Neue Biomarker im Serum und im Urin zur Detektion des Prostatakarzinoms

Zusammenfassung

Das prostataspezifische Antigen (PSA) hat in den letzten 3 Jahrzehnten das Management des Prostatakarzinoms (PCa) revolutioniert. Dieser häufig genutzte Biomarker hat trotz der eindeutigen Korrelation zum PCa eine geringe Spezifität, sodass ein dringender Bedarf an neuen Tumormarkern besteht, die v. a. klinisch relevante und aggressive Formen des PCa nachweisen können. Von allen Serummarkern zeigt nur der 2012 von der FDA zugelassene [−2]proPSA-basierte sogenannte „Prostate Health Index“ Phi eine verbesserte Spezifität gegenüber dem PSA und dem prozentualen freien PSA (%fPSA). Andere Kallikreine im Serum oder auch Sarkosin im Serum und Urin zeigen unterschiedliche Ergebnisse und sollten deshalb eher zurückhaltend bezüglich einer verbesserten PCa-Detektion bewertet werden. Im Urin hat der ebenfalls 2012 von der FDA zugelassene mRNA-basierte Urinmarker „Prostate Cancer Gene 3“ (PCA3) nachgewiesen, dass v. a. bei Wiederholungsbiopsien eine verbesserte diagnostische Genauigkeit im Vergleich zum PSA und %fPSA möglich ist. Allerdings gibt es beim PCA3 eine ungenügende diagnostische Sensitivität bei hohen Werten als auch eine fehlende Korrelation zur Tumoraggressivität. Die Entdeckung der TMPRSS2:ETS-Genfusionen im Jahr 2005, welche im Gewebe von etwa 50% aller PCa-Patienten auftreten, war ein Meilenstein in der Forschung des Prostatakarzinoms. Der auf der Plattform des PCA3 basierende Urintest für TMPRSS2:ETS zeigte allerdings nur in Kombination mit dem PCA3 eine verbesserte diagnostische Effizienz. Im direkten Vergleich der beiden besten derzeit verfügbaren Tumormarker sind Phi und PCA3 als gleichwertig anzusehen.

Abstract

Prostate-specific antigen (PSA) has revolutionized the management of prostate cancer (PCa) within the last 3 decades. This widely used tumour marker strongly correlates with the risk of harbouring a PCa but it lacks specificity. Therefore there is an urgent need for new biomarkers especially to detect clinically significant and aggressive PCa. Of all PSA-based markers, only the FDA-approved prostate health index phi shows improved specificity over percent free (%fPSA) and total PSA. Other serum kallikreins or sarcosine in serum or urine show more ambiguous data. In urine, the FDA-approved prostate cancer gene 3 (PCA3) has also proven its utility in the detection and management of early PCa with advantages as compared with PSA and %fPSA. However, some aspects of its correlation with aggressiveness and the low sensitivity at very high values have to be re-examined. The detection of alterations of the androgen regulated TMPRSS2 and ETS transcription factor genes in tissue of ~50% of all PCa patients was a milestone in PCa research. But only the combination of the urinary assays for TMPRSS2:ERG gene fusion and PCA3 (both use the same platform) show the expected improved accuracy for PCa detection. Comparisons of phi and PCA3, the best available PCa biomarkers so far, show an equal performance of both parameters.

