Prostate Cancer Molecular Prognosis

  • Joshua I. Warrick
  • Scott A. Tomlins
Part of the Molecular Pathology Library book series (MPLB)


Prostate cancer is biologically and clinically diverse-tumors ranging from small, indolent tumors that will never clinically manifest, to aggressive carcinomas that readily metastasize and cause mortality. While several pathologic and clinical variables, such as Gleason score and serum prostate-specific antigen level, are valuable for prognosis, several clinical situations exist in which these variables do not inform fully on tumor behavior and patient management. Molecular tests may be useful in these clinical situations, such as active surveillance. Many tests have been developed and are in development and may be done on tissue or urine specimens. This chapter will review the prognostic value of several molecular tests for prostate cancer, in the context of known pathologic and clinical prognostic variables.


MYC PTEN TP53 Active surveillance qRT-PCR assays Expression profiling 


  1. 1.
    Caras RJ, Sterbis JR. Prostate cancer nomograms: a review of their use in cancer detection and treatment. Curr Urol Rep. 2014;15(3):391. PubMed PMID: 24452739.PubMedCrossRefGoogle Scholar
  2. 2.
    Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. Grading Committee. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 2016;40(2):244–52. PubMed PMID: 26492179.PubMedGoogle Scholar
  3. 3.
    Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. 1966;50(3):125–8. PubMed PMID: 5948714.PubMedGoogle Scholar
  4. 4.
    Chen H, Liu W, Roberts W, Hooker S, Fedor H, DeMarzo A, et al. 8q24 allelic imbalance and MYC gene copy number in primary prostate cancer. Prostate Cancer Prostatic Dis. 2010;13(3):238–43. PubMed PMID: 20634801. Pubmed Central PMCID: 3963483.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Sato H, Minei S, Hachiya T, Yoshida T, Takimoto Y. Fluorescence in situ hybridization analysis of c-myc amplification in stage TNM prostate cancer in Japanese patients. Int J Urol. 2006;13(6):761–6. PubMed PMID: 16834657.PubMedCrossRefGoogle Scholar
  6. 6.
    Jenkins RB, Qian J, Lieber MM, Bostwick DG. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res. 1997;57(3):524–31. PubMed PMID: 9012485.PubMedGoogle Scholar
  7. 7.
    Zafarana G, Ishkanian AS, Malloff CA, Locke JA, Sykes J, Thoms J, et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer. 2012;118(16):4053–62. PubMed PMID: 22281794.PubMedCrossRefGoogle Scholar
  8. 8.
    Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239–43. PubMed PMID: 22722839. Pubmed Central PMCID: 3396711.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Antonarakis ES, Keizman D, Zhang Z, Gurel B, Lotan TL, Hicks JL, et al. An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy. Cancer. 2012;118(24):6063–71. PubMed PMID: 22674438. Pubmed Central PMCID: 3572534.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Krohn A, Diedler T, Burkhardt L, Mayer PS, De Silva C, Meyer-Kornblum M, et al. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol. 2012;181(2):401–12. PubMed PMID: 22705054.PubMedCrossRefGoogle Scholar
  11. 11.
    Li Y, Su J, DingZhang X, Zhang J, Yoshimoto M, Liu S, et al. PTEN deletion and heme oxygenase-1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome. J Pathol. 2011;224(1):90–100. PubMed PMID: 21381033.PubMedCrossRefGoogle Scholar
  12. 12.
    Lotan TL, Gurel B, Sutcliffe S, Esopi D, Liu W, Xu J, et al. PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res. 2011;17(20):6563–73. PubMed PMID: 21878536. Pubmed Central PMCID: 3195839.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Reid AH, Attard G, Brewer D, Miranda S, Riisnaes R, Clark J, et al. Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer. Mod Pathol. 2012;25(6):902–10. PubMed PMID: 22460813.PubMedCrossRefGoogle Scholar
  14. 14.
