Newly discovered biomarkers ideally should prove clinical usefulness, provide additional detection, staging, and prognosis information to improve individual risk assessment, and potentially permit targeted cancer therapy.
To review, display, and evaluate the current evidence regarding the biologic and analytic approach of urinary prostate cancer gene 3 (PCA3) in prostate cancer (PCa) detection, staging, and prognosis, and its therapeutic potential.
A systematic and comprehensive Medline search was performed using the Medical Subject Headings search terms PCA3, DD3, UPM3, prostate cancer, cell-lines, prostate tissue, prostate biopsy, detection, diagnosis, radical prostatectomy, staging, grading, progression, and gene therapy. Results were restricted to English-language papers published within the period 1999–2011.
The PCA3 gene is highly overexpressed in specific PCa cell lines and prostatic tumours. In 2006, a simple and robust urine test (Progensa) became commercially available. Despite its costs, prostate cancer antigen 3 (PCA3) is superior to prostate-specific antigen (PSA) and percent free PSA in the early detection of PCa. PCA3 improves the diagnostic accuracy of externally validated nomograms among men with an elevated PSA undergoing biopsy. PCA3 independently predicts low-volume disease and pathologically insignificant PCa but is not associated with locally advanced disease and is limited in the prediction of aggressive cancer. Preliminary data demonstrate that combining PCA3 with other new biomarkers further improves diagnostic and prognostic accuracy. Finally, findings of the first PCA3-Gene-ViroTherapy study suggest therapeutic potential by exploiting PCA3 overexpression.
PCA3, integrated in novel biopsy nomograms or risk stratification tools, can be used to counsel or confirm biopsy indications. If confirmed in further studies, using PCA3 together with established staging risk factors could assist clinicians in specific pretreatment decision making. So far no evidence for the usefulness of PCA3 in active surveillance programs has been presented.
Keywords: PCA3, Prostate biopsy, Prostate cancer detection, Staging, Targeted therapy.
In 1999, through a joint effort of researchers at Radboud University in Nijmegen in the Netherlands and Johns Hopkins University in the United States, Bussemakers et al. identified the DD3 gene (later called prostate cancer antigen 3 [PCA3]), which is highly overexpressed in prostatic tumours . Several studies confirmed this, reporting significantly higher PCA3 messenger RNA (mRNA) expression in malignant versus nonmalignant prostatic tissue , , , , , and . However, most of these analyses did not find significant correlations between PCA3 tissue levels and tumour stage and aggressiveness , , , and .
Three different assays measuring urinary PCA3 mRNA after digital rectal examination (DRE) were then developed , , and . Out of prostate cells shed into urine after prostate massage, these assays measure PCA3 mRNA, which is highly upregulated in neoplastic prostate tissue, simultaneously with prostate-specific antigen (PSA) mRNA, which is not upregulated in prostate cancer (PCa) and used to normalise for the amount of prostate-specific RNA in the molecular test sample.
After the third-generation PCA3 assay (Progensa)  attained Conformité européenne (CE) approval in 2006, several clinical studies were conducted to evaluate PCA3 as a novel diagnostic marker, to counsel or confirm biopsy indications, and to rule out aggressive cancer at biopsy. The clinical staging significance of preoperative urinary PCA3 was assessed to identify pathologic favourable and/or unfavourable features, such as small-volume/insignificant PCa, locally advanced disease, and aggressive disease. Based on promising findings from previous studies, the novel marker was further evaluated in its ability to predict biopsy progression in men undergoing active surveillance (AS) and as a first-line diagnostic test in prescreened men. (Table 1)
|Clinical scenario/end points||Reference||Patients, n||Risk factors||Results|
|Deras et al. ||570||PSA, DRE, age, PV
|Chun et al. ||809||PSA, DRE, age
|Marks et al. ||226||PSA
|Haese et al. ||463||PSA, DRE, age, %fPSA, PV
|Roobol et al. ||721||PSA, DRE, age, %fPSA, PV
|Tosoian et al. ||294||PSA, age, %fPSA, PV
|Progression at Bx (yes vs no):
PSA: 5.0 vs 4.0; p
%fPSA: 18 vs 21; p
PCA3: 47 vs 33; p
|Nakanishi et al. ||83||PSA, DRE, age, race, PV, PPC
|Prediction of tumour volume <0.5 ml
|Whitman et al. ||72||PSA, DRE, age, race, PV, Bx-GS, PPC, PCA3||Prediction of extracapsular extension:
|Hessels et al. ||70||PSA, DRE, age, PV, Bx-GS
|Correlation of PCA3 to pathologic features:
Tumour volume <0.5 ml: p
Insignificant PCa: p
Extracapsular extension: p
Prostatectomy GS ≥7: p
|Auprich et al. ||305||PSA, DRE, age, race, PV, Bx-GS, PPC, PCA3||Prediction of tumour volume <0.5 ml:
Prediction of insignificant PCa:
Beyond these clinical implications, further research was also directed at evaluating its potential use in combination with other new biomarkers and as a novel target for PCa therapy, which all reflects a highly promising future for PCA3.
