Urinary prostate cancer antigen 3 (PCA3) assay in combination with established clinical risk factors improves the identification of men at risk of harboring prostate cancer (PCa) at initial biopsy (IBX).
To develop and validate internally the first IBX-specific PCA3-based nomogram that allows an individual assessment of a man's risk of harboring any PCa and high-grade PCa (HGPCa).
Design, setting, and participants
Clinical and biopsy data including urinary PCA3 score of 692 referred IBX men at risk of PCa were collected within two prospective multi-institutional studies.
IBX (≥10 biopsy cores) with standard risk factor assessment including prebiopsy urinary PCA3 measurement.
Outcome measurements and statistical analysis
PCA3 assay cut-off thresholds were investigated. Regression coefficients of logistic risk factor analyses were used to construct specific sets of PCA3-based nomograms to predict any PCa and HGPCa at IBX. Accuracy estimates for the presence of any PCa and HGPCa were quantified using area under the curve of the receiver operator characteristic analysis and compared with a clinical model. Bootstrap resamples were used for internal validation. Decision curve analyses quantified the clinical net benefit related to the novel PCA3-based IBX nomogram versus the clinical model.
Results and limitations
Any PCa and HGPCa were diagnosed in 46% (n
The internally validated PCA3-based IBX-specific nomogram outperforms a clinical prediction model without PCA3 for the prediction of any PCa, leading to the avoidance of unnecessary biopsies while missing only a few cases of HGPCa. Our findings support the concepts of a combination of novel markers with established clinical risk factors and the superiority of decision tools that are specific to a clinical scenario.
Keywords: Biomarker, Decision curve analysis, Nomogram, Initial prostate biopsy, Internal validation, Prostate cancer, Prostate cancer antigen 3.
In current clinical practice, only about 4 of 10 men who are suspected of harboring prostate cancer (PCa) due to an elevated prostate-specific antigen (PSA) level >4 ng/ml or a suspicious digital rectal examination (DRE) show a positive initial prostate biopsy (IBX)  and . In other words, one could argue that about 60% of these IBX-negative men could have been saved from further prostatic evaluations. Instead, most of these IBX-negative men most likely remain suspicious and undergo even further subsequent prostatic evaluations consisting of serial PSA tests, DREs, and potentially multiple repeated prostate biopsies. These are associated with potential adverse biopsy-related events such as infections, bleeding, or urinary obstruction  as well as the emotional confrontation with a potential cancer diagnosis . Thus it is of great clinical importance to assess PCa risk correctly prior to an IBX to prevent a significant proportion of men from having to undergo such a vicious cycle.
Previously reported prostate biopsy nomograms for IBX settings, which are based mainly on clinical variables, demonstrated satisfactory predictive accuracy (PA) estimates between 67% and 77%, respectively , , , , , , and . Novel diagnostic markers, which carry the potential to overcome PSA's low specificity in the diagnostic arena, may help improve PA estimates of such nomograms. Several studies have shown that a commercially available urinary prostate cancer antigen 3 (PCA3) assay in combination with established clinical risk factors may support clinicians to better identify men at risk of PCa , , , , , , , , and . Its principle resides in PCA3's messenger mRNA overexpression in malignant prostate tissue, detected in the patient's urine after DRE . Consequently, one externally validated PCA3-based mixed-biopsy nomogram to assess an individual's PCa risk became available . Unfortunately, this robust nomogram is not biopsy-scenario specific because it is based on IBX and repeat biopsy men. Therefore, clinicians may be reluctant to use it because the odds of harboring PCa significantly change with the number of biopsy sessions .
To address this void, we developed and validated the first PCA3-based IBX-specific nomogram that allows a more accurate identification of any PCa and high-grade prostate cancer (HGPCa), as well as avoidance of unnecessary IBX.