    Yoshimoto M, Ding K, Sweet JM, Ludkovski O, Trottier G, Song KS, et al. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol. 2013;26(3):435–47. PubMed PMID: 23018874.PubMedCrossRefGoogle Scholar
  15. 15.
    Zu K, Martin NE, Fiorentino M, Flavin R, Lis RT, Sinnott JA, et al. Protein expression of PTEN, insulin-like growth factor I receptor (IGF-IR), and lethal prostate cancer: a prospective study. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1984–93. PubMed PMID: 23983239. Pubmed Central PMCID: 3818474.PubMedCrossRefGoogle Scholar
  16. 16.
    Lotan TL, Carvalho FL, Peskoe SB, Hicks JL, Good J, Fedor HL, et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol. 2015;28(1):128–37. PubMed PMID: 24993522. Pubmed Central PMCID: 4282985.PubMedCrossRefGoogle Scholar
  17. 17.
    Chaux A, Peskoe SB, Gonzalez-Roibon N, Schultz L, Albadine R, Hicks J, et al. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod Pathol. 2012;25(11):1543–9. PubMed PMID: 22684219.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Choucair K, Ejdelman J, Brimo F, Aprikian A, Chevalier S, Lapointe J. PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity. BMC Cancer. 2012;12:543. PubMed PMID: 23171135. Pubmed Central PMCID: 3527151PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Shah RB, Bentley J, Jeffery Z, DeMarzo AM. Heterogeneity of PTEN and ERG expression in prostate cancer on core needle biopsies: implications for cancer risk stratification and biomarker sampling. Hum Pathol. 2015;46(5):698–706. PubMed PMID: 25724568.PubMedCrossRefGoogle Scholar
  20. 20.
    Krohn A, Freudenthaler F, Harasimowicz S, Kluth M, Fuchs S, Burkhardt L, et al. Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer. Mod Pathol. 2014;27:1612. PubMed PMID: 24762546.PubMedCrossRefGoogle Scholar
  21. 21.
    Pepe MS, Janes H, Li CI. Net risk reclassification p values: valid or misleading? J Natl Cancer Inst. 2014;106(4):dju041. PubMed PMID: 24681599. Pubmed Central PMCID: 3982889.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kattan MW. Judging new markers by their ability to improve predictive accuracy. J Natl Cancer Inst. 2003;95(9):634–5. PubMed PMID: 12734304.PubMedCrossRefGoogle Scholar
  23. 23.
    Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Making. 2006;26(6):565–74. PubMed PMID: 17099194.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Braun M, Goltz D, Shaikhibrahim Z, Vogel W, Bohm D, Scheble V, et al. ERG protein expression and genomic rearrangement status in primary and metastatic prostate cancer—a comparative study of two monoclonal antibodies. Prostate Cancer Prostatic Dis. 2012;15(2):165–9. PubMed PMID: 22231490.PubMedCrossRefGoogle Scholar
  25. 25.
    Furusato B, Tan SH, Young D, Dobi A, Sun C, Mohamed AA, et al. ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis. 2010;13(3):228–37. PubMed PMID: 20585344. Pubmed Central PMCID: 3010744.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Park K, Tomlins SA, Mudaliar KM, Chiu YL, Esgueva R, Mehra R, et al. Antibody-based detection of ERG rearrangement-positive prostate cancer. Neoplasia. 2010;12(7):590–8. PubMed PMID: 20651988. Pubmed Central PMCID: 2907585.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Rubin MA, Maher CA, Chinnaiyan AM. Common gene rearrangements in prostate cancer. J Clin Oncol. 2011;29(27):3659–68. PubMed PMID: 21859993.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Tomlins SA, Bjartell A, Chinnaiyan AM, Jenster G, Nam RK, Rubin MA, et al. ETS gene fusions in prostate cancer: from discovery to daily clinical practice. Eur Urol. 2009;56(2):275–86. PubMed PMID: 19409690.PubMedCrossRefGoogle Scholar
  29. 29.