This review considers the current clinical evidence investigating PCA3's clinical role in screening, early detection, AS, and preoperative staging. Several significant aspects such as test applicability and robustness, combinations with other new biomarkers, and potential further applications of PCA3 are also discussed.
2. Evidence acquisition
A systematic review of the literature was performed in February 2011 using the National Library of Medicine's PubMed database (1999–2011). This search included both Medical Subjects Heading (MeSH) search terms and free-text protocols. Specifically, the MeSH search was conducted by combining the following terms retrieved from the MeSH browser provided by Medline: PCA3, DD3, UPM3, prostate cancer, cell lines, prostate tissue, prostate biopsy, detection, diagnosis, radical prostatectomy, staging, grading, progression, and gene therapy. The search results were subsequently restricted to the English language. This approach resulted in 47 PCA3 studies, selected by the 10 authors to discuss in this collaborative review, including 9 basic papers, 19 and 7 reports on diagnostic and staging, respectively, and 12 studies on new diagnostic and therapeutic concepts of PCA3.
3. Evidence synthesis
3.1. History of PCA3: from characterisation to development of a urine test
Bussemakers et al. were the first to identify and characterise the DD3PCA3 or PCA3DD3 gene (Fig. 1) comparing PCa tissue with nonmalignant prostatic tissue. Using a reverse transcriptase polymerase chain reaction (RT-PCR) method, they detected PCA3 overexpressed in cancerous tissue with low expression in benign prostatic tissue and not measurable in the normal tissue of numerous organs such as the prostate, testis, bladder, kidney seminal vesicles, brain, and lung. Specifically, the expression of PCA3, a noncoding RNA located on chromosome 9q21–22 whose function is unknown, is highly prostate specific, and it was overexpressed in 94.6% of tumour lesions, in only 1 of 7 human PCa cell lines (lymph node carcinoma of the prostate), and in none of 18 nonmalignant prostate samples .
Using a quantitative real-time RT-PCR technique, comparing PCA3 with human telomerase reverse transcriptase, de Kok et al. demonstrated a 34-fold versus 6-fold higher mRNA expression in malignant compared with nonmalignant prostatic tissue, even if the samples contained <10% tumour (Fig. 2) .
These fundamental findings promoted the development of a PCA3 diagnostic test. Based on the idea of prostate cells shedding into the urine after prostate massage, Hessels et al. reported first on PCA3 mRNA measurement in sedimented urine. In detail, the first voided proportion of urine was collected after a thorough rectal examination of the prostate, consisting of exactly three strokes, with firm pressure to depress the prostate surface for several millimetres, applied from the base to the apex and from the lateral to the median line for each lobe. PSA mRNA was used to normalise the test for the number of prostate cells in the urine sediment. Although PSA expression is constant in normal cells and weakly (1.5-fold) downregulated in PCa cells, the so-called PCA3 score, which is the ratio between PCA3 mRNA over PSA mRNA multiplied by 1000, was presented as a new diagnostic tool. Using a determined PCA3-PSA cut-off of 200
Using the second-generation PCA3 test (uPM3 assay), Tinzl et al. at first compared the new urinary marker to PSA among men undergoing initial and repeat biopsy for an elevated PSA. Although the informative rate (79%) in this study was inferior to current third-generation assays, PCA3 outperformed PSA, achieving a sensitivity and specificity of 82% and 76% versus 87% and 16%, respectively . Despite this remarkable diagnostic improvement, 21% of all samples would not have provided any information about patients’ risk of PCa. Using the same assay, Fradet et al. confirmed this diagnostic superiority (PCA3 vs PSA: area under the curve [AUC] 81% vs 40%) in the first multicentre cohort of 443 men undergoing 6- to 10-core random biopsy, although again among men preselected for biopsy based on an elevated PSA .