2. Material and methods
2.1. Patient population
Our study cohort consisted of 772 men subjected to ≥10 cores at IBX due to suspicious DRE and/or elevated total PSA levels (2.5–10 ng/ml) from two prospective multi-institutional studies from Europe and North America  and . Patients with symptoms of urinary tract infections, any medical therapy affecting PSA levels, and/or a history of PCa or invasive treatment for benign prostatic hyperplasia were not recruited for the studies, as previously described . Patients with suspicious DREs were included, even if their PSA levels were >10 ng/ml. However, due to clinical as well as statistical considerations, men with a PSA ≥20 ng/ml (n
2.2. Clinical evaluation
PSA levels were measured before DRE and transrectal ultrasound (TRUS). DRE findings were classified as unsuspicious versus suspicious. TRUS-derived total prostate volume was calculated in all patients using the prolate ellipse formula (0.52
2.3. Statistical analyses
The PCA3 assay score was explored with respect to a possible cut-off value that could be more informative than the unaltered continuous variable and previously used cut-off formats  and . The PCA3 cut-off value (≤21 vs >21) was identified using the minimum p value approach . Previously reported PCA3 cut-offs were used in subsequent univariable and multivariable logistic regression models (LRMs). Multicolinearity analyses between PCA3 and other clinical variables, which were included in the multivariate model, were also performed. Invariably, PCA3 score was not correlated to any other variable.
LRMs addressed the presence of any PCa at IBX. Risk factors were age, DRE, PSA, prostate volume, and PCA3. The number of biopsy cores was not considered because we aimed to develop a model that helps to better identify men suspicious of harboring PCa prior to the first prostate biopsy. Multivariable LRM coefficients were used to construct various nomogram sets with and without PCA3. Area under the curve (AUC) of the receiver operator characteristic analysis was used to quantify the PA of each multivariable model predicting any PCa at IBX. The AUC of high-grade PCa prediction (HGPCa, defined as Gleason sum ≥7) was derived from the predicted probabilities of any PCa according to a method previously described by Vickers et al. . In this analysis, men with IBX Gleason sum ≤6 were classified the same way as men with negative IBX. For internal validation and to reduce overfit bias, 200 bootstrap resamples were used . Model PA differences were tested for statistical significance using the Mantel-Haenszel test. The extent of over- or underestimation of the observed versus predicted PCa rate at biopsy was explored graphically. Various nomogram-derived probability cut-offs were tested to assess the ability to predict PCa and HGPCa.
Finally, to determine whether PCA3 inclusion in a clinical model improves its predictive net benefit, we relied on decision curve analyses (DCAs) . DCAs examine the theoretical relationship between the threshold probability of IBX outcome (PCa) and the relative value of false-positive and false-negative results to determine the value (net benefit) of a predictive model .
All tests were two sided with a statistical significance set at p
Overall, 46% of the men (n
|Entire initial biopsy cohort||No cancer at initial biopsy||Low-grade PCa at initial biopsy||HGPCa at initial biopsy||p value|
|No. of patients (%)||692 (100)||374 (54)||181 (26)||137 (20)||–|
|PSA ≥10.1 ng/ml||28 (4.0)||8 (2.1)||13 (7.2)||7 (5.1)||0.01|
|Total prostate volume, cm3||<0.001|
|495 (71.5)||299 (79.9)||138 (76.2)||15 (10.9)|
|197 (28.5)||75 (20.1)||43 (23.8)||122 (89.1)|
|PCA3 assay score||<0.001|
|239 (34.5)||189 (50.5)||37 (20.4)||13 (9.5)||<0.001|
|453 (65.5)||185 (49.5)||144 (79.6)||124 (90.5)|
|287 (41.5)||220 (58.8)||52 (28.7)||15 (10.9)||<0.001|
|405 (58.5)||154 (41.2)||129 (71.3)||122 (89.1)|
|319 (46.1)||235 (62.8)||62 (34.3)||22 (16.1)||<0.001|
|373 (53.9)||139 (37.2)||119 (65.7)||115 (83.9)|
|412 (59.5)||284 (75.9)||85 (47.0)||43 (31.4)||<0.001|
|280 (40.5)||90 (24.1)||96 (53.0)||94 (68.6)|
|Biopsy cores, no.||0.01|
|Positive cores, no.||<0.001|
|Biopsy Gleason sum, no. (%)||–|
In univariable and multivariable LRMs, PCA3 (regardless of its coding), PSA, DRE, and prostate volume achieved independent predictor status of PCa at IBX (all p
|OR (95% CI)||p value||AUC (95% CI)||AUC (95% CI)|
|Age, yr||1.04 (1.03–1.06)||<0.001||0.606 (0.569–0.642)||0.615 (0.579–0.652)|
|Serum PSA, ng/mL||1.16 (1.09–1.24)||<0.001||0.600 (0.564–0.637)||0.634 (0.599–0.670)|
|Prostate volume, cm3||0.98 (0.97–0.98)||<0.001||0.651 (0.616–0.687)||0.639 (0.604–0.675)|
|DRE (suspicious vs unsuspicious)||2.48 (1.77–3.48)||<0.001||0.591 (0.554–0.628)||0.682 (0.647–0.717)|
|PCA3 assay score, continuously coded||1.01 (1.01–1.02)||<0.001||0.739 (0.706–0.771)||0.729 (0.696–0.762)|
|PCA3 assay score >17 vs ≤17||5.48 (3.81–7.88)||<0.001||0.674 (0.639–0.709)||0.656 (0.621–0.691)|
|PCA3 assay score >21 vs ≤21||5.35 (3.81–7.51)||<0.001||0.689 (0.654–0.723)||0.690 (0.656–0.725)|
|PCA3 assay score >24 vs ≤24||4.71 (3.4–6.52)||<0.001||0.682 (0.647–0.717)||0.687 (0.653–0.722)|
|PCA3 assay score >35 vs ≤35||4.68 (3.38–6.49)||<0.001||0.678 (0.644–0.713)||0.675 (0.641–0.710)|
* The AUC for the prediction of HGPCa was calculated from the predicted probabilities of any PCa according to a method previously described by Vickers et al. . In this analysis, men with initial biopsy (IBX) Gleason sum ≤6 were classified the same as men with negative IBX.
