Prognostic Biomarkers Used for Localised Prostate Cancer Management: A Systematic Review

Published:March 07, 2017DOI:



      Prostate cancer stratification is based on tumour size, pretreatment PSA level, and Gleason score, but it remains imperfect. Current research focuses on the discovery and validation of novel prognostic biomarkers to improve the identification of patients at risk of aggressive cancer or of tumour relapse.


      This systematic review by the Intergroupe Coopérateur Francophone de Recherche en Onco-urologie (ICFuro) analysed new evidence on the analytical validity and clinical validity and utility of six prognostic biomarkers (PHI, 4Kscore, MiPS, GPS, Prolaris, Decipher).

      Evidence acquisition

      All available data for the six biomarkers published between January 2002 and April 2015 were systematically searched and reviewed. The main endpoints were aggressive prostate cancer prediction, additional value compared to classical prognostic parameters, and clinical benefit for patients with localised prostate cancer.

      Evidence synthesis

      The preanalytical and analytical validations were heterogeneous for all tests and often not adequate for the molecular signatures. Each biomarker was studied for specific indications (candidates for a first or second biopsy, and potential candidates for active surveillance, radical prostatectomy, or adjuvant treatment) for which the level of evidence (LOE) was variable. PHI and 4Kscore were the biomarkers with the highest LOE for discriminating aggressive and indolent tumours in different indications.


      Blood biomarkers (PHI and 4Kscore) have the highest LOE for the prediction of more aggressive prostate cancer and could help clinicians to manage patients with localised prostate cancer. The other biomarkers show a potential prognostic value; however, they should be evaluated in additional studies to confirm their clinical validity.