    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 (New York, NY). 2005;310(5748):644–8. PubMed PMID: 16254181.CrossRefGoogle Scholar
  30. 30.
    Falzarano SM, Zhou M, Carver P, Tsuzuki T, Simmerman K, He H, et al. ERG gene rearrangement status in prostate cancer detected by immunohistochemistry. Virchows Arch. 2011;459(4):441–7. PubMed PMID: 21773753.PubMedCrossRefGoogle Scholar
  31. 31.
    Rosen P, Sesterhenn IA, Brassell SA, McLeod DG, Srivastava S, Dobi A. Clinical potential of the ERG oncoprotein in prostate cancer. Nat Rev Urol. 2012;9(3):131–7. PubMed PMID: 22331093.PubMedCrossRefGoogle Scholar
  32. 32.
    van Leenders GJ, Boormans JL, Vissers CJ, Hoogland AM, Bressers AA, Furusato B, et al. Antibody EPR3864 is specific for ERG genomic fusions in prostate cancer: implications for pathological practice. Mod Pathol. 2011;24(8):1128–38. PubMed PMID: 21499236.PubMedCrossRefGoogle Scholar
  33. 33.
    Xu B, Chevarie-Davis M, Chevalier S, Scarlata E, Zeizafoun N, Dragomir A, et al. The prognostic role of ERG immunopositivity in prostatic acinar adenocarcinoma: a study including 454 cases and review of the literature. Hum Pathol. 2014;45(3):488–97. PubMed PMID: 24406017.PubMedCrossRefGoogle Scholar
  34. 34.
    Tomlins SA, Alshalalfa M, Davicioni E, Erho N, Yousefi K, Zhao S, et al. Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. Eur Urol. 2015;68:555. PubMed PMID: 25964175.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Berg KD, Vainer B, Thomsen FB, Roder MA, Gerds TA, Toft BG, et al. ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer. Eur Urol. 2014;66(5):851–60. PubMed PMID: 24630684.PubMedCrossRefGoogle Scholar
  36. 36.
    Bhalla R, Kunju LP, Tomlins SA, Christopherson K, Cortez C, Carskadon S, et al. Novel dual-color immunohistochemical methods for detecting ERG-PTEN and ERG-SPINK1 status in prostate carcinoma. Mod Pathol. 2013;26(6):835–48. PubMed PMID: 23348902. Pubmed Central PMCID: 3672354.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bismar TA, Yoshimoto M, Duan Q, Liu S, Sircar K, Squire JA. Interactions and relationships of PTEN, ERG, SPINK1 and AR in castration-resistant prostate cancer. Histopathology. 2012;60(4):645–52. PubMed PMID: 22260502.PubMedCrossRefGoogle Scholar
  38. 38.
    Leinonen KA, Tolonen TT, Bracken H, Stenman UH, Tammela TL, Saramaki OR, et al. Association of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancer. Clin Cancer Res. 2010;16(10):2845–51. PubMed PMID: 20442300.PubMedCrossRefGoogle Scholar
  39. 39.
    Tomlins SA, Rhodes DR, Yu J, Varambally S, Mehra R, Perner S, et al. The role of SPINK1 in ETS rearrangement-negative prostate cancers. Cancer Cell. 2008;13(6):519–28. PubMed PMID: 18538735.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Flavin RJ, Pettersson A, Hendrickson WK, Fiorentino M, Finn SP, Kunz L, et al. SPINK1 protein expression and prostate cancer progression. Clin Cancer Res. 2014;20:4904. PubMed PMID: 24687926.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Smith SC, Tomlins SA. Prostate cancer SubtyPINg biomarKers and outcome: is clarity emERGing? Clin Cancer Res. 2014;20(18):4733–6. PubMed PMID: 24944315. Pubmed Central PMCID: 4167216.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Grupp K, Diebel F, Sirma H, Simon R, Breitmeyer K, Steurer S, et al. SPINK1 expression is tightly linked to 6q15- and 5q21-deleted ERG-fusion negative prostate cancers but unrelated to PSA recurrence. Prostate. 2013;73(15):1690–8. PubMed PMID: 23843146.PubMedGoogle Scholar
  43. 43.