In 2006, Groskopf et al. presented a prototype of a quantitative, validated PCA3-based urine test using post-DRE whole-urine specimens further processed in a single-tube format, which is thus fundamentally different from earlier developed assays  and . Assay stability was evaluated in archived urine specimens stored at either 4
The analytic performance of the newly developed PCA3 assay subsequently was intensively tested in a multicentre evaluation (n
Although the US Food and Drug Administration approval process is currently ongoing, the CE approved the PCA3 test in November 2006 to assist clinicians in counselling and confirming initial and repeat biopsy indications.
3.2. Clinical applicability of prostate cancer antigen 3 for early detection
Despite substantial improvements in early detection due to PSA  and , a main limitation remains the high proportion of men detected with nonmalignant findings at first or subsequent biopsy. Therefore, one of the most important clinical rationales of a meaningful PCA3 application aims at reducing the number of potentially unnecessary biopsies.
Marks and coworkers first tested this in 226 consecutive men undergoing repeat biopsy. They demonstrated PCA3's superiority over PSA (AUC: 0.68 vs 0.52; p
Subsequently, US and European prospective multicentre trials were conducted in patients undergoing initial or repeat biopsy by Deras et al.  and first or second repeat biopsy by Haese et al. (Fig. 3) . Within these studies comparable diagnostic accuracies of US and European men at first repeat biopsy (AUC: 0.68 vs 0.65) were reported. Interestingly, PCA3 predicted biopsy outcome in European men on second repeat biopsy with slightly increased accuracy compared with those on first repeat biopsy (AUC: 0.67 vs 0.65). This aspect, which seems counterintuitive, stands in contrast to the findings of Deras et al.  and needs to be validated in further PCA3 biopsy protocols. Both studies revealed conflicting results in PCA3's association with cancer aggressiveness, which is discussed in the next section of this review. However, both studies demonstrated that combining PCA3 with established biopsy risk factors such as age, PSA, DRE, prostate volume, and percent free PSA (%fPSA) improved the diagnostic accuracy in multivariable regression models. A subgroup analysis (n
In line with previous studies, incorporating PCA3 in the Prostate Cancer Prevention Trial risk calculator (PCPT-RC) improved the diagnostic accuracy compared with the established biopsy risk factors (AUC: 0.65 vs 0.70) . Applying the most stringent statistical criteria following Kattan  and , Chun et al. demonstrated in a large mixed biopsy patient cohort from Europe and North America (n
In this context, Perdona and coworkers directly compared the updated PCPT-RC, including PCA3, and Chun's PCA3-based nomogram. They demonstrated significantly better discriminative power of the updated PCPT-RC (AUC: 0.80 vs 0.72; p
Regarding health care expenses, it must be acknowledged that different European countries have different reimbursement systems. In general, urinary PCA3
Taken together, using mainly data from two multicentre trials, PCA3 was confirmed as a reliable predictor of PCa at biopsy, demonstrating superiority over PSA and %fPSA. Its combination with established risk factors demonstrated improved accuracy and applicability of newly developed diagnostic tools to assist clinicians in biopsy decision making among men who already met an established criteria for biopsy (ie, elevated PSA or abnormal DRE). However, whether PCA3 should be used as a continuous coded variable or whether different cut-offs (eg, PCA3 score 35) should be used at each specific biopsy scenario (eg, initial, first repeat, second repeat) must be addressed in future trials.
3.3. Potential use of prostate cancer antigen 3 in screening and active surveillance
Most recently, PCA3 was assessed as a first-line screening test within the European Randomised Study of Screening for Prostate Cancer trial. A PCA3 score ≥10 demonstrated a positive predictive value of 17.1 compared with 18.8 for a PSA value ≥3.0 ng/ml. Interestingly, PCA3 versus PSA missed substantially fewer cancers (32.0% vs 64.7%) and serious cancers (26.3 vs 57.9%). Because this unique study evaluated a PSA-prescreened cohort (third round or more; 33% had a negative first biopsy), a consecutive study in unscreened patients, avoiding attribution bias, should be conducted to further assess PCA3 as a potential screening marker .