Schlüsselwörter

Prostatakarzinom - Diagnostik - PSA - Biomarker

Key words

prostate cancer - diagnosis - PSA - biomarkers

• Literatur

• 1 Ward AM, Catto JW, Hamdy FC. Prostate specific antigen: biology, biochemistry and available commercial assays. Ann Clin Biochem 2001; 38: 633-651
• 2 Lilja H, Oldbring J, Rannevik G et al. Seminal vesicle-secreted proteins and their reactions during gelation and liquefaction of human semen. J Clin Invest 1987; 80: 281-285
• 3 Stenman UH. Prostate-specific antigen, clinical use and staging: an overview. Br J Urol 1997; 79 (Suppl. 01) 53-60
• 4 Wang MC, Valenzuela LA, Murphy GP et al. Purification of a human prostate specific antigen. Invest Urol 1979; 17: 159-163
• 5 Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery-what we have learned and where we are going. J Urol 1999; 162: 293-306
• 6 Schroder FH, Roobol MJ, van der Kwast TH et al. velocity predict prostate cancer in pre-screened populations?. Eur Urol 2006; 49: 460-465
• 7 Thompson IM, Ankerst DP, Chi C et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006; 98: 529-534
• 8 Berger AP, Deibl M, Strasak A et al. Large-scale study of clinical impact of PSA velocity: long-term PSA kinetics as method of differentiating men with from those without prostate cancer. Urology 2007; 69: 134-138
• 9 Loeb S, Roehl KA, Catalona WJ et al. Prostate specific antigen velocity threshold for predicting prostate cancer in young men. J Urol 2007; 177: 899-902
• 10 Stamey TA, Caldwell M, McNeal JE et al. The prostate specific antigen era in the United States is over for prostate cancer: What happened in the last 20 years?. J Urol 2004; 172: 1297-1301
• 11 Mistry K, Cable G. Meta-analysis of prostate-specific antigen and digital rectal examination as screening tests for prostate carcinoma. J Am Board Fam Pract 2003; 16: 95-101
• 12 Lilja H, Christensson A, Dahlen U et al. Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. Clin Chem 1991; 37: 1618-1625
• 13 Stenman UH, Leinonen J, Alfthan H et al. A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer. Cancer Res 1991; 51: 222-226
• 14 Christensson A, Lilja H. Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 1994; 220: 45-53
• 15 Stenman UH, Leinonen J, Zhang WM et al. Prostate-specific antigen. Semin Cancer Biol 1999; 9: 83-93
• 16 Jung K, Brux B, Lein M et al. Molecular forms of prostate-specific antigen in malignant and benign prostatic tissue: biochemical and diagnostic implications. Clin Chem 2000; 46: 47-54
• 17 Mikolajczyk SD, Millar LS, Wang TJ et al. “BPSA,” a specific molecular form of free prostate-specific antigen, is found predominantly in the transition zone of patients with nodular benign prostatic hyperplasia. Urology 2000; 55: 41-45
• 18 Ornstein DK, Englert C, Gillespie JW et al. Characterization of intracellular prostate-specific antigen from laser capture microdissected benign and malignant prostatic epithelium. Clin Cancer Res 2000; 6: 353-356
• 19 Zhang WM, Leinonen J, Kalkkinen N et al. Prostate-specific antigen forms a complex with and cleaves a₁-protease inhibitor in vitro. Prostate 1997; 33: 87-96
• 20 Zhang WM, Finne P, Leinonen J et al. Characterization and immunological determination of the complex between prostate-specific antigen and alpha2-macroglobulin. Clin Chem 1998; 44: 2471-2479
• 21 Zhang WM, Finne P, Leinonen J et al. Measurement of the complex between prostate-specific antigen and alpha1-protease inhibitor in serum. Clin Chem 1999; 45: 814-821
• 22 Zhang WM, Finne P, Leinonen J et al. Determination of prostate-specific antigen complexed to alpha(2)-macroglobulin in serum increases the specificity of free to total PSA for prostate cancer. Urology 2000; 56: 267-272