      Patient summary

      We reviewed studies assessing the value of six prognostic biomarkers for prostate cancer. On the basis of the available evidence, some biomarkers could help in discriminating between aggressive and non-aggressive tumours with an additional value compared to the prognostic parameters currently used by clinicians.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Urology Focus
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Wong M.C.
        • Goggins W.B.
        • Wang H.H.
        • et al.
        Global incidence and mortality for prostate cancer: analysis of temporal patterns and trends in 36 countries.
        Eur Urol. 2016; 70: 862-874
        • Simon R.M.
        • Paik S.
        • Hayes D.F.
        Use of archived specimens in evaluation of prognostic and predictive biomarkers.
        J Natl Cancer Inst. 2009; 101: 1446-1452
        • Semjonow A.
        • Kopke T.
        • Eltze E.
        • Pepping-Schefers B.
        • Burgel H.
        • Darte C.
        Pre-analytical in-vitro stability of [−2]proPSA in blood and serum.
        Clin Biochem. 2010; 43: 926-928
        • Lamy P.J.
        • Montels F.
        • Tosi D.
        • et al.
        [Evaluation of (-2)proPSA in combination with total PSA and free PSA for the early detection of prostate cancer].
        Ann Biol Clin. 2013; 71: 537-544
        • Igawa T.
        • Takehara K.
        • Onita T.
        • Ito K.
        • Sakai H.
        Stability of [−2]pro-PSA in whole blood and serum: analysis for optimal measurement conditions.
        J Clin Lab Anal. 2014; 28: 315-319
        • Sokoll L.J.
        • Chan D.W.
        • Klee G.G.
        • et al.
        Multi-center analytical performance evaluation of the Access Hybritech p2PSA immunoassay.
        Clin Chim Acta. 2012; 413: 1279-1283
        • Parekh D.J.
        • Punnen S.
        • Sjoberg D.D.
        • et al.
        A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer.
        Eur Urol. 2015; 68: 464-470
        • Vaisanen V.
        • Peltola M.T.
        • Lilja H.
        • Nurmi M.
        • Pettersson K.
        Intact free prostate-specific antigen and free and total human glandular kallikrein 2. Elimination of assay interference by enzymatic digestion of antibodies to F(ab′)2 fragments.
        Anal Chem. 2006; 78: 7809-7815
        • Leyten G.H.
        • Hessels D.
        • Jannink S.A.
        • 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
        • Tomlins S.A.
        • Day J.R.
        • Lonigro R.J.
        • et al.
        Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment.
        Eur Urol. 2016; 70: 45-53
        • Tomlins S.A.
        • Aubin S.M.
        • Siddiqui J.
        • et al.
        Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA.
        Sci Transl Med. 2011; 3: 94ra72
        • Knezevic D.
        • Goddard A.D.
        • Natraj N.
        • et al.
        Analytical validation of the Oncotype DX prostate cancer assay - a clinical RT-PCR assay optimized for prostate needle biopsies.
        BMC Genomics. 2013; 14: 690
        • Jansen F.H.
        • van Schaik R.H.
        • Kurstjens J.
        • et al.
        Prostate-specific antigen (PSA) isoform p2PSA in combination with total PSA and free PSA improves diagnostic accuracy in prostate cancer detection.
        Eur Urol. 2010; 57: 921-927
        • Wang W.
        • Wang M.
        • Wang L.
        • Adams T.S.
        • Tian Y.
        • Xu J.
        Diagnostic ability of %p2PSA and prostate health index for aggressive prostate cancer: a meta-analysis.
        Sci Rep. 2014; 4: 5012
        • Loeb S.
        • Sanda M.G.
        • Broyles D.L.
        • et al.
        The prostate health index selectively identifies clinically significant prostate cancer.
        J Urol. 2015; 193: 1163-1169
        • Foley R.W.
        • Gorman L.
        • Sharifi N.
        • et al.
        Improving multivariable prostate cancer risk assessment using the Prostate Health Index.
        BJU Int. 2016; 117: 409-417
        • Na R.
        • Ye D.
        • Liu F.
        • et al.
        Performance of serum prostate-specific antigen isoform [−2]proPSA (p2PSA) and the prostate health index (PHI) in a Chinese hospital-based biopsy population.
        Prostate. 2014; 74: 1569-1575
        • de la Calle C.
        • Patil D.
        • Wei J.T.
        • et al.
        Multicenter evaluation of the Prostate Health Index to detect aggressive prostate cancer in biopsy naive men.
        J Urol. 2015; 194: 65-72
        • Boegemann M.
        • Stephan C.
        • Cammann H.
        • et al.
        The percentage of prostate-specific antigen (PSA) isoform [−2]proPSA and the Prostate Health Index improve the diagnostic accuracy for clinically relevant prostate cancer at initial and repeat biopsy compared with total PSA and percentage free PSA in men aged ≤65 years.
        BJU Int. 2016; 117: 72-79
        • 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
        • Carlsson S.
        • Maschino A.
        • Schroder F.
        • et al.
        Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam.
        Eur Urol. 2013; 64: 693-699
        • Vickers A.J.
        • Cronin A.M.
        • Aus G.
        • 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
        • Vickers A.
        • Cronin A.
        • Roobol M.
        • et al.
        Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication.
        J Clin Oncol. 2010; 28: 2493-2498
        • Vickers A.J.
        • Cronin A.M.
        • Aus G.
        • et al.
        Impact of recent screening on predicting the outcome of prostate cancer biopsy in men with elevated prostate-specific antigen: data from the European Randomized Study of Prostate Cancer Screening in Gothenburg, Sweden.
        Cancer. 2010; 116: 2612-2620
        • Vickers A.J.
        • Cronin A.M.
        • Roobol M.J.
        • et al.
        A four-kallikrein panel predicts prostate cancer in men with recent screening: data from the European Randomized Study of Screening for Prostate Cancer, Rotterdam.
        Clin Cancer Res. 2010; 16: 3232-3239
        • Bryant R.J.
        • Sjoberg D.D.
        • Vickers A.J.
        • et al.
        Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study.
        J Natl Cancer Inst. 2015; 107: djv095
        • Braun K.
        • Sjoberg D.D.
        • Vickers A.J.
        • Lilja H.
        • Bjartell A.S.
        A four-kallikrein panel predicts high-grade cancer on biopsy: independent validation in a community cohort.
        Eur Urol. 2016; 69: 505-511
        • Gupta A.
        • Roobol M.J.
        • Savage C.J.
        • et al.
        A four-kallikrein panel for the prediction of repeat prostate biopsy: data from the European Randomized Study of Prostate Cancer screening in Rotterdam, Netherlands.
        Br J Cancer. 2010; 103: 708-714