    Prensner JR, Iyer MK, Sahu A, Asangani IA, Cao Q, Patel L, et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013;45(11):1392–8. PubMed PMID: 24076601. Pubmed Central PMCID: 3812362.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Prensner JR, Zhao S, Erho N, Schipper M, Iyer MK, Dhanasekaran SM, et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol. 2014;15(13):1469–80. PubMed PMID: 25456366.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bottcher R, Hoogland AM, Dits N, Verhoef EI, Kweldam C, Waranecki P, et al. Novel long non-coding RNAs are specific diagnostic and prognostic markers for prostate cancer. Oncotarget. 2015;6(6):4036–50. PubMed PMID: 25686826.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Mehra R, Shi Y, Udager AM, Prensner JR, Sahu A, Iyer MK, et al. A novel RNA in situ hybridization assay for the long noncoding RNA SChLAP1 predicts poor clinical outcome after radical prostatectomy in clinically localized prostate cancer. Neoplasia. 2014;16(12):1121–7. PubMed PMID: 25499224. Pubmed Central PMCID: 4309259.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Muss HB. Adjuvant chemotherapy in older women with breast cancer: who and what? J Clin Oncol. 2014;32(19):1996–2000. PubMed PMID: 24868030.PubMedCrossRefGoogle Scholar
  48. 48.
    Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C, et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One. 2013;8(6):e66855. PubMed PMID: 23826159. Pubmed Central PMCID: 3691249.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP, et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol. 2013;190(6):2047–53. PubMed PMID: 23770138. Pubmed Central PMCID: 4097302.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ross AE, Feng FY, Ghadessi M, Erho N, Crisan A, Buerki C, et al. A genomic classifier predicting metastatic disease progression in men with biochemical recurrence after prostatectomy. Prostate Cancer Prostatic Dis. 2014;17(1):64–9. PubMed PMID: 24145624.PubMedCrossRefGoogle Scholar
  51. 51.
    Badani K, Thompson DJ, Buerki C, Davicioni E, Garrison J, Ghadessi M, et al. Impact of a genomic classifier of metastatic risk on postoperative treatment recommendations for prostate cancer patients: a report from the DECIDE study group. Oncotarget. 2013;4(4):600–9. PubMed PMID: 23592338. Pubmed Central PMCID: 3720607.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Badani KK, Thompson DJ, Brown G, Holmes D, Kella N, Albala D, et al. Effect of a genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. BJU Int. 2015;115(3):419–29. PubMed PMID: 24784420. Pubmed Central PMCID: 4371645.PubMedCrossRefGoogle Scholar
  53. 53.
    Cooperberg MR, Davicioni E, Crisan A, Jenkins RB, Ghadessi M, Karnes RJ. 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(2):326–33. PubMed PMID: 24998118. Pubmed Central PMCID: 4282620.PubMedCrossRefGoogle Scholar
  54. 54.
    Den RB, Feng FY, Showalter TN, Mishra MV, Trabulsi EJ, Lallas CD, 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(5):1038–46. PubMed PMID: 25035207.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Klein EA, Yousefi K, Haddad Z, Choeurng V, Buerki C, Stephenson AJ, 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(4):778–86. PubMed PMID: 25466945.PubMedCrossRefGoogle Scholar
  56. 56.
    Den RB, Yousefi K, Trabulsi EJ, Abdollah F, Choeurng V, Feng FY, et al. Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol. 2015;33(8):944–51. PubMed PMID: 25667284.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Cooperberg MR, Hilton JF, Carroll PR. The CAPRA-S score: a straightforward tool for improved prediction of outcomes after radical prostatectomy. Cancer. 2011;117(22):5039–46. PubMed PMID: 21647869. Pubmed Central PMCID: 3170662.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Stephenson AJ, Scardino PT, Eastham JA, Bianco FJ Jr, Dotan ZA, Fearn PA, et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst. 2006;98(10):715–7. PubMed PMID: 16705126. Pubmed Central PMCID: 2242430.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Cooperberg MR, Simko JP, Cowan JE, Reid JE, Djalilvand A, Bhatnagar S, et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol. 2013;31(11):1428–34. PubMed PMID: 23460710.PubMedCrossRefGoogle Scholar
  60. 60.