• 23 Stenman UH, Finne P, Zhang WM et al. Prostate-specific antigen and other prostate cancer markers. Urology 2000; 56: 893-898
• 24 Allard WJ, Zhou Z, Yeung KK. Novel immunoassay for the measurement of complexed prostate-specific antigen in serum. Clin Chem 1998; 44: 1216-1223
• 25 Lein M, Kwiatkowski M, Semjonow A et al. A multicenter clinical trial on the use of complexed prostate specific antigen in low prostate specific antigen concentrations. J Urol 2003; 170: 1175-1179
• 26 Stephan C, Schnorr D, Loening SA et al. Use of prostate-specific antigen (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/ml: systematic review and meta-analysis. Eur Urol 2005; 48: 386-399 Eur Urol 2005; 48: 1059-1060
• 27 Roddam AW, Duffy MJ, Hamdy FC et al. Use of prostate-specific antigen (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/ml: systematic review and meta-analysis. Eur Urol 2005; 48: 386-399
• 28 Lein M, Jung K, Hammerer P et al. A multicenter clinical trial on the use of alpha₁-antichymotrypsin-prostate-specific antigen in prostate cancer diagnosis. Prostate 2001; 47: 77-84
• 29 Stephan C, Jung K, Lein M et al. PSA and other tissue kallikreins for prostate cancer detection. Eur J Cancer 2007; 43: 1918-1926
• 30 Stenman UH. Detection of complexes between prostate-specific antigen and protease inhibitors in plasma. Clin Chem 2010; 56: 1895-1896
• 31 Haese A, Graefen M, Noldus J et al. Prostatic volume and ratio of free-to-total prostate specific antigen in patients with prostatic cancer or benign prostatic hyperplasia. J Urol 1997; 158: 2188-2192
• 32 Stephan C, Jung K, Lein M et al. The ratio of free to total prostate specific antigen in serum is correlated to the prostate volume. Int J Cancer 1996; 67: 461-462
• 33 Stephan C, Lein M, Jung K et al. The influence of prostate volume on the ratio of free to total prostate specific antigen in serum of patients with prostate carcinoma and benign prostate hyperplasia. Cancer 1997; 79: 104-109
• 34 Catalona WJ, Smith DS, Wolfert RL et al. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 1995; 274: 1214-1220
• 35 Catalona WJ, Partin AW, Slawin KM 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
• 36 Jung K, Stephan C, Lein M et al. Analytical performance and clinical validity of two free prostate-specific antigen assays compared. Clin Chem 1996; 42: 1026-1033
• 37 Partin AW, Catalona WJ, Southwick PC et al. Analysis of percent free prostate-specific antigen (PSA) for prostate cancer detection: influence of total PSA, prostate volume, and age. Urology 1996; 48: 55-61
• 38 Stephan C, Jung K, Lein M et al. Freies prostataspezifisches Antigen im Serum: eine Meßgröße zur Diskrimination zwischen Patienten mit Prostatakarzinom und benigner Prostatahyperplasie. J Lab Med 1996; 20: 7-12
• 39 Stephan C, Jung K, Lein M et al. Molecular forms of prostate-specific antigen and human kallikrein 2 as promising tools for early diagnosis of prostate cancer. Cancer Epidemiol Biomarkers Prev 2000; 9: 1133-1147
• 40 Catalona WJ, Partin AW, Finlay JA et al. Use of percentage of free prostate-specific antigen to identify men at high risk of prostate cancer when PSA levels are 2.51 to 4 ng/mL and digital rectal examination is not suspicious for prostate cancer: an alternative model. Urology 1999; 54: 220-224
• 41 Jung K, Stephan C, Elgeti U et al. Molecular forms of prostate-specific antigen in serum with concentrations of total prostate-specific antigen <4 µg/l – are they useful tools for early detection and screening of prostate cancer?. Int J Cancer 2001; 93: 759-765
• 42 Roehl KA, Antenor JA, Catalona WJ. Robustness of free prostate specific antigen measurements to reduce unnecessary biopsies in the 2.6 to 4.0 ng/ml range. J Urol 2002; 168: 922-925