Recently, Tosoian et al. assessed PCA3's ability to rule out clinically significant PCa in men undergoing AS as defined by the biopsy criteria of Epstein et al. . A trend towards higher median PCA3 scores in patients with GS upgrading at follow-up biopsy (72 vs 50.8; p
3.4. Prostate cancer antigen 3: a prognostic marker to predict tumour volume, stage, and grade?
Given that PCA3 is highly overexpressed in PCa tissue and improves the prediction of biopsy outcome, several studies have focused on its potential ability to predict PCa stage and aggressiveness before definitive therapy.
Bostwick et al. at first reported on 24 patients undergoing radical prostatectomy (RP) after being diagnosed with PCa based on a suspicious urinary UPM3 test. The assessed RP specimens demonstrated no difference in cancer volume, location, stage, and GS compared with RP specimens of men diagnosed with PCa based on PSA or suspicious DRE findings .
Using the Progensa PCA3 assay, Nakanishi and coworkers analysing 83 RP samples reported that the urinary PCA3 score significantly correlated with tumour volume (TV), GS, and independently predicted small-volume diseases (TV
The largest published series so far on urinary PCA3's correlation to clinicopathologic features (n
The assumption that higher PCA3 scores are associated with more aggressive cancer is based on the hypothesis that with increasing dedifferentiation, PCa cells become more invasive and could therefore more easily be shed into the ductal system of the prostatic gland after DRE or that larger tumours simply have more surface area over which to shed PCA3  and . Although most studies, especially in RP cohorts, failed to confirm this hypothesis , , , , and , some authors suggest that, following Gleason's scoring system , tumours with pattern 4 and 5 increasingly lose their glandular differentiation and luminas, disabling cells to be shed into urine after DRE in correlation with their TV. Therefore, potentially higher PCA3 mRNA tissue levels, resulting from larger tumour masses, might not be adequately measured by the urinary test .
Taken together, evaluations on PCA3's potential prognostic ability, which are currently based on a relatively small number of patients (n
3.5. Potential prostate cancer antigen 3 score alterations over time and following bioptic or medical intervention
Within the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial, urinary PCA3, PSA, and %fPSA were available at the year 2 and year 4 follow-up biopsy in 1072 men (age: 50–75 yr; PSA: 2.5–10 ng/ml; one previous negative 6- to 12-core biopsy). On univariable analyses for the prediction of year 4 biopsy outcome based on year 2 biomarker values, PCA3 score was exclusively found as a significant predictor for a positive follow-up biopsy at year 4. Interestingly, PCA3 scores in biopsy-positive men only slightly increased (+15.7%) within the study period .
Larre et al, evaluating urinary PCA3 scores before and 2
In this context, the influence of dutasteride (5α-reductase inhibitor [5-ARI]) on prostatic markers was assessed by Gils et al. . In 16 men with benign prostatic hyperplasia (BPH) and 9 men with clinically localised PCa (all treated with 5-ARI), PSA, testosterone, dihydrotestosterone (DHT), and urinary PCA3 were measured at baseline and 1, 2, and 3 mo thereafter. As expected, dutasteride reduced DHT (>90%), halved PSA levels, decreased prostate volume (10–16%), and increased testosterone (20–30%). In contrast, 5-ARI treatment had a widely variable effect on PCA3 scores, which increased (75–284%) and decreased (14–77%) over time, irrespective of whether patients with or without PCa were observed . This needs to be taken into account when counselling patients on dutasteride who are designated for a PCA3 test.
3.6. New perspectives
3.6.1. Combination of prostate cancer antigen 3 with new biomarkers
Since PCA3 was introduced as highly PCa specific and as a clinically useful marker to predict biopsy outcome, its combined use with other new tumour markers may further improve its diagnostic accuracy. Therefore, transcripts of a fusion between the transmembrane-serine protease gene (TMPRSS2) and the v-ets erythroblastosis virus E26 oncogene (ERG) were evaluated in combination with PCA3 in the post-DRE urine of 108 patients undergoing prostate biopsy. It is of note that TMPRSS2-ERG fusion transcripts were only found in 59% of the primary PCa tissue specimens, and the included patients did not represent a typical biopsy cohort because PCa detection rate was quite high with 72% due to PSA levels ranging from 1.1 to 1619 ng/ml. Urine sediments of men diagnosed with PCa were positive for TMPRSS2-ERG fusion transcripts and PCA3 (cut-off: 48) in 37% and 62%, respectively. Combining both markers improved the sensitivity to 73%, yet a considerable decreased specificity of 63%, compared with 93% of TMPRSS2-ERG fusion alone .