|Variables||Multivariable analyses predicting any PCa at IBX|
|Base model‡||Base model‡ plus PCA3 (cc)||Base model‡ plus PCA3-17||Base model‡ plus PCA3-21||Base model‡ plus PCA3-24||Base model‡ plus
|OR (95% CI); p||OR (95% CI); p||OR (95% CI); p||OR (95% CI); p||OR (95% CI); p||OR (95% CI); p|
|Age, yr||1.05 (1.03–1.07); <0.001||1.03 (1.01–1.06); 0.005||1.02 (1–1.05); 0.04||1.02 (1–1.05); 0.06||1.02 (1–1.05); 0.04||1.03 (1–1.05); 0.02|
|Serum PSA, ng/ml||1.24 (1.15–1.33); <0.001||1.24 (1.14–1.33); <0.001||1.24 (1.15–1.34); <0.001||1.23 (1.14–1.33); <0.001||1.23 (1.14–1.33); <0.001||1.23 (1.14–1.33); <0.001|
|Prostate volume, cm3||0.97 (0.96–0.98); <0.001||0.97 (0.96–0.98); <0.001||0.97 (0.96–0.98); <0.001||0.97 (0.96–0.98); <0.001||0.97 (0.96–0.98); <0.001||0.97 (0.96–0.98); <0.001|
|DRE (suspicious vs unsuspicious)||1.79 (1.23–2.59); 0.002||1.76 (1.20–2.58); 0.004||1.88 (1.27–2.79); 0.002||1.76 (1.19–2.61); 0.005||1.78 (1.21–2.64); 0.004||1.81 (1.22–2.78); 0.003|
|PCA3 assay score||–||1.01 (1.01–1.02); <0.001||5.14 (3.43–7.69); <0.001||4.93 (3.38–7.20); <0.001||4.19 (2.92–6.02); <0.001||3.94 (2.75–5.65); <0.001|
|Bias-corrected AUC for prediction of any PCa (%)
|Increment AUC (%);
Mantel-Haenszel test (p value)†
|Bias-corrected AUC for prediction of HGPCa (%)§
|Increment AUC (%);
Mantel-Haenszel test (p value)†
* Head-to-head comparison of predictive accuracy estimates of the clinical base nomogram versus different PCA3-based nomograms for prediction of any prostate cancer and high-grade prostate cancer.
† Comparison of AUC increment was made for each PCA3-based nomogram to the clinical base model.
‡ The clinical base model consisted of age, PSA, DRE, and prostate volume.
§ The AUC for prediction of HGPCa was calculated from the predicted probabilities of any PCa according to a method previously described by Vickers et al. . In this analysis, men with IBX Gleason sum ≤6 were classified the same as men with negative IBX.