• 43 Lee R, Localio AR, Armstrong K et al. A meta-analysis of the performance characteristics of the free prostate-specific antigen test. Urology 2006; 67: 762-768
• 44 Stephan C, Cammann H, Meyer HA et al. An artificial neural network for five different assay systems of prostate-specific antigen in prostate cancer diagnostics. BJU Int 2008; 102: 799-805
• 45 Stephan C, Rittenhouse H, Cammann H et al. New markers and multivariate models for prostate cancer detection. Anticancer Res 2009; 29: 2589-2600
• 46 Stephan C, Lein M, Jung K et al. Can prostate specific antigen derivatives reduce the frequency of unnecessary prostate biopsies?[Letter]. J Urol 1997; 157: 1371
• 47 Lee CT, Scardino PT. Percent free Prostate-specific antigen for first-time prostate biopsy. Urology 2001; 57: 594-598
• 48 Finne P, Auvinen A, Aro J et al. Estimation of prostate cancer risk on the basis of total and free prostate-specific antigen, prostate volume and digital rectal examination. Eur Urol 2002; 41: 619-626
• 49 Larsen SB, Brasso K, Iversen P et al. Baseline prostate-specific antigen measurements and subsequent prostate cancer risk in the Danish Diet, Cancer and Health cohort. Eur J Cancer 2013; 49: 3041-3048
• 50 Finne P, Auvinen A, Maattanen L et al. Diagnostic value of free prostate-specific antigen among men with a prostate-specific antigen level of <3.0 microg per liter. Eur Urol 2008; 54: 362-370
• 51 Stephan C, Stroebel G, Heinau M et al. The ratio of prostate-specific antigen (PSA) to prostate volume (PSA density) as a parameter to improve the detection of prostate carcinoma in PSA values in the range of <4 ng/mL. Can cer 2005; 104: 993-1003
• 52 Lilja H, Ulmert D, Bjork T et al. Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years. J Clin Oncol 2007; 25: 431-436
• 53 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
• 54 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
• 55 Stephan C, Cammann H, Meyer HA et al. PSA and new biomarkers within multivariate models to improve early detection of prostate cancer. Cancer Lett 2007; 249: 18-29
• 56 Stephan C, Jung K, Cammann H et al. An artificial neural network considerably improves the diagnostic power of percent free prostate-specific antigen in prostate cancer diagnosis: Results of a 5-year investigation. Int J Cancer 2002; 99: 466-473
• 57 Stephan C, Vogel B, Cammann H et al. Nutzung von artifiziellen neuronalen Netzwerken zur Risikoabschätzung eines Prostatakarzinoms: Biopsieindikationen im PSA-Bereich 2-20 µg/l. Urologe A 2003; 42: 1221-1229
• 58 Stephan C, Cammann H, Semjonow A et al. Multicenter evaluation of an artificial neural network to increase prostate cancer detection rate and reduce unnecessary biopsies. Clin Chem 2002; 48: 1279-1287
• 59 Stephan C, Cammann H, Jung K. Risikobewertung per Mausklick. Dtsch Ärztebl 2004; 101: B672-B673
• 60 Stephan C, Cammann H, Rittenhouse H et al. New biomarkers and application of multivariate models for detection of prostate cancer. Aktuelle Urol 2009; 40: 221-230
• 61 Finne P, Finne R, Auvinen A et al. Predicting the outcome of prostate biopsy in screen-positive men by a multilayer perceptron network. Urology 2000; 56: 418-422
• 62 Karakiewicz PI, Benayoun S, Kattan MW et al. Development and validation of a nomogram predicting the outcome of prostate biopsy based on patient age, digital rectal examination and serum prostate specific antigen. J Urol 2005; 173: 1930-1934
• 63 Babaian RJ, Fritsche H, Ayala A et al. Performance of a neural network in detecting prostate cancer in the prostate-specific antigen reflex range of 2.5 to 4.0 ng/mL. Urology 2000; 56: 1000-1006
