSAD missed 1% of csPCa 0.610–0.761),with with p < 0.001 ISUP-GG (Figure ≥ 4 (9/934), 2A). while MRI-PMbdex MRI-PMbdex did notshowed miss any net benefit over mPSAD in of them. detecting csPCa (Figure 2B). Table 3. Performance The selected thresholdsof of mPSAD and MRI-PMbdex, MRI-PMbdex andwith respective mPSAD thresholds of provided 0.628 ng/mL2 and sensitivities of 67.3% 13.5%, in the entire study population and grade groups of detected tumours. and 90.9% as well as specificities of 87.7% and 21.4%, respectively, in men with PI-RADS < 3. The MRI-PMbdex avoided Parameter mPSAD whereas mPSAD 82.2% of prostate biopsies, MRI-PMbdex avoided 20.2%. However, the probabilities of missed csPCa were 32.7% and 9.1%,887/934 Sensitivity 887/934 (95.0) (95.0) for MRI-PMbdex and Specificity 294/2091 (19.6) 765/1498 (51.1) mPSAD, respectively. MRI-PMbdex did not detect 0.9% of PCa with ISUP-GG = 3 (5/55), Negative predictive value 294/341 (86.2) 765/812 (94.2) while mPSAD did not detect 0.2% (1/55) (Table Positive predictive value 4). 887/2091 (42.4) 887/1620 (54.8) Accuracy 1181/2432 (48.6) 1652/2432 (67.9) Table 4. Performance of mPSAD and MRI-PMbdex,341/2432 with respective thresholds of 0.628 2 Avoided biopsies (14.0) 812/2432 (33.4)ng/mL and 13.5%, in menMissed with PI-RADS csPCa < 3. 47/934 (5%) 47/934 (5%) Parameter mPSAD MRI-PMbdex Sensitivity 50/55 (90.9) 37/55 (67.3) Specificity 106/495 (21.4) 434/495 (87.7) Negative predictive value 106/111 (95.5) 434/452 (96.0) Positive predictive value 50/439 (11.4) 37/98 (67.3) Accuracy 156/550 (28.4) 471/550 (85.6) Cancers 2022, 14, x FOR PEER REVIEW 9 of 24 Cancers 2022, 14, 2374 8 of 22 Odds ratios (95% CI) 4.61 (3.35–6.35) 19.70 (14.44–26.86) p Value Table 4. Cont. <0.001 <0.001 GG 2 25 25 Parameter mPSAD MRI-PMbdex GG 3 13 22 Avoided biopsies 111/550 (20.2) 452/550 (82.2) GG 4 8 0 Missed csPCa 5/55 (9.1) 18/55 (32.7) GG 5 1 0 Odds ratio (95% CI) 2.27 (1.06–7.00) 14.62 (7.84–27, 29) p Value =0.033 <0.001 3.3. Performance of mPSAD and MRI-PMbdex According to the PI-RADS Categories GG 2 4 13 Among the 550 men with negative mpMRI (PI-RADS < 3), the MRI-PMbdex exhibited GG 3 1 5 an AUC of 0.824 (95% CI: 0.756–0.892), while mPSAD exhibited an AUC of 0.685 (95% CI: GG 4 0 0 0.610–0.761), with p < 0.001 (Figure 2A). MRI-PMbdex showed net benefit over mPSAD in GG 5 0 0 detecting csPCa (Figure 2B). Figure 2. Cont. Cancers 2022, 14, x FOR PEER REVIEW 10 of 24 Cancers 2022, 14, 2374 9 of 22 Figure 2. The ROC curves and AUCs show the efficacy of mPSAD (PSAD in the graphic) and MRI- Figure 2. The PMbdex ROCincurves (model and AUCs the graphic) showcsPCa in detecting the efficacy of mPSAD in men with PI-RADS (PSAD in the < 3 (A). The DCAsgraphic) and MRI- showing PMbdex the net benefit of mPSAD and MRI-PMbdex over performing biopsies on all men according to theshowing (model in the graphic) in detecting csPCa in men with PI-RADS < 3 (A). The DCAs the net benefit csPCa of mPSAD probability and threshold MRI-PMbdex over performing biopsies on all men according to the (B). csPCa probability threshold (B). Among the 645 men with PI-RADS 3, MRI-PMbdex exhibited an AUC of 0.768 (95% CI: 0.717–0.819), while mPSAD exhibited an AUC of 0.696 (95% CI: 0.641–0.750), with p < 0.001 The selected thresholds of MRI-PMbdex and mPSAD provided sensitivities of 67.3% (Figure 3A). Thus, MRI-PMbdex showed net benefit over mPSAD from the 18% csPCa and probability 90.9% as well as specificities of 87.7% and 21.4%, respectively, in men with PI-RADS threshold (Figure 3B). < 3. TheThe MRI-PMbdex avoided selected thresholds 82.2% of prostate of MRI-PMbdex and mPSAD biopsies, providedwhereas mPSAD sensitivities of 78.9%avoided 20.2%. andHowever, 92.7% as welltheasprobabilities