In addition, Laxman and coworkers evaluated golgi membrane protein 1 (GOLM1), serine peptidase inhibitor, Kazal type 1 (SPINK1), PCA3, and TMPRSS2-ERG fusion in sedimented urine of men before biopsy (n
Despite the fact that the reported studies used PCA3 cut-off values (19.9, 48) different from the more established cut-off value of 35 reported in previous studies , , , , , and , a substantial improvement in predicting biopsy outcome was demonstrated by combining PCA3 and new biomarkers in a limited number of patients. If these promising results could be confirmed by further studies, combinations of new biomarkers including PCA3 may potentially offer an interesting new perspective on the early detection and staging of PCa. However, because to date most of the markers combined with PCA3 are still in their experimental phase, it remains to be assessed which marker panel has the greatest potential to improve predictive ability compared with established markers.
3.6.2. Detection of prostate cancer antigen 3 in circulating tumour cells
In PCa patients, circulating tumour cells (CTCs) are correlated with a poor prognosis . For this reason detection of specific biomarkers found in prostatic CTCs could potentially indicate an advanced and aggressive stage of disease.
In 2008, Väänänen et al. described a quantitative RT-PCR assay for the detection of PCA3 mRNA in peripheral blood and evaluated 67 patients with locally advanced (n
In summary, the detection of PCA3 mRNA expression in CTCs from peripheral blood proved to be feasible, although what role this has in identifying patients with poor prognosis is unknown because the data to date are quite limited and further studies are needed.
3.6.3. Prostate cancer antigen 3 as a novel gene therapy target
Because Van der Poel et al. demonstrated the high PCa specificity of PCA3 and using a specific diphtheria toxin model highlighted its potential use as a precursor to suicide gene therapy , a combination of PCA3's promoter region driving expression of a suicide gene could be used to process novel PCa therapies. In theory, this combined therapeutic construct will bind, interact, and finally induce cell death in PCa tissue, and nonmalignant and nonprostatic cells will not be involved in this highly specific therapeutic cascade.
Based on this concept, Fan and coworkers developed an oncolytic adenovirus (Ad.DD3-E1A-IL-24), in which replication is driven by the PCA3DD3 promoter, carrying the therapeutic gene interleukin (IL)-24. Its in vitro and in vivo effects were investigated in DU-145 cell lines and in DU-145 xenograft tumours in nude mice. In five of six treated mice, tumours were completely eliminated within 50 d. Most remarkably, all mice stayed alive until the end of observation . Despite nonnegligible discrepancies regarding the therapeutic effect of Ad.DD3-E1A-IL-24 in vitro and in vivo, this study demonstrated “Gene-ViroTherapy's” excellent antitumoural efficacy in an initial small single tumour model study in mice. Therefore further investigations on PCA3's potential role in PCa gene therapy should be intensively promoted in the future.
3.7. Actual role of prostate cancer antigen 3 in clinical routine
In the European Association of Urology Guidelines 2011 , the use of PCA3 in the detection setting is classified as experimental and therefore cannot be recommended. However PCA3's value in identifying PCa, especially in men with an initially negative biopsy, is supported by growing level 2a evidence , , , , , , , , and . Therefore, PCA3 may be most clinically relevant in the repeat biopsy setting, using a cut-off of 35 to confirm repeat prostate biopsy indication.
This systematic review of PCA3 studies published within the last 12 yr reveals that the PCA3 gene is highly PCa specific, and its application on initial technically challenging research assays to today's standardised commercially available platforms offers simple applicability and reliable robustness. Based on PCA3's confirmed superiority over PSA and %fPSA in the further stratification of men selected for biopsy based on an elevated PSA and/or abnormal DRE, its combined use with established biopsy risk factors, particularly within nomograms or risk calculators, may assist clinicians in counselling and confirming biopsy indications. Based on relatively small patient numbers, PCA3 was identified to independently predict small-volume and insignificant PCa; however, PCA3 was not associated with advanced disease and was limited in the prediction of aggressive cancer in men undergoing RP. In several pilot studies, PCA3 together with other potential new markers improved the multivariable accuracy in predicting biopsy outcome, although by only a modest amount (2–5%). Finally, the implementation of the PCA3 promoter in developing new highly PCa-specific gene therapies represents a promising perspective in the near future.