    Cuzick J, Berney DM, Fisher G, Mesher D, Moller H, Reid JE, 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(6):1095–9. PubMed PMID: 22361632. Pubmed Central PMCID: 3304411.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, 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(3):245–55. PubMed PMID: 21310658. Pubmed Central PMCID: 3091030.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Bishoff JT, Freedland SJ, Gerber L, Tennstedt P, Reid J, Welbourn W, et al. Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J Urol. 2014;192(2):409–14. PubMed PMID: 24508632.PubMedCrossRefGoogle Scholar
  63. 63.
    Sommariva S, Tarricone R, Lazzeri M, Ricciardi W, Montorsi F. Prognostic value of the cell cycle progression score in patients with prostate cancer: a systematic review and meta-analysis. Eur Urol. 2016;69:107. PubMed PMID: 25481455.PubMedCrossRefGoogle Scholar
  64. 64.
    Crawford ED, Scholz MC, Kar AJ, Fegan JE, Haregewoin A, Kaldate RR, et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. Curr Med Res Opin. 2014;30(6):1025–31. PubMed PMID: 24576172.PubMedCrossRefGoogle Scholar
  65. 65.
    Shore N, Concepcion R, Saltzstein D, Lucia MS, van Breda A, Welbourn W, et al. Clinical utility of a biopsy-based cell cycle gene expression assay in localized prostate cancer. Curr Med Res Opin. 2014;30(4):547–53. PubMed PMID: 24320750.PubMedCrossRefGoogle Scholar
  66. 66.
    Freedland SJ, Gerber L, Reid J, Welbourn W, Tikishvili E, Park 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(5):848–53. PubMed PMID: 23755923. Pubmed Central PMCID: 3710548.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Cuzick J. Prognostic value of a cell cycle progression score for men with prostate cancer. Recent Results Cancer Res. 2014;202:133–40. PubMed PMID: 24531787.PubMedCrossRefGoogle Scholar
  68. 68.
    Arvold ND, Chen MH, Moul JW, Moran BJ, Dosoretz DE, Banez LL, et al. Risk of death from prostate cancer after radical prostatectomy or brachytherapy in men with low or intermediate risk disease. J Urol. 2011;186(1):91–6. PubMed PMID: 21571341.PubMedCrossRefGoogle Scholar
  69. 69.
    Dall’Era MA, Konety BR, Cowan JE, Shinohara K, Stauf F, Cooperberg MR, et al. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer. 2008;112(12):2664–70. PubMed PMID: 18433013.PubMedCrossRefGoogle Scholar
  70. 70.
    Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA. 1994;271(5):368–74. PubMed PMID: 7506797.PubMedCrossRefGoogle Scholar
  71. 71.
    Hardie C, Parker C, Norman A, Eeles R, Horwich A, Huddart R, et al. Early outcomes of active surveillance for localized prostate cancer. BJU Int. 2005;95(7):956–60. PubMed PMID: 15839912.PubMedCrossRefGoogle Scholar
  72. 72.
    Kakehi Y, Kamoto T, Shiraishi T, Ogawa O, Suzukamo Y, Fukuhara S, et al. Prospective evaluation of selection criteria for active surveillance in Japanese patients with stage T1cN0M0 prostate cancer. Jpn J Clin Oncol. 2008;38(2):122–8. PubMed PMID: 18272471.PubMedCrossRefGoogle Scholar
  73. 73.
    Lawrentschuk N, Klotz L. Active surveillance for low-risk prostate cancer: an update. Nat Rev Urol. 2011;8(6):312–20. PubMed PMID: 21519351.PubMedCrossRefGoogle Scholar
  74. 74.