specificities ofof missed 52.1% and csPCa were 32.7%inand 20.5%, respectively, men9.1%, with for MRI-PMbdex PI-RADS 3. and MRI-PMbdex avoided 46.8% mPSAD, respectively. of prostate biopsies, MRI-PMbdex did notwhile mPSAD detect avoided 0.9% of PCa 18.3%. withHowever, ISUP-GG = 3 the probabilities of missed csPCa were 21.7% (5/55), while mPSAD did not detect 0.2% (1/55) (Table 4).and 7.3%, respectively. mPSAD did not detect 2.8% of PCa with ISUP-GG ≥ 3 (3/109), whereas MRI-PMbdex did not detect 10% (11/109) (Table 5). Table 4. Performance of mPSAD and MRI-PMbdex, with respective thresholds of 0.628 ng/mL2 and 13.5%, in men with PI-RADS < 3. Parameter mPSAD MRI-PMbdex Sensitivity 50/55 (90.9) 37/55 (67.3) Specificity 106/495 (21.4) 434/495 (87.7) Negative predictive value 106/111 (95.5) 434/452 (96.0) Cancers 2022, 14, 2374 10 of 22 Table 5. Performance of mPSAD and MRI-PMbdex, with respective thresholds of 0.628 ng/mL2 and 13.5%, in men with PI-RADS 3. Parameter mPSAD MRI-PMbdex Sensitivity 101/109 (92.7) 86/109 (78.9) Specificity 110/536 (20.5) 279/536 (52.1) Negative Cancers 2022, 14, x FOR PEER REVIEW predictive value 110/118 (93.2) 279/302 (92.4) 11 of 24 Positive predictive value 101/527 (19.2) 86/343 (25.1) Accuracy 211/645 (32.5) 365/645 (56.6) Missed csPCa 5/55 (9.1) 18/55 (32.7) Avoided biopsies Odds ratio (95% CI) 118/645 (18.3) 2.27 (1.06–7.00) 302/645 14.62 (7.84–27, 29) (46.8) Missed p ValuecsPCa 8/109 (7.3) =0.033 23/109 (21.1) <0.001 GG 2 Ratio (95% CI) Odds 4 3.26 (1.54–6.90) 134.06 (2.49–6.63) GG 3 1 5 p Value <0.001 <0.001 GG 4 0 0 GG GG25 5 0 0 12 GG 3 2 11 Among the 645 men with PI-RADS 3, MRI-PMbdex exhibited an AUC of 0.768 (95% GG CI: 40.717–0.819), while mPSAD exhibited an AUC1 of 0.696 (95% CI: 0.641–0.750), with 0 p< 0.001 GG 5 (Figure 3A). Thus, MRI-PMbdex showed 0net benefit over mPSAD from the0 18% csPCa probability threshold (Figure 3B). Figure 3. Cont. Cancers 2022, 14,2022, Cancers 237414, x FOR PEER REVIEW 12 of 24 11 of 22 Figure 3. The Figure ROC 3. The ROCcurves andAUCs curves and AUCs show show the the efficacy efficacy of mPSAD of mPSAD (PSAD (PSAD in the and in the graphic) graphic) MRI- and MRI- PMbdex (model in the graphic) in detecting csPCa in men with PI-RADS 3 (A). The PMbdex (model in the graphic) in detecting csPCa in men with PI-RADS 3 (A). The DCAs showingDCAs showing the net benefit of mPSAD and MRI-PMbdex over performing biopsies on all men according to the the csPCa net benefit of mPSAD probability and threshold (B).MRI-PMbdex over performing biopsies on all men according to the csPCa probability threshold (B). The selected thresholds of MRI-PMbdex and mPSAD provided sensitivities of 78.9% Among and 92.7% as the 841 well men with of as specificities PI-RADS 52.1% and4,20.5%, the MRI-PMbdex showed respectively, in men an AUC of 0.823 with PI-RADS (95%3. MRI-PMbdex avoided CI: 0.769–0.851), 46.8% while of prostate mPSAD showedbiopsies, while mPSAD an AUC of 0.742avoided (95% CI: 18.3%. How- 0.709–0.775), with ever, the probabilities of missed csPCa were 21.7% and 7.3%, p < 0.001 (Figure 4A). MRI-PMbdex showed net benefit over mPSAD in detecting respectively. mPSAD did csPCa fromnotthe detect 20%2.8% of PCa with probability ISUP-GG while threshold, ≥ 3 (3/109), mPSADwhereas MRI-PMbdex showed did not net benefit detect over performing 10% (11/109) (Table 5). biopsies on all men from the 35% probability threshold (Figure 4B). The5.selected Table thresholds Performance of mPSAD for and MRI-PMbdex and MRI-PMbdex, with mPSAD respective provided thresholds sensitivities of 0.628 ng/mL2 and of 98.6% and13.5%, 94.3% as well in men with as specificities PI-RADS 3. of 12.2% and 16.2%, respectively, in men with PI-RADS 4. MRI-PMbdex avoided Parameter 6.5% of prostate biopsies, while mPSAD avoided mPSAD MRI-PMbdex 10.7%. Moreover, theSensitivity rate of missed csPCa was 1.4% for MRI-PMbdex 101/109 (92.7)and 5.7% for mPSAD. 