• 64 Carlson GD, Calvanese CB, Partin AW. An algorithm combining age, total prostate-specific antigen (PSA), and percent free PSA to predict prostate cancer: results on 4298 cases. Urology 1998; 52: 455-461
• 65 Finne P, Finne R, Bangma C et al. Algorithms based on prostate-specific antigen (PSA), free PSA, digital rectal examination and prostate volume reduce false-positive PSA results in prostate cancer screening. Int J Cancer 2004; 111: 310-315
• 66 Horninger W, Bartsch G, Snow PB et al. The problem of cutoff levels in a screened population. Cancer 2001; 91: 1667-1672
• 67 Remzi M, Anagnostou T, Ravery V et al. An artificial neural network to predict the outcome of repeat prostate biopsies. Urology 2003; 62: 456-460
• 68 Virtanen A, Gomari M, Kranse R et al. Estimation of prostate cancer probability by logistic regression: free and total prostate-specific antigen, digital rectal examination, and heredity are significant variables. Clin Chem 1999; 45: 987-994
• 69 Mikolajczyk SD, Millar LS, Wang TJ et al. A precursor form of prostate-specific antigen is more highly elevated in prostate cancer compared with benign transition zone prostate tissue. Cancer Res 2000; 60: 756-759
• 70 Mikolajczyk SD, Marker KM, Millar LS et al. A truncated precursor form of prostate-specific antigen is a more specific serum marker of prostate cancer. Cancer Res 2001; 61: 6958-6963
• 71 Nurmikko P, Vaisanen V, Piironen T et al. Production and characterization of novel anti-prostate-specific antigen (PSA) monoclonal antibodies that do not detect internally cleaved Lys145-Lys146 inactive PSA. Clin Chem 2000; 46: 1610-1618
• 72 Nurmikko P, Pettersson K, Piironen T et al. Discrimination of prostate cancer from benign disease by plasma measurement of intact, free prostate-specific antigen lacking an internal cleavage site at Lys145-Lys146. Clin Chem 2001; 47: 1415-1423
• 73 Peter J, Unverzagt C, Krogh TN et al. Identification of precursor forms of free prostate-specific antigen in serum of prostate cancer patients by immunosorption and mass spectrometry. Cancer Res 2001; 61: 957-962
• 74 Mikolajczyk SD, Marks LS, Partin AW et al. Free prostate-specific antigen in serum is becoming more complex. Urology 2002; 59: 797-802
• 75 Wang TJ, Slawin KM, Rittenhouse HG et al. Benign prostatic hyperplasia-associated prostate-specific antigen (BPSA) shows unique immunoreactivity with anti-PSA monoclonal antibodies. Eur J Biochem 2000; 267: 4040-4045
• 76 Canto EI, Singh H, Shariat SF et al. Serum BPSA outperforms both total PSA and free PSA as a predictor of prostatic enlargement in men without prostate cancer. Urology 2004; 63: 905-910
• 77 Linton HJ, Marks LS, Millar LS et al. Benign prostate-specific antigen (BPSA) in serum is increased in benign prostate disease. Clin Chem 2003; 49: 253-259
• 78 Slawin KM, Shariat S, Canto E. BPSA: A Novel Serum Marker for Benign Prostatic Hyperplasia. Rev Urol 2005; 7 (Suppl. 08) S52-S56
• 79 Stephan C, Cammann H, Deger S et al. Benign prostatic hyperplasia-associated free prostate-specific antigen improves detection of prostate cancer in an artificial neural network. Urology 2009; 74: 873-877
• 80 Steuber T, Nurmikko P, Haese A et al. Discrimination of benign from malignant prostatic disease by selective measurements of single chain, intact free prostate specific antigen. J Urol 2002; 168: 1917-1922
• 81 Mikolajczyk SD, Grauer LS, Millar LS et al. A precursor form of PSA (pPSA) is a component of the free PSA in prostate cancer serum. Urology 1997; 50: 710-714
• 82 Bangma CH, Wildhagen MF, Yurdakul G et al. The value of (-7, -5)pro-prostate-specific antigen and human kallikrein-2 as serum markers for grading prostate cancer. BJU Int 2004; 93: 720-724