    Soloway MS, Soloway CT, Eldefrawy A, Acosta K, Kava B, Manoharan M. Careful selection and close monitoring of low-risk prostate cancer patients on active surveillance minimizes the need for treatment. Eur Urol. 2010;58(6):831–5. PubMed PMID: 20800964.PubMedCrossRefGoogle Scholar
  75. 75.
    van As NJ, Parker CC. Active surveillance with selective radical treatment for localized prostate cancer. Cancer J. 2007;13(5):289–94. PubMed PMID: 17921727.PubMedCrossRefGoogle Scholar
  76. 76.
    van den Bergh RC, Vasarainen H, van der Poel HG, Vis-Maters JJ, Rietbergen JB, Pickles T, et al. Short-term outcomes of the prospective multicentre ‘Prostate Cancer Research International: Active Surveillance’ study. BJU Int. 2010;105(7):956–62. PubMed PMID: 19817747.PubMedCrossRefGoogle Scholar
  77. 77.
    Aizer AA, Chen MH, Hattangadi J, D’Amico AV. Initial management of prostate-specific antigen-detected, low-risk prostate cancer and the risk of death from prostate cancer. BJU Int. 2014;113(1):43–50. PubMed PMID: 23473327.PubMedCrossRefGoogle Scholar
  78. 78.
    Epstein JI, Feng Z, Trock BJ, Pierorazio PM. Upgrading and downgrading of prostate cancer from biopsy to radical prostatectomy: incidence and predictive factors using the modified Gleason grading system and factoring in tertiary grades. Eur Urol. 2012;61(5):1019–24. PubMed PMID: 22336380.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Knezevic D, Goddard AD, Natraj N, Cherbavaz DB, Clark-Langone KM, Snable J, 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. PubMed PMID: 24103217. Pubmed Central PMCID: 4007703.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Klein EA, Cooperberg MR, Magi-Galluzzi C, Simko JP, Falzarano SM, Maddala T, 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(3):550–60. PubMed PMID: 24836057.PubMedCrossRefGoogle Scholar
  81. 81.
    Cullen J, Rosner IL, Brand TC, Zhang N, Tsiatis AC, Moncur J, 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. PubMed PMID: 25465337.PubMedCrossRefGoogle Scholar
  82. 82.
    Irshad S, Bansal M, Castillo-Martin M, Zheng T, Aytes A, Wenske S, et al. A molecular signature predictive of indolent prostate cancer. Sci Transl Med. 2013;5(202):202ra122. PubMed PMID: 24027026. Pubmed Central PMCID: 3943244.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Blume-Jensen P, Berman D, Rimm DL, Shipitsin M, Putzi M, Nifong TP, et al. Development and clinical validation of an in situ biopsy based multi-marker assay for risk stratification in prostate cancer. Clin Cancer Res. 2015;21:2591. PubMed PMID: 25733599.PubMedCrossRefGoogle Scholar
  84. 84.
    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(23):5975–9. PubMed PMID: 10606244.PubMedGoogle Scholar
  85. 85.
    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(9):2695–8. PubMed PMID: 11980670.PubMedGoogle Scholar
  86. 86.
    Schmidt U, Fuessel S, Koch R, Baretton GB, Lohse A, Tomasetti S, et al. Quantitative multi-gene expression profiling of primary prostate cancer. Prostate. 2006;66(14):1521–34. PubMed PMID: 16921506.PubMedCrossRefGoogle Scholar
  87. 87.
    Adam A, Engelbrecht MJ, Bornman MS, Manda SO, Moshokoa E, Feilat RA. The role of the PCA3 assay in predicting prostate biopsy outcome in a South African setting. BJU Int. 2011;108(11):1728–33. PubMed PMID: 21507188.PubMedCrossRefGoogle Scholar
  88. 88.