In DCAs, the PCA3-based IBX nomogram (PCA3 cut-off: 21) was clearly superior to the base model without PCA3 with a higher net benefit for all threshold probabilities >18% (Fig. 2). For example, applying a nomogram-derived probability threshold of 30% above which a man would be considered to harbor PCa, use of the PCA3-based IBX nomogram would result in a net reduction of 16 unnecessary prostate biopsies per 100 patients without a decrease in the number of men with PCa who duly have an IBX, compared with the scenario where all men undergo IBX . The net reduction of unnecessary biopsies associated with the use of the PCA3-based IBX nomogram relative to a base model without PCA3 was 9 per 100 biopsies. Specifically, IBX could be avoided in 207 men without PCa (55%), and 41 men with PCa (13%) would not undergo IBX. More importantly, of these 41 men only 3 (2%) harbor HGPCa (all Gleason score 3
|Model||Probability cut-off, %||Biopsies performed, n (%)||Biopsies not performed, n (%)||Biopsies not performed in men without PCaa, n (%)||Any PCa detectedb,n (%)||Any PCa missed, n (%)||NPV for any PCa, %||HGPCa detectedb,n (%)||HGPCa missed, n (%)||NPV for HGPCa, %|
|All biopsies||692 (100)||NA||NA||318 (46)||NA||100||137 (100)||NA||100|
|Base model§||15||657 (95)||35 (5)||32 (9)||315 (99)||3 (1)||91||137 (100)||0 (0)||100|
|20||613 (89)||79 (11)||68 (18)||307 (97)||11 (3)||86||135 (98.5)||2 (1.5)*||97|
|25||568 (82)||124 (18)||98 (26)||292 (92)||26 (8)||79||135 (96)||6 (4)*||95|
|30||525 (76)||167 (24)||131 (35)||282 (89)||36 (11)||78||134 (93)||10 (7)*||94|
|35||469 (68)||223 (32)||170 (45)||265 (83)||53 (17)||76||129 (91)||13 (9)**||94|
|40||410 (59)||282 (41)||208 (56)||244 (77)||74 (23)||74||126 (85)||20 (15)***||93|
|Basel model§ plus PCA3||15||597 (86)||95 (14)||84 (22)||307 (97)||11 (3)||88||136 (99.3)||1 (0.7)‡||99|
|20||536 (77)||156 (23)||136 (36)||298 (94)||20 (6)||87||135 (98.5)||2 (1.5)‡||99|
|25||492 (71)||200 (29)||172 (46)||290 (91)||28 (9)||86||135 (98.5)||2 (1.5)‡||99|
|30||444 (64)||248 (36)||207 (55)||277 (87)||41 (13)||83||134 (98)||3 (2)‡||99|
|35||405 (59)||287 (41)||232 (62)||263 (83)||55 (17)||81||129 (94)||8 (6)‡‡||97|
|40||384 (55)||308 (45)||245 (66)||255 (80)||63 (20)||80||126 (92)||11 (8)‡‡||96|
§ The clinical base model consisted of age, PSA, DRE, and prostate volume.
a Percentage is indicative of specificity.
b Percentage is indicative of sensitivity.
One man had Gleason score 4
One man had Gleason score 4
One man had Gleason score 4
All men had Gleason score 3
One man had Gleason score 4
To further substantiate our findings, an additional PCA3-based nomogram to specifically predict HGPCa at IBX (data not shown) was built. However, in direct comparison, it neither showed superior performance nor did it allow detection of more HGPCa relative to the present PCA3-based nomogram to predict any PCa (Table 5).
|Model||Probability cut-off, %||Biopsies performed, n (%)||Biopsies not performed, n (%)||HGPCa detected†, n (%)||HGPCa missed,n (%)||NPV, %|
|PCA3-based IBX nomogram to predict any PCa||15||597 (86)||95 (14)||136 (99.3)||1 (0.7)||99|
|20||536 (77)||156 (23)||135 (98.5)||2 (1.5)||99|
|25||492 (71)||200 (29)||135 (98.5)||2 (1.5)||99|
|30||444 (64)||248 (36)||134 (98)||3 (2)||99|
|35||405 (59)||287 (41)||129 (94)||8 (6)||97|
|PCA3-based IBX nomogram specifically to predict HGPCa||15||329 (48)||363 (52)||120 (88)||17 (12)||95|
|20||256 (37)||436 (63)||104 (76)||33 (24)||92|
|25||194 (28)||498 (72)||91 (66)||46 (34)||91|
|30||158 (23)||534 (77)||78 (57)||59 (43)||89|
|35||141 (20)||551 (80)||71 (52)||66 (48)||88|
* According to different nomogram-derived probability cut-offs of the PCA3 assay–based IBX nomogram (PCA3 cut-off: 21) to predict any PCa relative to a PCA3-based IBX nomogram to predict specifically HGPCa.
† Percentage indicates sensitivity.