• 83 Lein M, Semjonow A, Graefen M et al. A multicenter clinical trial on the use of (-5, -7) pro prostate specific antigen. J Urol 2005; 174: 2150-2153
• 84 Mikolajczyk SD, Catalona WJ, Evans CL et al. Proenzyme forms of prostate-specific antigen in serum improve the detection of prostate cancer. Clin Chem 2004; 50: 1017-1025
• 85 Catalona WJ, Bartsch G, Rittenhouse HG et al. Serum pro prostate specific antigen improves cancer detection compared to free and complexed prostate specific antigen in men with prostate specific antigen 2 to 4 ng/ml. J Urol 2003; 170: 2181-2185
• 86 Catalona WJ, Partin AW, Sanda MG 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
• 87 Sokoll LJ, Wang Y, Feng Z et al. [-2]proenzyme prostate specific antigen for prostate cancer detection: a national cancer institute early detection research network validation study. J Urol 2008; 180: 539-543
• 88 Stephan C, Kahrs AM, Cammann H et al. A [-2]proPSA-based artificial neural network significantly improves differentiation between prostate cancer and benign prostatic diseases. Prostate 2009; 69: 198-207
• 89 Stephan C, Vincendeau S, Houlgatte A et al. Multicenter evaluation of [-2]proprostate-specific antigen and the prostate health index for detecting prostate cancer. Clin Chem 2013; 59: 306-314
• 90 Jansen FH, van Schaik RH, 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
• 91 Le BV, Griffin CR, Loeb S et al. [-2]Proenzyme prostate specific antigen is more accurate than total and free prostate specific antigen in differentiating prostate cancer from benign disease in a prospective prostate cancer screening study. J Urol 2010; 183: 1355-1359
• 92 Lazzeri M, Haese A, de la Taille A et al. Serum isoform [-2]proPSA derivatives significantly improve prediction of prostate cancer at initial biopsy in a total PSA range of 2-10 ng/ml: a multicentric European study. Eur Urol 2013; 63: 986-994
• 93 Sokoll LJ, Sanda MG, Feng Z 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
• 94 Hori S, Blanchet JS, McLoughlin J. From prostate-specific antigen (PSA) to precursor PSA (proPSA) isoforms: a review of the emerging role of proPSAs in the detection and management of early prostate cancer. BJU Int 2013; 112: 717-728
• 95 Heijnsdijk E, Huang J, Denham D et al. The cost-effectiveness of prostate cancer detection using the prostate health index phi. Eur Urol Suppl 2012; 11: e260
• 96 Filella X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clin Chem Lab Med 2013; 51: 729-739
• 97 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
• 98 Ferro M, Bruzzese D, Perdona S 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
• 99 Roobol MJ, Carlsson SV. Risk stratification in prostate cancer screening. Nat Rev Urol 2013; 10: 38-48
• 100 Loeb S. Prostate Health Index (PHI): golden bullet or just another prostate cancer marker?. Eur Urol 2013; 63: 995-996
• 101 Melichar B. PSA, PCA3 and the phi losophy of prostate cancer management. Clin Chem Lab Med 2013; 51: 707-712
• 102 Rittenhouse HG, Finlay JA, Mikolajczyk SD et al. Human Kallikrein 2 (hK2) and prostate-specific antigen (PSA): two closely related, but distinct, kallikreins in the prostate. Crit Rev Clin Lab Sci 1998; 35: 275-368
• 103 Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 2001; 22: 184-204
• 104 Lundwall A, Band V, Blaber M et al. A comprehensive nomenclature for serine proteases with homology to tissue kallikreins. Biol Chem 2006; 387: 637-641
• 105 Kumar A, Mikolajczyk SD, Goel AS et al. Expression of pro form of prostate-specific antigen by mammalian cells and its conversion to mature, active form by human kallikrein 2. Cancer Res 1997; 57: 3111-3114