        • Hugosson J.
        • Aus G.
        • Lilja H.
        • Lodding P.
        • Pihl C.G.
        Results of a randomized, population-based study of biennial screening using serum prostate-specific antigen measurement to detect prostate carcinoma.
        Cancer. 2004; 100: 1397-1405
        • Benchikh A.
        • Savage C.
        • Cronin A.
        • et al.
        A panel of kallikrein markers can predict outcome of prostate biopsy following clinical work-up: an independent validation study from the European Randomized Study of Prostate Cancer screening, France.
        BMC Cancer. 2010; 10: 635
        • Isharwal S.
        • Makarov D.V.
        • Sokoll L.J.
        • et al.
        ProPSA and diagnostic biopsy tissue DNA content combination improves accuracy to predict need for prostate cancer treatment among men enrolled in an active surveillance program.
        Urology. 2011; 77 (763.e1–6)
        • Tosoian J.J.
        • Loeb S.
        • Feng Z.
        • et al.
        Association of [−2]proPSA with biopsy reclassification during active surveillance for prostate cancer.
        J Urol. 2012; 188: 1131-1136
        • Hirama H.
        • Sugimoto M.
        • Ito K.
        • Shiraishi T.
        • Kakehi Y.
        The impact of baseline [−2]proPSA-related indices on the prediction of pathological reclassification at 1 year during active surveillance for low-risk prostate cancer: the Japanese multicenter study cohort.
        J Cancer Res Clin Oncol. 2014; 140: 257-263
        • Lin D.W.
        • Newcomb L.F.
        • Brown E.C.
        • et al.
        Urinary TMPRSS2:ERG and PCA3 in an active surveillance cohort: results from a baseline analysis in the Canary Prostate Active Surveillance Study.
        Clin Cancer Res. 2013; 19: 2442-2450
        • Klein E.A.
        • Cooperberg M.R.
        • Magi-Galluzzi C.
        • et al.
        A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling.
        Eur Urol. 2014; 66: 550-560
        • Cullen J.
        • Rosner I.L.
        • Brand T.C.
        • et al.
        A Biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer.
        Eur Urol. 2015; 68: 123-131
        • Guazzoni G.
        • Lazzeri M.
        • Nava L.
        • 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.
        Eur Urol. 2012; 61: 455-466
        • Fossati N.
        • Buffi N.M.
        • Haese A.
        • 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
        • Eminaga O.
        • Bogemann M.
        • Breil B.
        • et al.
        Preoperative prostate-specific antigen isoform p2PSA ≤22.5 pg/ml predicts advanced prostate cancer in patients undergoing radical prostatectomy.
        Urol Oncol. 2014; 32: 1317-1326
        • Ferro M.
        • Lucarelli G.
        • Bruzzese D.
        • 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
        • Mearini L.
        • Nunzi E.
        • Ferri C.
        • et al.
        Use of the Prostate Health Index for the detection of aggressive prostate cancer at radical prostatectomy.
        Urol Int. 2015; 95: 390-399
        • Cantiello F.
        • Russo G.I.
        • Ferro M.
        • 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.e15–23)
        • Stattin P.
        • Vickers A.J.
        • Sjoberg D.D.
        • et al.
        Improving the specificity of screening for lethal prostate cancer using prostate-specific antigen and a panel of kallikrein markers: a nested case-control study.
        Eur Urol. 2015; 68: 207-213
        • Tallon L.
        • Luangphakdy D.
        • Ruffion A.
        • 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
        • Bishoff J.T.
        • Freedland S.J.
        • Gerber L.
        • et al.
        Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy.
        J Urol. 2014; 192: 409-414
        • Cuzick J.
        • Swanson G.P.
        • Fisher G.
        • et al.
        Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study.
        Lancet Oncol. 2011; 12: 245-255
        • Cooperberg M.R.
        • Simko J.P.
        • Cowan J.E.
        • et al.
        Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort.
        J Clin Oncol. 2013; 31: 1428-1434
        • Cuzick J.
        • Berney D.M.
        • Fisher G.
        • et al.
        Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort.
        Br J Cancer. 2012; 106: 1095-1099
        • Cuzick J.
        • Stone S.
        • Fisher G.
        • et al.
        Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort.
        Br J Cancer. 2015; 113: 382-389
        • Freedland S.J.
        • Gerber L.
        • Reid J.
        • et al.
        Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy.
        Int J Radiat Oncol Biol Phys. 2013; 86: 848-853
        • Karnes R.J.
        • Bergstralh E.J.
        • Davicioni E.
        • et al.
        Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population.
        J Urol. 2013; 190: 2047-2053
        • Klein E.A.
        • Yousefi K.
        • Haddad Z.
        • et al.
        A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy.
        Eur Urol. 2015; 67: 778-786
        • Ross A.E.
        • Johnson M.H.
        • Yousefi K.
        • et al.
        Tissue-based genomics augments post-prostatectomy risk stratification in a natural history cohort of intermediate- and high-risk men.
        Eur Urol. 2016; 69: 157-165
        • Erho N.
        • Crisan A.
        • Vergara I.A.
        • et al.
        Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy.
        PLoS One. 2013; 8: e66855
        • Ross A.E.
        • Feng F.Y.
        • Ghadessi M.
        • et al.
        A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy.
        Prostate Cancer Prostatic Dis. 2014; 17: 64-69
        • Den R.B.
        • Feng F.Y.
        • Showalter T.N.
        • et al.
        Genomic prostate cancer classifier predicts biochemical failure and metastases in patients after postoperative radiation therapy.
        Int J Radiat Oncol Biol Phys. 2014; 89: 1038-1046
        • Den R.B.
        • Yousefi K.
        • Trabulsi E.J.
        • et al.
        Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy.
        J Clin Oncol. 2015; 33: 944-951
        • Cooperberg M.R.
        • Davicioni E.
        • Crisan A.
        • Jenkins R.B.
        • Ghadessi M.
        • Karnes R.J.
        Combined value of validated clinical and genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort.
        Eur Urol. 2015; 67: 326-333
        • Cornu J.N.
        • 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
        • Arsov C.
        • Jankowiak F.
        • Hiester A.
        • et al.
        Prognostic value of a cell-cycle progression score in men with prostate cancer managed with active surveillance after MRI-guided prostate biopsy—a pilot study.
        Anticancer Res. 2014; 34: 2459-2466