Study concept and design: Auprich, Bjartell, Chun, Freedland, Haese, van der Poel, Schalken, Stenzl, de la Taille, Tombal.
Acquisition of data: None.
Analysis and interpretation of data: None.
Drafting of the manuscript: Auprich.
Critical revision of the manuscript for important intellectual content: Auprich, Bjartell, Chun, Freedland, Haese, van der Poel, Schalken, Stenzl, de la Taille, Tombal.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Other (specify): None.
Financial disclosures: I certify 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: None.
Funding/Support and role of the sponsor: None.
-  M.J. Bussemakers, A. van Bokhoven, G.W. Verhaegh, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59:5975-5979
-  J.B. de Kok, G.W. Verhaegh, R.W. Roelofs, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002;62:2695-2698
-  D. Hessels, J.M.T. Klein Gunnewiek, I. van Oort, et al. DD3PCA3-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol. 2003;44:8-16 discussion 15–6 Crossref.
-  K.A. Landers, M.J. Burger, M.A. Tebay, et al. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int J Cancer. 2005;114:950-956 Crossref.
-  U. Schmidt, S. Fuessel, R. Koch, et al. Quantitative multi-gene expression profiling of primary prostate cancer. Prostate. 2006;66:1521-1534 Crossref.
-  H. Bialkowska-Hobrzanska, D.K. Driman, R. Fletcher, V. Harry, H. Razvi. Expression of human telomerase reverse transcriptase, survivin, DD3 and PCGEM1 messenger RNA in archival prostate carcinoma tissue. Can J Urol. 2006;13:2967-2974
-  I. Popa, Y. Fradet, G. Beaudry, H. Hovington, G. Beaudry, B. Tetu. Identification of PCA3 (DD3) in prostatic carcinoma by in situ hybridization. Mod Pathol. 2007;20:1121-1127 Crossref.
-  J. Klecka, L. Holubec, M. Pesta, et al. Differential display code 3 (DD3/PCA3) in prostate cancer diagnosis. Anticancer Res. 2010;30:665-670
-  M. Tinzl, M. Marberger, S. Horvath, C. Chypre. DD3PCA3 RNA analysis in urine – a new perspective for detecting prostate cancer. Eur Urol. 2004;46:182-187 discussion 187 Crossref.
-  J. Groskopf, S.M. Aubin, I.L. Deras, et al. APTIMA PCA3 molecular urine test: development of a method to aid in the diagnosis of prostate cancer. Clin Chem. 2006;52:1089-1095 Crossref.
-  Y. Fradet, F. Saad, A. Aprikian, et al. uPM3, a new molecular urine test for the detection of prostate cancer. Urology. 2004;64:311-315 discussion 315–6 Crossref.
-  L.J. Sokoll, W. Ellis, P. Lange, et al. A multicenter evaluation of the PCA3 molecular urine test: pre-analytical effects, analytical performance, and diagnostic accuracy. Clin Chim Acta. 2008;389:1-6 Crossref.
-  D. Schilling, J. Hennenlotter, M. Munz, U. Bokeler, K.D. Sievert, A. Stenzl. Interpretation of the prostate cancer gene 3 in reference to the individual clinical background: implications for daily practice. Urol Int. 2010;85:159-165 Crossref.
-  A. Haese, A. de la Taille, H. van Poppel, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol. 2008;54:1081-1088 Abstract, Full-text, PDF, Crossref.
-  L.S. Marks, Y. Fradet, I.L. Deras, et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology. 2007;69:532-535 Crossref.
-  S.B. Shappell, J. Fulmer, D. Arguello, B.S. Wright, J.R. Oppenheimer, M.J. Putzi. PCA3 urine mRNA testing for prostate carcinoma: patterns of use by community urologists and assay performance in reference laboratory setting. Urology. 2009;73:363-368 Crossref.
-  J.J. Tosoian, S. Loeb, A. Kettermann, et al. Accuracy of PCA3 measurement in predicting short-term biopsy progression in an active surveillance program. J Urol. 2010;183:534-538 Crossref.
-  R. Wang, A.M. Chinnaiyan, R.L. Dunn, K.J. Wojno, J.T. Wei. Rational approach to implementation of prostate cancer antigen 3 into clinical care. Cancer. 2009;115:3879-3886 Crossref.
