Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions

Prostate Cancer and Prostatic Diseases volume 20, pages 12–19 (2017)Cite this article

Subjects

Abstract

BACKGROUND:

The diagnosis of prostate cancer (PCa) is currently based on serum PSA testing and/or abnormal digital rectal examination and histopathologic evaluation of prostate biopsies. The main drawback of PSA testing is the lack of specificity for PCa. To improve early detection of PCa more specific biomarkers are needed. In the past few years, many new promising biomarkers have been identified; however, to date, only a few have reached clinical practice.

METHODS:

In this review, we discuss new blood-based and urinary biomarker models that are promising for usage in PCa detection, follow-up and treatment decision-making. These include Prostate Health Index (PHI), prostate cancer antigen 3 (PCA3), four-kallikrein panel (4K), transmembrane protease serine 2-ERG (TMPRSS2-ERG), ExoDx Prostate Intelliscore, SelectMDx and the Mi-Prostate score. Only few head-to-head studies are available for these new fluid-based biomarkers and/or models. The blood-based PHI and urinary PCA3 are two US Food and Drug Administration-approved biomarkers for diagnosis of PCa. In the second part of this review, we give an overview of published studies comparing these two available biomarkers for prediction of (1) PCa upon prostate biopsy, (2) pathological features in radical prostatectomy specimen and (3) significant PCa in patients eligible for active surveillance.

RESULTS:

Studies show opposing results in comparison of PHI with PCA3 for prediction of PCa upon initial and repeat prostate biopsy. PHI and PCA3 are able to predict pathological findings on radical prostatectomy specimen, such as tumor volume and Gleason score. Only PHI could predict seminal vesicle invasion and only PCA3 could predict multifocality. There is some evidence that PHI outperforms PCA3 in predicting significant PCa in an active surveillance population.

CONCLUSIONS:

Future research should focus on independent validation of promising fluid-based biomarkers/models, and prospective comparison of biomarkers with each other.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.

    Article  PubMed  Google Scholar 

  2. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: 1320–1328.

    Article  PubMed  Google Scholar 

  3. Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst 2009; 101: 374–383.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Salagierski M, Schalken JA . Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. J Urol 2012; 187: 795–801.

    Article  CAS  PubMed  Google Scholar 

  5. Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, Parnes HL et al. Prevalence of prostate cancer among men with a prostate-specific antigen level <or =4.0 ng per milliliter. N Engl J Med 2004; 350: 2239–2246.

    Article  CAS  PubMed  Google Scholar 

  6. Truong M, Yang B, Jarrard DF . Toward the detection of prostate cancer in urine: a critical analysis. J Urol 2013; 189: 422–429.

    Article  CAS  PubMed  Google Scholar 

  7. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279: 1542–1547.

    Article  CAS  PubMed  Google Scholar 

  8. Mikolajczyk SD, Catalona WJ, Evans CL, Linton HJ, Millar LS, Marker KM et al. Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem 2004; 50: 1017–1025.

    Article  CAS  PubMed  Google Scholar 

  9. Guazzoni G, Nava L, Lazzeri M, Scattoni V, Lughezzani G, Maccagnano C et al. Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting. Eur Urol 2011; 60: 214–222.

    Article  CAS  PubMed  Google Scholar 

  10. Sokoll LJ, Sanda MG, Feng Z, Kagan J, Mizrahi IA, Broyles DL et al. A prospective, multicenter, National Cancer Institute Early Detection Research Network study of [−2]proPSA: improving prostate cancer detection and correlating with cancer aggressiveness. Cancer Epidemiol Biomarkers Prev 2010; 19: 1193–1200.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH et al. A multicenter study of [−2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol 2011; 185: 1650–1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Loeb S, Catalona WJ . The Prostate Health Index: a new test for the detection of prostate cancer. Ther Adv Urol 2014; 6: 74–77.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res 1999; 59: 5975–5979.

    CAS  PubMed  Google Scholar 

  14. de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res 2002; 62: 2695–2698.

    CAS  PubMed  Google Scholar 

  15. Hessels D, Klein Gunnewiek JM, van Oort I, Karthaus HF, van Leenders GJ, van Balken B et al. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003; 44: 8–15 discussion 15-16.