86/109 (78.9) The rate of missed PCa Specificity with ISUP-GG ≥ 4 was 0.9% (5/439) for 110/536 (20.5) mPSAD and 0% for MRI-PMbdex 279/536 (52.1) (Table 6). Negative predictive value 110/118 (93.2) 279/302 (92.4) Positive predictive value 101/527 (19.2) 86/343 (25.1) Table 6. Performance of mPSAD and MRI-PMbdex, Accuracy with(32.5) 211/645 respective thresholds 365/645of 0.628 ng/mL2 and (56.6) 13.5%, in men Avoided with PI-RADS 4. biopsies 118/645 (18.3) 302/645 (46.8) Parameter mPSAD MRI-PMbdex Sensitivity 414/439 (94.3) 433/439 (98.6) Specificity 65/402 (16.2) 42/402 (12.2) Negative predictive value 65/90 (72.2) 49/55 (89.1) Positive predictive value 414/751 (55.1) 433/786 (55.1) Cancers 2022, 14, 2374 12 of 22 Cancers 2022, 14, x FOR PEER REVIEW 13 of 24 Table 6. Cont. Missed csPCa 8/109 (7.3) 23/109 (21.1) Parameter Odds Ratio (95% CI) mPSAD 3.26 (1.54–6.90) MRI-PMbdex 4.06 (2.49–6.63) p Value Accuracy <0.001 479/841 (57.0) <0.001 482/841 (57.3) GG Avoided 2 biopsies 90/841 (10.7)5 12 55/841 (6.5) GG Missed 3 csPCa 25/439 (5.7) 2 6/43911 (1.4) GG Odds 4 Ratio (95% CI) 1 3.19 (1.97–5.18) 0 10.02 (4.24–23.66) GG 5 0 0 p Value <0.001 <0.001 GG 2 Among 12 the 841 men with PI-RADS 4, the MRI-PMbdex 1 0.823 (95% showed an AUC of CI: 0.769–0.851), GG 3 while mPSAD showed an AUC 8 of 0.742 (95% CI: 0.709–0.775), 5 with p < 0.001 GG(Figure 4 4A). MRI-PMbdex showed net benefit 5 over mPSAD in detecting0 csPCa from the 20% probability threshold, while mPSAD showed net benefit over performing biop- GG 5 0 0 sies on all men from the 35% probability threshold (Figure 4B). Figure 4. Cont. Cancers 2022, 14, x FOR PEER REVIEW 14 of 24 Cancers 2022, 14, 2374 13 of 22 Figure Figure4.4.The TheROC ROCcurves curvesand andAUCs AUCsshow showthetheefficacy efficacyofofmPSAD mPSAD(PSAD (PSADininthe thegraphic) graphic)and andMRI- MRI- PMbdex (model in the graphic) in detecting csPCa in men with PI-RADS 4 (A). The DCAs PMbdex (model in the graphic) in detecting csPCa in men with PI-RADS 4 (A). The DCAs showing showing the net benefit of mPSAD and MRI-PMbdex over performing biopsies on all men according to the the net benefit of mPSAD and MRI-PMbdex over performing biopsies on all men according to the csPCa probability threshold (B). csPCa probability threshold (B). The selected Finally, thresholds among the 396for men MRI-PMbdex with PI-RADS and5,mPSAD provided sensitivities the MRI-PMbdex showed anofAUC 98.6%of and 94.3% as well as specificities of 12.2% and 16.2%, respectively, in men 0.787 (95% CI: 0.728–0.846), while mPSAD showed an AUC of 0.761 (95% CI: 0.698–0.825), with PI-RADS 4.with MRI-PMbdex avoided5A). p < 0.001 (Figure 6.5%Neither of prostate biopsies, while MRI-PMbdex mPSADshowed nor mPSAD avoidednet10.7%. Moreo- benefit over ver, the rate of performing missedon biopsies csPCa wasuntil all men 1.4%afor MRI-PMbdex csPCa probabilityand 5.7% for threshold ofmPSAD. 65% wasThe rate reached. ofInmissed PCa addition, with from theISUP-GG ≥ 4 was threshold 65% probability 0.9% (5/439) for mPSAD of csPCa, and 0% for MRI-PMbdex both MRI-PMbdex and mPSAD (Table 6). showed minimal benefit over performing biopsies on all men (Figure 5B). The selected thresholds for MRI-PMbdex and mPSAD provided sensitivities of 100% Table 6. Performance and 97.3% as well asof mPSAD and MRI-PMbdex, specificities of 4.6% and with 20%,respective thresholds respectively, in menof 0.628 with ng/mL 2 and PI-RADS 5. 