We used data of a large multi-institutional PCA3 cohort of European and North American patients who underwent IBX to successfully develop the first IBX-specific PCA3-based nomogram. After bias correction, accuracies of this novel clinical decision tool are 80.7% for prediction of any PCa and 82.9% for prediction of HGPCa, respectively, which is remarkably high (Table 5). Of note, these accuracies were only achieved by combining PCA3 with established clinical risk factors. Application of the PCA3-based IBX nomogram may avoid unnecessary IBX in a considerable number of men at the expense of missing only a few men harboring HGPCa (Table 4), and inclusion of PCA3 led to a more distinct reduction of unnecessary biopsies relative to a clinical base model (age, PSA, DRE, and prostate volume) without PCA3 (Table 4). An additional PCA3-based nomogram to specifically predict HGPCa was not superior to the present PCA3-based nomogram to predict any PCa. Consequently, only the PCA3-based IBX nomogram to predict any PCa is presented and discussed.
In total, any PCa was detected in 46% of patients, whereas 20% had HGPCa (Gleason sum ≥7), which appears comparable with the 42% reported by Nam et al. , albeit rates reported from screening trials are lower (24.5%) . This may primarily be explained by differences between early detection and screening cohorts. And in contrast to the current study, the vast majority of patients in the screening trials underwent a sextant biopsy  and .
Regarding overall accuracy, the novel PCA3-based IBX nomogram compares favorably with previously published models , , , , , , and  as displayed in Table 6. However, comparison of different decision tools can be difficult due to inherent differences of development populations that cannot all be accounted for. Due to missing clinical information, we were unable to perform a true head-to-head comparison. For example, Zaytoun et al.  or Nam et al.  recently developed IBX prediction tools relying on age, PSA, percentage of free PSA (%fPSA), DRE, race, and family history. Unfortunately, the latter two variables were unavailable in our patient cohort (Table 1), and %fPSA was not considered in our study because not all of the assessed patients had available %fPSA information. Thus the size of the study cohort would have been too small.
|Study||Patients, n||Biopsy setting||Variables||Predictive accuracy, %||Validation type|
|Karakiewicz et al. ||1762||IBX||Age, PSA, DRE, %fPSA||77||External|
|Nam et al. ||3108||IBX||Age, race, family history of PCa, symptom score, PSA, %fPSA, DRE||74||Split sample|
|Chun et al. ||2900||IBX||Age, DRE, PSA, %fPSA, sampling density||77||External|
|Kawamura et al. ||1037||IBX; ethnic specific (Japanese)||Age, DRE, PSA, %fPSA, PV||73||Split sample|
|Sooriakumaran et al. ||599||IBX||Age, PSA, DRE, %fPSA||72||External|
|Chun et al. ||809||Mixed biopsy||Age, PSA, DRE, PV, biopsy history, PCA3||75||External|
|Zaytoun et al. ||1551||IBX||Age, PSA, %fPSA, family history of PCa, abnormal DRE, race||73||Split sample|
|Present study||692||IBX||Age, PSA, DRE, PV, PCA3 (cut-off: 21)||81||Internal|
In contradistinction to those nomograms  and , we demonstrate within the present PCA3-based IBX nomogram (Fig. 1) that consideration of prostate volume within biopsy nomograms is crucial, as previously shown , , , and . Different biologic and statistical explanations may be advanced to explain prostate volume's effect within multivariable diagnostic models , but a more practical consideration may be even more important. Specifically, location and direction of biopsy cores need to be adjusted for volume already in the IBX setting and not only within repeat biopsy decision tools.
A disadvantage of our novel PCA3 IBX nomogram resides in the nature of its validation  and . Clearly, an external validation represents the gold standard. However, first calibration of the novel PCA3 IBX nomogram (Fig. 1b) virtually overlaps the line of perfect predictions. Second, although not the gold standard, an internal validation using 200 bootstrap resamples were used indicating the robustness of our novel tool. Finally, the transatlantic, multi-institutional nature of our study supports our hypothesis that after validation this novel tool will be applicable to both North American and European patients. Taken together, we demonstrate the first IBX-specific, internally validated PCA3-based nomogram based on most contemporary international patients with the so far highest reported overall discriminative ability and performance.