    Article  CAS  PubMed  Google Scholar 

  16. Hessels D, Schalken JA . Urinary biomarkers for prostate cancer: a review. Asian J Androl 2013; 15: 333–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Groskopf J, Aubin SM, Deras IL, Blase A, Bodrug S, Clark C 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.

    Article  CAS  PubMed  Google Scholar 

  18. Marks LS, Fradet Y, Deras IL, Blase A, Mathis J, Aubin SM et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology 2007; 69: 532–535.

    Article  PubMed  Google Scholar 

  19. Schalken JA, Hessels D, Verhaegh G . New targets for therapy in prostate cancer: differential display code 3 (DD3(PCA3)), a highly prostate cancer-specific gene. Urology 2003; 62 (Suppl 1): 34–43.

    Article  PubMed  Google Scholar 

  20. Hessels D, Schalken JA . Recurrent gene fusions in prostate cancer: their clinical implications and uses. Curr Urol Rep 2013; 14: 214–222.

    Article  PubMed  Google Scholar 

  21. Ploussard G, Haese A, Van Poppel H, Marberger M, Stenzl A, Mulders PF 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.

    Article  PubMed  Google Scholar 

  22. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–648.

    Article  CAS  PubMed  Google Scholar 

  23. Perner S, Mosquera JM, Demichelis F, Hofer MD, Paris PL, Simko J et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol 2007; 31: 882–888.

    Article  PubMed  Google Scholar 

  24. Hessels D, Smit FP, Verhaegh GW, Witjes JA, Cornel EB, Schalken JA . 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.

    Article  CAS  PubMed  Google Scholar 

  25. Rajput AB, Miller MA, De Luca A, Boyd N, Leung S, Hurtado-Coll A et al. Frequency of the TMPRSS2:ERG gene fusion is increased in moderate to poorly differentiated prostate cancers. J Clin Pathol 2007; 60: 1238–1243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rostad K, Hellwinkel OJ, Haukaas SA, Halvorsen OJ, Oyan AM, Haese A et al. TMPRSS2:ERG fusion transcripts in urine from prostate cancer patients correlate with a less favorable prognosis. APMIS 2009; 117: 575–582.

    Article  CAS  PubMed  Google Scholar 

  27. Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012; 21: 1497–1509.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO et al. Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer 2009; 100: 1603–1607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. McKiernan J, Donovan MJ, O'Neill V, Bentink S, Noerholm M, Belzer S et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol 2016; 2: 882–889.

    Article  PubMed  Google Scholar 

  30. Donovan MJ, Noerholm M, Bentink S, Belzer S, Skog J, O'Neill V et al. A molecular signature of PCA3 and ERG exosomal RNA from non-DRE urine is predictive of initial prostate biopsy result. Prostate Cancer Prostatic Dis 2015; 18: 370–375.

    Article  CAS  PubMed  Google Scholar 

  31. Vickers AJ, Cronin AM, Aus G, Pihl CG, Becker C, Pettersson K et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden. BMC Med 2008; 6: 19.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Vickers A, Cronin A, Roobol M, Savage C, Peltola M, Pettersson K et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol 2010; 28: 2493–2498.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Parekh DJ, Punnen S, Sjoberg DD, Asroff SW, Bailen JL, Cochran JS et al. A multi-institutional prospective trial in the USA confirms that the 4 K score accurately identifies men with high-grade prostate cancer. Eur Urol 2015; 68: 464–470.

    Article  PubMed  Google Scholar 

  34. Nordstrom T, Vickers A, Assel M, Lilja H, Gronberg H, Eklund M . Comparison between the Four-kallikrein Panel and Prostate Health Index for predicting prostate cancer. Eur Urol 2015; 68: 139–146.

    Article  PubMed  Google Scholar 

  35. Leyten GH, Hessels D, Smit FP, Jannink SA, de Jong H, Melchers WJ et al. Identification of a candidate gene panel for the early diagnosis of prostate cancer. Clin Cancer Res 2015; 21: 3061–3070.