    Ankerst DP, Groskopf J, Day JR, Blase A, Rittenhouse H, Pollock BH, et al. Predicting prostate cancer risk through incorporation of prostate cancer gene 3. J Urol. 2008;180(4):1303–8. discussion 8. PubMed PMID: 18707724.PubMedCrossRefGoogle Scholar
  89. 89.
    Auprich M, Haese A, Walz J, Pummer K, de la Taille A, Graefen M, et al. External validation of urinary PCA3-based nomograms to individually predict prostate biopsy outcome. Eur Urol. 2010;58(5):727–32. PubMed PMID: 20619529.PubMedCrossRefGoogle Scholar
  90. 90.
    Chun FK, de la Taille A, van Poppel H, Marberger M, Stenzl A, Mulders PF, et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol. 2009;56(4):659–67. PubMed PMID: 19304372.PubMedCrossRefGoogle Scholar
  91. 91.
    Crawford ED, Rove KO, Trabulsi EJ, Qian J, Drewnowska KP, Kaminetsky JC, et al. Diagnostic performance of PCA3 to detect prostate cancer in men with increased prostate specific antigen: a prospective study of 1,962 cases. J Urol. 2012;188(5):1726–31. PubMed PMID: 22998901.PubMedCrossRefGoogle Scholar
  92. 92.
    Deras IL, Aubin SM, Blase A, Day JR, Koo S, Partin AW, et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol. 2008;179(4):1587–92. PubMed PMID: 18295257.PubMedCrossRefGoogle Scholar
  93. 93.
    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(6):1089–95. PubMed PMID: 16627561.PubMedCrossRefGoogle Scholar
  94. 94.
    Haese A, de la Taille A, van Poppel H, Marberger M, Stenzl A, Mulders PF, et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol. 2008;54(5):1081–8. PubMed PMID: 18602209.PubMedCrossRefGoogle Scholar
  95. 95.
    Hansen J, Auprich M, Ahyai SA, de la Taille A, van Poppel H, Marberger M, et al. Initial prostate biopsy: development and internal validation of a biopsy-specific nomogram based on the prostate cancer antigen 3 assay. Eur Urol. 2013;63(2):201–9. PubMed PMID: 22854248.PubMedCrossRefGoogle Scholar
  96. 96.
    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(1):8–15. discussion -6. PubMed PMID: 12814669.PubMedCrossRefGoogle Scholar
  97. 97.
    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(3):534–42. PubMed PMID: 23201468.PubMedCrossRefGoogle Scholar
  98. 98.
    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(3):532–5. PubMed PMID: 17382159.PubMedCrossRefGoogle Scholar
  99. 99.
    Ochiai A, Okihara K, Kamoi K, Oikawa T, Shimazui T, Murayama S, et al. Clinical utility of the prostate cancer gene 3 (PCA3) urine assay in Japanese men undergoing prostate biopsy. BJU Int. 2013;111(6):928–33. PubMed PMID: 23331404.PubMedCrossRefGoogle Scholar
  100. 100.
    Perdona S, Cavadas V, Di Lorenzo G, Damiano R, Chiappetta G, Del Prete P, 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(1):81–7. PubMed PMID: 20947244.PubMedCrossRefGoogle Scholar
  101. 101.
    Roobol MJ, Schroder FH, van Leeuwen P, Wolters T, van den Bergh RC, van Leenders GJ, 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(4):475–81. PubMed PMID: 20637539.PubMedCrossRefGoogle Scholar
  102. 102.
    van Gils MP, Hessels D, van Hooij O, Jannink SA, Peelen WP, Hanssen SL, et al. The time-resolved fluorescence-based PCA3 test on urinary sediments after digital rectal examination; a Dutch multicenter validation of the diagnostic performance. Clin Cancer Res. 2007;13(3):939–43. PubMed PMID: 17289888.PubMedCrossRefGoogle Scholar
  103. 103.