13.5%, in men with PI-RADS 4. MRI-PMbdex avoided 0.8% of prostate biopsies, while mPSAD avoided 5.6%. The rate of missed csPCaParameter was 0% for MRI-PMbdex and 2.7% for mPSAD. Moreover, mPSAD mPSAD did not MRI-PMbdex detect 4 Sensitivity PCa with ISUP-GG ≥ 4 (Table 7). 414/439 (94.3) 433/439 (98.6) Specificity 65/402 (16.2) 42/402 (12.2) Negative predictive value 65/90 (72.2) 49/55 (89.1) Positive predictive value 414/751 (55.1) 433/786 (55.1) Cancers 2022, 14, 2374 14 of 22 Table 7. Performance of MRI-PSAD and Barcelona MRI-predictive model in men with PI-RADS 5, from the respective thresholds of 0.628 ng/mL2 and 13.5%. Parameter mPSAD MRI-PMbdex Sensitivity 322/331 (97.3) 331/331 (100) Specificity 13/65 (20.0) 3/65 (4.6) Negative predictive value 13/22 (59.1) 3/3 (100) Positive predictive value 322/374 (86.1) 331/393 (84.2) Accuracy 335/396 (84.6) 334/396 (84.3) Avoided biopsies 22/396 (5.6) 3/396 (0.8) Missed csPCa 9/331 (2.7) 0/331 (0) Odds Ratio (95% CI) 8.94 (3.63–21.98) - p Value <0.001 =0.004 GG 2 2 0 GG 3 3 0 GG 4 Cancers 2022, 14, x FOR PEER REVIEW 3 0 16 of 24 GG 5 1 0 Figure 5. Cont. Cancers 2022, 14, 2374 Cancers 2022, 14, x FOR PEER REVIEW 17 of 24 15 of 22 Figure 5. The ROC curves Figureand AUCs 5. The showand ROC curves theAUCs efficacy show ofthe mPSAD efficacy (PSAD of mPSAD in(PSAD the graphic) and MRI- in the graphic) and MRI- PMbdex (model in thePMbdex (model graphic) in the graphic) in detecting in detecting csPCa in mencsPCawith in men with 5PI-RADS PI-RADS 5 (A). (A). The DCAsThe DCAs showing showing the net benefit of mPSAD and MRI-PMbdex over performing biopsies on all men according to the the net benefit of mPSAD and MRI-PMbdex over performing biopsies on all men according to the csPCa probability threshold (B). csPCa probability threshold (B). The selected thresholds for MRI-PMbdex and mPSAD provided sensitivities of 100% 4. Discussion and 97.3% as well as specificities of 4.6% and 20%, respectively, in men with PI-RADS 5. MRI-PMbdex First, the characteristics avoided 0.8% of suspected of prostate PCa regardingbiopsies, while mPSAD PI-RADS avoided categories 5.6%. The rate of are considered. missed csPCa was 0% for MRI-PMbdex and 2.7% for mPSAD. Moreover, mPSAD did not The similar characteristics of men with PI-RADS 1 and PI-RADS 2, in addition to similar detect 4 PCa with ISUP-GG ≥ 4 (Table 7). csPCa detection rates (9.8% vs. 10.6%) and high iPCa over detection rates (above 50%) in both subsets, justifyTable considering these 7. Performance two PI-RADS of MRI-PSAD categories and Barcelona as a negative MRI-predictive mpMRI. model in men The 5, with PI-RADS from the respective thresholds of 0.628 ng/mL 2 and 13.5%. observed 90% negative predictive value of mpMRI was in the recently reported ranges (i.e., 80–95%) [10–12]. The characteristics Parameter of suspected PCa with PI-RADS 3MRI-PMbdex mPSAD were closer to those with PI-RADS 2 than those with PI-RADS 4. Moreover, Sensitivity the csPCa detection 322/331 (97.3) rate 331/331 (100) with PI-RADS 3 (16.9%) was closer Specificity to that of men with PI-RADS 13/65 (20.0) 2 (10.8%) than 3/65 that (4.6) of men with PI-RADS 4 (52.2%). Negative predictivePI-RADS Therefore, value 3 is an 13/22 (59.1) scenario more uncertain 3/3 (100) similar to a negative MRI than toPositive PI-RADS predictive 4; thisvalue justifies why some 322/374authors (86.1) consider 331/393 men(84.2) with Accuracy 335/396 (84.6) 334/396 (84.3) PI-RADS < 4 as candidates to avoid prostate biopsy [9,15]. Finally, the characteristics of Avoided biopsies 22/396 (5.6) 3/396 (0.8) those with PI-RADS 5 were notably different from those with PI-RADS 4. Furthermore, the Missed csPCa 9/331 (2.7) 0/331 (0) csPCa risk increased with PI-RAD 5, reaching 83.6%. Taking Odds Ratio (95% CI) these factors into account, 8.94 (3.63–21.98) - it is clear that considering PI-RADS > 3 in the same group as the other categories is inadvisable. Hence, the data of men with PI-RADS 4 and PI-RADS 5 should be considered separately [5]. PSAD was introduced by Benson et al. in 1992 to improve the specificity of serum PSA in distinguishing men with localised PCa from those with benign prostatic enlarge- ment [17,63]. Shortly after, it was incorporated by Catalona et al. as a tool for prostate biopsy decision-making in the early detection of PCa [64]. The inverse relationship between prostate volume and PCa risk has been recently confirmed in a systematic review of the literature from the last thirty years [65]. Transrectal ultrasonography was recommended for assessing the prostate volumetry for PSAD calculation from the beginning, as it yields a more accurate assessment than suprapubic ultrasonography [66]. Most studies analysing Cancers 2022, 14, 2374 16 of 22 the clinical usefulness of PSAD have assessed the prostate volume just before TRUS system- atic biopsies [67–70]. However, routine TRUS prostate volume assessment for calculating PSAD is not typically performed for prostate biopsy decision-making. The spread ERSPC (European Randomised Screening Prostate Cancer) risk calculator has incorporated the highly subjective prostate volume estimation from DRE [71,72]. The main reason for the current resurgence of PSAD may be the spread of pre-biopsy MRI [73], which provides the most accurate prostate volume assessment without additional cost; this helps avoid TRUS, which is time-consuming and cumbersome [74]. mPSAD has been directly incorporated as ng/mL2 into some MRI-PM [23,26,32,33,75] or indirectly incorporated from serum PSA and prostate volume into other MRI-PM [28,38,76–79]. Logistical regressions performed to develop MRI-PM have shown PSAD to be the most powerful predictor of csPCa after the PI-RADS score. Recent studies analysing the clinical usefulness of mPSAD for csPCa detection according to PI-RADS categories have shown its dynamic behaviour, which suggests the need for different thresholds to obtain similar predictive values in different PI-RADS categories [21,80]. Nevertheless, the proper mPSAD thresholds for specific PI- RADS categories should be selected from each area, given the specific characteristics of cared populations of men with suspected PCa [22,81]. The most recent MRI-PMs share the latest PI-RADS versions, with direct or indirect mPSAD, and may share other independent clinical predictors, such as age, PCa family history, initial or repeat biopsy, and DRE. Our study is the first to compare mPSAD and MRI-PM in a head-to-head manner for improving the selection of candidates for prostate biopsy in suspected PCa men after mpMRI. The compared MRI-PMbdex shared the same predictors of csPCa as the recent Barcelona MRI-PM. MRI-PMbdex and mPSAD avoid the inconveniences of modern mark- ers as they are free of cost, do not require sample procurement, and require very little time for the assessment. This study was carried out on a sizable, multicentre population repre- senting a metropolitan area. In all participant institutions, the criteria for PCa suspicion and diagnostic approach adhered to the EAU PCa guidelines [7]. MRI-PMbdex outperformed mPSAD in the entire population, and it exhibited net benefit over mPSAD, which, in turn, exhibited a slight benefit over performing biopsies on all men. The behaviour of both tools regarding PI-RADS categories showed that MRI-PMbdex outperformed mPSAD in each PI-RADS ≤ 4 category, with different degrees of benefit. However, clinical benefit was found for any tool in men with PI-RADS 5. Additionally, mPSAD did not detect more aggressive tumours compared to MRI-PMbdex in men with PI-RADS ≥ 4. The different