    Article  CAS  PubMed  Google Scholar 

  36. Van Neste L, Hendriks RJ, Dijkstra S, Trooskens G, Cornel EB, Jannink SA et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol 2016; 70: 740–748.

    Article  CAS  PubMed  Google Scholar 

  37. Leyten GH, Hessels D, Jannink SA, Smit FP, de Jong H, Cornel EB et al. Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer. Eur Urol 2014; 65: 534–542.

    Article  CAS  PubMed  Google Scholar 

  38. Cornu JN, Cancel-Tassin G, Egrot C, Gaffory C, Haab F, Cussenot O . Urine TMPRSS2:ERG fusion transcript integrated with PCA3 score, genotyping, and biological features are correlated to the results of prostatic biopsies in men at risk of prostate cancer. Prostate 2013; 73: 242–249.

    Article  CAS  PubMed  Google Scholar 

  39. Salami SS, Schmidt F, Laxman B, Regan MM, Rickman DS, Scherr D et al. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol Oncol 2013; 31: 566–571.

    Article  CAS  PubMed  Google Scholar 

  40. Tomlins SA, Day JR, Lonigro RJ, Hovelson DH, Siddiqui J, Kunju LP et al. Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2016; 70: 45–53.

    Article  CAS  PubMed  Google Scholar 

  41. Tonry CL, Leacy E, Raso C, Finn SP, Armstrong J, Pennington SR . The role of proteomics in biomarker development for improved patient diagnosis and clinical decision making in prostate cancer. Diagnostics 2016; 6: 27.

    Article  PubMed Central  Google Scholar 

  42. Ferro M, Bruzzese D, Perdona S, Mazzarella C, Marino A, Sorrentino A et al. Predicting prostate biopsy outcome: prostate health index (PHI) and prostate cancer antigen 3 (PCA3) are useful biomarkers. Clin Chim Acta 2012; 413: 1274–1278.

    Article  CAS  PubMed  Google Scholar 

  43. Seisen T, Roupret M, Brault D, Leon P, Cancel-Tassin G, Comperat E et al. Accuracy of the prostate health index versus the urinary prostate cancer antigen 3 score to predict overall and significant prostate cancer at initial biopsy. Prostate 2015; 75: 103–111.

    Article  PubMed  Google Scholar 

  44. Scattoni V, Lazzeri M, Lughezzani G, De Luca S, Passera R, Bollito E et al. Head-to-head comparison of prostate health index and urinary PCA3 for predicting cancer at initial or repeat biopsy. J Urol 2013; 190: 496–501.

    Article  PubMed  Google Scholar 

  45. Stephan C, Jung K, Semjonow A, Schulze-Forster K, Cammann H, Hu X et al. Comparative assessment of urinary prostate cancer antigen 3 and TMPRSS2:ERG gene fusion with the serum [−2]proprostate-specific antigen-based prostate health index for detection of prostate cancer. Clin Chem 2013; 59: 280–288.

    Article  CAS  PubMed  Google Scholar 

  46. Porpiglia F, Russo F, Manfredi M, Mele F, Fiori C, Bollito E et al. The roles of multiparametric magnetic resonance imaging, PCA3 and prostate health index-which is the best predictor of prostate cancer after a negative biopsy? J Urol 2014; 192: 60–66.

    Article  PubMed  Google Scholar 

  47. Perdona S, Bruzzese D, Ferro M, Autorino R, Marino A, Mazzarella C et al. Prostate health index (PHI) and prostate cancer antigen 3 (PCA3) significantly improve diagnostic accuracy in patients undergoing prostate biopsy. Prostate 2013; 73: 227–235.

    Article  PubMed  Google Scholar 

  48. Ferro M, Bruzzese D, Perdona S, Marino A, Mazzarella C, Perruolo G et al. Prostate health index (Phi) and prostate cancer antigen 3 (PCA3) significantly improve prostate cancer detection at initial biopsy in a total PSA range of 2-10 ng/ml. PLoS ONE 2013; 8: e67687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cantiello F, Russo GI, Ferro M, Cicione A, Cimino S, Favilla V et al. Prognostic accuracy of Prostate Health Index and urinary Prostate Cancer Antigen 3 in predicting pathologic features after radical prostatectomy. Urol Oncol 2015; 33: 163 e115–123.