    Laxman B, Tomlins SA, Mehra R, Morris DS, Wang L, Helgeson BE, et al. Noninvasive detection of TMPRSS2:ERG fusion transcripts in the urine of men with prostate cancer. Neoplasia. 2006;8(10):885–8. PubMed PMID: 17059688.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    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(5):566–71. PubMed PMID: 21600800. Pubmed Central PMCID: 3210917.PubMedCrossRefGoogle Scholar
  105. 105.
    Tomlins SA, Aubin SM, Siddiqui J, Lonigro RJ, Sefton-Miller L, Miick S, et al. Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. Sci Transl Med. 2011;3(94):94ra72. PubMed PMID: 21813756. Pubmed Central PMCID: 3245713.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    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. PubMed PMID: 25985884.PubMedCrossRefGoogle Scholar
  107. 107.
    Young A, Palanisamy N, Siddiqui J, Wood DP, Wei JT, Chinnaiyan AM, et al. Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden. Am J Clin Pathol. 2012;138(5):685–96. PubMed PMID: 23086769.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Cavadas V, Osorio L, Sabell F, Teves F, Branco F, Silva-Ramos M. Prostate cancer prevention trial and European randomized study of screening for prostate cancer risk calculators: a performance comparison in a contemporary screened cohort. Eur Urol. 2010;58(4):551–8. PubMed PMID: 20580483.PubMedCrossRefGoogle Scholar
  109. 109.
    Lin DW, Newcomb LF, Brown EC, Brooks JD, Carroll PR, Feng Z, 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(9):2442–50. PubMed PMID: 23515404.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Danila DC, Fleisher M, Scher HI. Circulating tumor cells as biomarkers in prostate cancer. Clin Cancer Res. 2011;17(12):3903–12. PubMed PMID: 21680546. Pubmed Central PMCID: 3743247.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, et al. Circulating tumour cells as prognostic markers in progressive, castration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol. 2009;10(3):233–9. PubMed PMID: 19213602. Pubmed Central PMCID: 2774131.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Attard G, Swennenhuis JF, Olmos D, Reid AH, Vickers E, A’Hern R, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res. 2009;69(7):2912–8. PubMed PMID: 19339269.PubMedCrossRefGoogle Scholar
  113. 113.
    Danila DC, Anand A, Sung CC, Heller G, Leversha MA, Cao L, et al. TMPRSS2-ERG status in circulating tumor cells as a predictive biomarker of sensitivity in castration-resistant prostate cancer patients treated with abiraterone acetate. Eur Urol. 2011;60(5):897–904. PubMed PMID: 21802835.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Miyamoto DT, Lee RJ, Stott SL, Ting DT, Wittner BS, Ulman M, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov. 2012;2(11):995–1003. PubMed PMID: 23093251. Pubmed Central PMCID: 3508523.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Sullivan HC, Edgar MA, Cohen C, Kovach CK, HooKim K, Reid MD. The utility of ERG, CD31 and CD34 in the cytological diagnosis of angiosarcoma: an analysis of 25 cases. J Clin Pathol. 2015;68(1):44–50. PubMed PMID: 25352641.PubMedCrossRefGoogle Scholar
  116. 116.
    Scher HI, Heller G, Molina A, Attard G, Danila DC, Jia X, et al. Circulating tumor cell biomarker panel as an individual-level surrogate for survival in metastatic castration-resistant prostate cancer. J Clin Oncol. 2015;33(12):1348–55. PubMed PMID: 25800753. Pubmed Central PMCID: 4397279.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Haffner MC, De Marzo AM, Yegnasubramanian S, Epstein JI, Carter HB. Diagnostic challenges of clonal heterogeneity in prostate cancer. J Clin Oncol. 2015;33(7):e38–40. PubMed PMID: 24638011.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of PathologyPenn State Milton S. Hershey Medical CenterHersheyUSA
  2. 2.Department of PathologyUniversity of Michigan Medical SchoolAnn ArborUSA
  3. 3.Department of UrologyUniversity of Michigan Medical SchoolAnn ArborUSA
  4. 4.Michigan Center for Translational PathologyAnn ArborUSA

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