behaviour of mPSAD [21] and MRI-PMs [38] regarding PI-RADS categories is the conse- quence of the incidence of csPCa among them. We selected different thresholds of mPSAD to obtain similar performance in our series of PI-RADS 3 than that of Görtz et al. [22,81]. The use of appropriate thresholds in different populations has been previously described for mPSAD [19–21,82–95]. The limitations of this study include the design, which is prone to sampling and selection biases. Furthermore, no concordance analysis was performed by the pathologists, radiologists, and urologists involved in the study. In addition, the inter-variability that is inevitable among researchers involved in multicentric studies also exists. Moreover, prostate biopsies and mPSAD suffer from intrinsic limitations related to the heterogeneity of prostate cancer and prostate volume. The lack of histopathological analysis of surgi- cal specimens is another limitation, although not every PCa patient undergoes radical prostatectomy. While the definition we adopted for csPCa is the most common one, it may not represent the true csPCa. Moreover, as the MRI-PMbdex is not the developed Barcelona MRI-PM, the results cannot be attributed to this model. Hence, further studies analysing the clinical usefulness of mPSAD and MRI-PMs according to PI-RADS categories are needed. It will be important in the future to include the results of radiomics and radio-genomics to improve the next generation of MRI-PMs. It appears likely that we will have more pow- erful predictors than PI-RADS and a more refined definition of csPCa based on genomic Cancers 2022, 14, 2374 17 of 22 expression in addition to the current the pathology of prostate biopsies or surgical speci- mens [96,97]. 5. Conclusions MRI-PMbdex, which used the same predictors as the recent Barcelona MRI-PM, out- performed mPSAD in the proper selection of candidates for prostate biopsy. MRI-PMbdex exhibited net benefit over mPSAD in men with PI-RADS ≤ 4. However, regarding men with PI-RADS 5, neither tool showed clinical benefit over biopsy. The clinical usefulness of tools that improve the selection of candidates for prostate biopsy in the entire population does not represent those observed in each PI-RADS category. Author Contributions: Conceptualization, J.M., A.B.-F., M.T. and L.M.E.; methodology, J.M., A.B.-F. and L.M.E.; software, L.M.E. and A.B.-F.; formal analysis, J.M., A.B.-F., M.T. and L.M.E.; resources, J.M.; data curation, A.C., L.R., R.M., I.M.d.T., M.E.S., J.M.A., P.S., M.T. and J.P.; interpretation, J.M., A.B.-F. and L.M.E., A.S. and E.T.; writing—original draft preparation, J.M. and M.T.; writing—review and editing, J.M., A.B.-F., L.M.E., A.S. and E.T.; supervision, E.T.; project administration, J.M.; funding acquisition, J.M. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Instituto de Salut Carlos III (ESP), grant number PI20/01666. Institutional Review Board Statement: The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review of Vall d´Hebron Hospital Campus (PR/AG- 317/2017, approved on 28 August 2017). Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Conflicts of Interest: The authors declare no conflict of interest. Acronyms and Abbreviations CI confidence interval csPCa clinically significant PCa DRE digital rectal examination GG grade group iPCa insignificant PCa IQR interquartile range mPSAD MRI associated PSAD MRI magnetic resonance imaging PCa prostate cancer PI-RADS prostate imaging-report and data system PSA prostate-specific antigen PSAD PSA density PM predictive model PMbdex developed and externally validated Barcelona PM RC risk calculator TRUS transrectal ultrasound References 1. 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