    Article  Google Scholar 

  50. Tallon L, Luangphakdy D, Ruffion A, Colombel M, Devonec M, Champetier D et al. Comparative evaluation of urinary PCA3 and TMPRSS2: ERG scores and serum PHI in predicting prostate cancer aggressiveness. Int J Mol Sci 2014; 15: 13299–13316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ferro M, Lucarelli G, Bruzzese D, Perdona S, Mazzarella C, Perruolo G et al. Improving the prediction of pathologic outcomes in patients undergoing radical prostatectomy: the value of prostate cancer antigen 3 (PCA3), prostate health index (PHI) and sarcosine. Anticancer Res 2015; 35: 1017–1023.

    PubMed  Google Scholar 

  52. Fossati N, Buffi NM, Haese A, Stephan C, Larcher A, McNicholas T et al. Preoperative prostate-specific antigen isoform p2PSA and its derivatives, %p2PSA and prostate health index, predict pathologic outcomes in patients undergoing radical prostatectomy for prostate cancer: Results from a Multicentric European Prospective Study. Eur Urol 2015; 68: 132–138.

    Article  CAS  PubMed  Google Scholar 

  53. Bul M, Zhu X, Valdagni R, Pickles T, Kakehi Y, Rannikko A et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol 2013; 63: 597–603.

    Article  PubMed  Google Scholar 

  54. van den Bergh RC, Ahmed HU, Bangma CH, Cooperberg MR, Villers A, Parker CC . Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol 2014; 65: 1023–1031.

    Article  PubMed  Google Scholar 

  55. Cantiello F, Russo GI, Cicione A, Ferro M, Cimino S, Favilla V et al. PHI and PCA3 improve the prognostic performance of PRIAS and Epstein criteria in predicting insignificant prostate cancer in men eligible for active surveillance. World J Urol 2016; 34: 485–493.

    Article  PubMed  Google Scholar 

  56. Porpiglia F, Cantiello F, De Luca S, Manfredi M, Veltri A, Russo F et al. In-parallel comparative evaluation between multiparametric magnetic resonance imaging, prostate cancer antigen 3 and the prostate health index in predicting pathologically confirmed significant prostate cancer in men eligible for active surveillance. BJU Int 2015; 118: 527–534.

    Article  PubMed  Google Scholar 

  57. Roehl KA, Antenor JA, Catalona WJ . Serial biopsy results in prostate cancer screening study. J Urol 2002; 167: 2435–2439.

    Article  PubMed  Google Scholar 

  58. Wolters T, van der Kwast TH, Vissers CJ, Bangma CH, Roobol M, Schroder FH et al. False-negative prostate needle biopsies: frequency, histopathologic features, and follow-up. Am J Surg Pathol 2010; 34: 35–43.

    Article  PubMed  Google Scholar 

  59. De Luca S, Passera R, Cappia S, Bollito E, Randone DF, Milillo A et al. Fluctuation in prostate cancer gene 3 (PCA3) score in men undergoing first or repeat prostate biopsies. BJU Int 2014; 114: E56–E61.

    Article  CAS  PubMed  Google Scholar 

  60. Nicholson A, Mahon J, Boland A, Beale S, Dwan K, Fleeman N et al. The clinical effectiveness and cost-effectiveness of the PROGENSA(R) prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation. Health Technol Assess 2015; 19: 1–191.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands

    R J Hendriks, I M van Oort & J A Schalken

Authors
  1. R J Hendriks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I M van Oort
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J A Schalken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J A Schalken.

Ethics declarations

Competing interests

JAS and IMvO have consultancy with honoraria for Astellas, Janssen and Sanofi. The remaining author declares no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hendriks, R., van Oort, I. & Schalken, J. Blood-based and urinary prostate cancer biomarkers: a review and comparison of novel biomarkers for detection and treatment decisions. Prostate Cancer Prostatic Dis 20, 12–19 (2017). https://doi.org/10.1038/pcan.2016.59

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/pcan.2016.59

This article is cited by

Search

Advanced search

Quick links