-  M. Nyberg, D. Ulmert, A. Lindgren, U. Lindstrom, P.A. Abrahamsson, A. Bjartell. PCA3 as a diagnostic marker for prostate cancer: a validation study on a Swedish patient population. Scand J Urol Nephrol. 2010;44:378-383 Crossref.
-  S.M. Aubin, J. Reid, M.J. Sarno, et al. PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. J Urol. 2010;184:1947-1952 Crossref.
-  F.H. Schroder, J. Hugosson, M.J. Roobol, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-1328 Crossref.
-  G.L. Andriole, E.D. Crawford, R.L. Grubb 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319 Crossref.
-  I.L. Deras, S.M. Aubin, A. Blase, et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol. 2008;179:1587-1592 Crossref.
-  G. Ploussard, A. Haese, H. van Poppel, et al. The prostate cancer gene 3 (PCA3) urine test in men with previous negative biopsies: does free-to-total prostate-specific antigen ratio influence the performance of the PCA3 score in predicting positive biopsies?. BJU Int. 2010;106:1143-1147 Crossref.
-  D.P. Ankerst, J. Groskopf, J.R. Day, et al. Predicting prostate cancer risk through incorporation of prostate cancer gene 3. J Urol. 2008;180:1303-1308 discussion 1308 Crossref.
-  M.W. Kattan. Evaluating a new marker's predictive contribution. Clin Cancer Res. 2004;10:822-824 Crossref.
-  M.W. Kattan. Judging new markers by their ability to improve predictive accuracy. J Natl Cancer Inst. 2003;95:634-635 Crossref.
-  F.K. Chun, A. de la Taille, H. van Poppel, et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol. 2009;56:659-668 Abstract, Full-text, PDF, Crossref.
-  M. Auprich, A. Haese, J. Walz, et al. External validation of urinary PCA3-based nomograms to individually predict prostate biopsy outcome. Eur Urol. 2010;58:727-732 Abstract, Full-text, PDF, Crossref.
-  S. Perdonà, V. Cavadas, G. Di Lorenzo, et al. Prostate cancer detection in the “grey area” of prostate-specific antigen below 10 ng/ml: head-to-head comparison of the updated PCPT calculator and Chun's nomogram, two risk estimators incorporating prostate cancer antigen 3. Eur Urol. 2011;59:81-87
-  M.J. Roobol, F.H. Schröder, P. van Leeuwen, et al. Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test. Eur Urol. 2010;58:475-481 Abstract, Full-text, PDF, Crossref.
-  J.I. Epstein, P.C. Walsh, M. Carmichael, C.B. Brendler. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994;271:368-374 Crossref.
-  D.G. Bostwick, V.E. Gould, J. Qian, M. Susani, M. Marberger. Prostate cancer detected by uPM3: radical prostatectomy findings. Mod Pathol. 2006;19:630-633 Crossref.
-  H. Nakanishi, J. Groskopf, H.A. Fritsche, et al. PCA3 molecular urine assay correlates with prostate cancer tumor volume: implication in selecting candidates for active surveillance. J Urol. 2008;179:1804-1809 discussion 1809–10
-  E.J. Whitman, J. Groskopf, A. Ali, et al. PCA3 score before radical prostatectomy predicts extracapsular extension and tumor volume. J Urol. 2008;180:1975-1978 discussion 1978–9
-  D. Hessels, M.P. van Gils, O. van Hooij, et al. Predictive value of PCA3 in urinary sediments in determining clinico-pathological characteristics of prostate cancer. Prostate. 2010;70:10-16 Crossref.
-  M.P. van Gils, D. Hessels, C.A. Hulsbergen-van de Kaa, et al. Detailed analysis of histopathological parameters in radical prostatectomy specimens and PCA3 urine test results. Prostate. 2008;68:1215-1222 Crossref.
-  M. Auprich, F.K.-H. Chun, J.F. Ward, et al. Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. Eur Urol. 2011;59:96-105 Abstract, Full-text, PDF, Crossref.
-  G. Ploussard, X. Durand, E. Xylinas, et al. Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance. Eur Urol. 2011;59:422-429 Abstract, Full-text, PDF, Crossref.