Another recurrent question refers to the clinical meaningfulness of the 4.5–7.1% overall accuracy increment related to PCA3 inclusion in the current study. De la Taille et al. reported a comparable adjusted overall accuracy increment of 5.5% at an IBX setting ; Chun et al. demonstrated accuracy increments related to PCA3 inclusion ranging between 2.3% and 4.6% in a mixed-biopsy cohort . Thus it is important to emphasize that consideration of one novel marker enables us to correctly predict IBX outcome in 9 additional men at risk out of 100 (net reduction) relative to the clinical model without PCA3 . This diagnostic PCA3 impact may appear small, but if once extrapolated to the total number of men undergoing an IBX in Europe and North America, respectively, the diagnostic PCA3 effect may then appear substantial. Of note, applying a nomogram-derived probability threshold of ≥30% advising an IBX, only 2% of men (n
Avoidance of unnecessary biopsies is crucial because prostate biopsies may cause adverse biopsy-related events such as infections, bleeding, or urinary obstruction , as well as significant psychological distress  and . The novel PCA3-based IBX nomogram has the potential to better identify men with PCa and HGPCa and equally important, those in whom an IBX may be spared (Table 4). Taken together, the urinary PCA3 score adds significant information to combinations with clinical risk factors and enables us to better risk stratify men prior to IBX.
Despite these encouraging findings, limitations certainly apply to our study. First, the lack of a central pathology review may have introduced outcome variability. However, all participating centers represent tertiary referral centers with experienced uropathologists. Second, even though this study relies on a relatively large PCA3 patient cohort, the absolute number of included patients is limited (Table 6). It is noteworthy that predictive models such as nomograms depend strongly on their development data . Consequently, PA discrepancies between different PCA3 codings between univariable and multivariable analyses may be biased due to the number of investigated patients. For example, inclusion of continuously coded PCA3
We clearly demonstrate that the construction of a PCA3-based IBX nomogram is more accurate than clinical models or a previously published mixed-biopsy cohort-based PCA3 nomogram. When applying nomogram-derived PCa probability thresholds ≤30%, only a few cases of HGPCa (≤2%) would be missed while avoiding up to 55% of biopsies. External validation of this novel PCA3-based IBX-specific nomogram is recommended prior to its clinical routine use.
Study concept and design: Hansen, Auprich, Ahyai, Chun.
Acquisition of data: Auprich, de la Taille, van Poppel, Marberger, Stenzl, Mulders, Abbou, Schalken, Fradet, Marks, Ellis, Partin, Pummer, Haese, Walz, Chun.
Analysis and interpretation of data: Hansen, Auprich, Briganti, Chun.
Drafting of the manuscript: Hansen, Auprich, Chun.
Critical revision of the manuscript for important intellectual content: Auprich, Ahyai, de la Taille, van Poppel, Marberger, Stenzl, Mulders, Huland, Fisch, Abbou, Schalken, Fradet, Marks, Ellis, Partin, Pummer, Graefen, Haese, Walz, Briganti, Shariat, Chun.
Statistical analysis: Hansen, Auprich, Chun.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Graefen, Auprich, Chun.
Other (specify): None.
Financial disclosures: Felix K. Chun certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Yves Fradet is president, CMO, and shareholder of DiagnoCure, the company that developed and licensed the test to GenProbe. Alan Partin is a study investigator for GenProbe. Hendrik van Poppel and Jack A. Schalken are editorial board members of the pca3.org Web site. Jack A. Schalken is an inventor on PCA3-related PCT applications owned by Radboud University Nijmegen MC. The remaining authors have nothing to disclose.
Funding/Support and role of the sponsor: Gen-Probe, Inc helped design and conduct the study, collect the data, and review and approve the manuscript.
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a Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
b Martini Clinic Prostate Cancer Center, University Hospital Eppendorf, Hamburg, Germany
c Hôpital Henri Mondor, Créteil, France
d Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium
e University of Vienna, Vienna, Austria
f Uniklinikum Tübingen, Tübingen, Germany
g Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
h Department of Urology, Université Laval, Quebec City, Quebec, Canada
i Urological Sciences Research Foundation, Culver City, CA, USA
j University of Washington Medical Center, Seattle, WA, USA
k Department of Urology, Johns Hopkins University Medical Institution, Baltimore, MD, USA
l Department of Urology, Medical University of Graz, Graz, Austria
m Department of Urology, Institut Paoli-Calmettes Cancer Centre, Marseille, France
n Department of Urology, Vita-Salute San Raffaele University, Milan, Italy
o Department of Urology, Weill Medical College of Cornell University, New York, NY, USA
Both authors contributed equally.
© 2012 European Association of Urology, Published by Elsevier B.V.