-  D.F. Gleason, G.T. Mellinger. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol. 1974;111:58-64
-  S. Larré, C. Ronsin, J. Irani. Immediate impact of ultrasound-guided prostate biopsies on PCA3 score. Eur Urol. 2010;57:1121-1122
-  M.P. van Gils, D. Hessels, W.P. Peelen, H. Vergunst, P.F. Mulders, J.A. Schalken. Preliminary evaluation of the effect of dutasteride on PCA3 in post-DRE urine sediments: a randomized, open-label, parallel-group pilot study. Prostate. 2009;69:1624-1634 Crossref.
-  D. Hessels, F.P. Smit, G.W. Verhaegh, J.A. Witjes, E.B. Cornel, J.A. Schalken. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin Cancer Res. 2007;13:5103-5108 Crossref.
-  B. Laxman, D.S. Morris, J. Yu, et al. A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. Cancer Res. 2008;68:645-649 Crossref.
-  B. Ouyang, B. Bracken, B. Burke, E. Chung, J. Liang, S.M. Ho. A duplex quantitative polymerase chain reaction assay based on quantification of alpha-methylacyl-CoA racemase transcripts and prostate cancer antigen 3 in urine sediments improved diagnostic accuracy for prostate cancer. J Urol. 2009;181:2508-2513 discussion 2513–4
-  M. Rigau, J. Morote, M.C. Mir, et al. PSGR and PCA3 as biomarkers for the detection of prostate cancer in urine. Prostate. 2010;70:1760-1767
-  D.C. Danila, G. Heller, G.A. Gignac, et al. Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res. 2007;13:7053-7058 Crossref.
-  R.M. Väänänen, M. Rissanen, O. Kauko, et al. Quantitative real-time RT-PCR assay for PCA3. Clin Biochem. 2008;41:103-108
K. Marangoni, T.G. Araujo, A.F. Neves, L.R. Goulart. The -786T
> C promoter polymorphism of the NOS3 gene is associated with prostate cancer progression. BMC Cancer. 2008;8:273 Crossref.
-  G. Shaw, A.M. Price, E. Ktori, et al. Hedgehog signalling in androgen independent prostate cancer. Eur Urol. 2008;54:1333-1343 Abstract, Full-text, PDF, Crossref.
-  M. Jost, J.R. Day, R. Slaughter, et al. Molecular assays for the detection of prostate tumor derived nucleic acids in peripheral blood. Mol Cancer. 2011;9:174
-  H.G. van der Poel, J. McCadden, G.W. Verhaegh, et al. A novel method for the determination of basal gene expression of tissue-specific promoters: an analysis of prostate-specific promoters. Cancer Gene Ther. 2001;8:927-935 Crossref.
-  J.K. Fan, N. Wei, M. Ding, et al. Targeting Gene-ViroTherapy for prostate cancer by DD3-driven oncolytic virus-harboring interleukin-24 gene. Int J Cancer. 2010;127:707-717 Crossref.
-  A. Heidenreich, J. Bellmunt, M. Bolla, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61-71 Abstract, Full-text, PDF, Crossref.
-  M. Remzi, A. Haese, H. van Poppel, et al. Follow-up of men with an elevated PCA3 score and a negative biopsy: does an elevated PCA3 score indeed predict the presence of prostate cancer?. BJU Int. 2010;106:1138-1142 Crossref.
-  D. Hessels, J.A. Schalken. The use of PCA3 in the diagnosis of prostate cancer. Nat Rev Urol. 2009;6:255-261 Crossref.
a Department of Urology, Medical University of Graz, Graz, Austria
b Department of Urology, Skåne University Hospital Malmö, Malmö, Sweden
c Department of Urology, University Clinic Eppendorf, Hamburg, Germany
d Department of Urology, CHU Henri Mondor, Paris, France
e Department of Surgery, Durham VA Medical Center and the Duke Prostate Center, Division of Urological Surgery, Departments of Surgery and Pathology, Duke University School of Medicine, Durham, NC, USA
f Martini Clinic Prostate Cancer Center, University Clinic Eppendorf, Hamburg, Germany
g Department of Experimental Urology, Radboud University Nijmegan Medical Center, Nijmegen, Netherlands
h Department of Urology, University Hospital and Faculty of Medicine, Tübingen, Germany
i Department of Urology, Clinique universitaire Saint Luc, Université catholique de Louvain, Brussels, Belgium
j Department of Urology, The Netherlands Cancer Institute, Amsterdam, Netherlands
© 2011 European Association of Urology, Published by Elsevier B.V.