• 106 Lövgren J, Rajakoski K, Karp M et al. Activation of the zymogen form of prostate-specific antigen by human glandular kallikrein 2. Biochem Biophys Res Commun 1997; 238: 549-555
• 107 Takayama TK, Fujikawa K, Davie EW. Characterization of the precursor of prostate-specific antigen. Activation by trypsin and by human glandular kallikrein. J Biol Chem 1997; 272: 21582-21588
• 108 Becker C, Piironen T, Pettersson K et al. Discrimination of men with prostate cancer from those with benign disease by measurements of human glandular kallikrein 2 (HK2) in serum. J Urol 2000; 163: 311-316
• 109 Kwiatkowski MK, Recker F, Piironen T et al. In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic „gray zone“ of total PSA 4 to 10 ng/mL. Urology 1998; 52: 360-365
• 110 Magklara A, Scorilas A, Catalona WJ et al. The combination of human glandular kallikrein and free prostate-specific antigen (PSA) enhances discrimination between prostate cancer and benign prostatic hyperplasia in patients with moderately increased total PSA. Clin Chem 1999; 45: 1960-1966
• 111 Nam RK, Diamandis EP, Toi A et al. Serum human glandular kallikrein-2 protease levels predict the presence of prostate cancer among men with elevated prostate-specific antigen. J Clin Oncol 2000; 18: 1036-1042
• 112 Partin AW, Catalona WJ, Finlay JA et al. Use of human glandular kallikrein 2 for the detection of prostate cancer: preliminary analysis. Urology 1999; 54: 839-845
• 113 Haese A, Noldus J, Graefen M et al. Human glandular kallikrein 2 (hK2) is superior to total PSA in predicting organ-confined disease and pathological stage of clinically localized prostate cancer with a total PSA <10 ng/ml. J Urol Suppl 2001; 165: 234
• 114 Haese A, Graefen M, Steuber T et al. Human glandular kallikrein 2 levels in serum for discrimination of pathologically organ-confined from locally-advanced prostate cancer in total PSA-levels below 10 ng/ml. Prostate 2001; 49: 101-109
• 115 Recker F, Kwiatkowski MK, Piironen T et al. Human glandular kallikrein as a tool to improve discrimination of poorly differentiated and non-organ-confined prostate cancer compared with prostate-specific antigen. Urology 2000; 55: 481-485
• 116 Stephan C, Jung K, Nakamura T et al. Serum human glandular kallikrein 2 (hK2) for distinguishing stage and grade of prostate cancer. Int J Urol 2006; 13: 238-243
• 117 Haese A, Graefen M, Becker C et al. The role of human glandular kallikrein 2 for prediction of pathologically organ confined prostate cancer. Prostate 2003; 54: 181-186
• 118 Stephan C, Jung K, Soosaipillai A et al. Clinical utility of human glandular kallikrein 2 within a neural network for prostate cancer detection. BJU Int 2005; 96: 521-527
• 119 Obiezu CV, Soosaipillai A, Jung K et al. Detection of human kallikrein 4 (HK4) in normal and cancerous prostatic tissues by immunofluorometry and immunohistochemistry. Clin Chem 2002; 48: 1232-1240
• 120 Nakamura T, Stephan C, Scorilas A et al. Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. Urology 2003; 61: 1042-1046
• 121 Stephan C, Yousef GM, Scorilas A et al. Quantitative analysis of kallikrein 15 (KLK15) gene expression in prostate tissue. J Urol 2003; 169: 361-364
• 122 Paliouras M, Diamandis EP. The kallikrein world: an update on the human tissue kallikreins. Biol Chem 2006; 387: 643-652
• 123 Thorek DL, Evans MJ, Carlsson SV et al. Prostate-specific kallikrein-related peptidases and their relation to prostate cancer biology and detection. Established relevance and emerging roles. Thromb Haemost 2013; 110: 484-492
• 124 Takayama TK, McMullen BA, Nelson PS et al. Characterization of hK4 (Prostase), a Prostate-Specific Serine Protease: Activation of the Precursor of Prostate Specific Antigen (pro- PSA) and Single-Chain Urokinase-Type Plasminogen Activator and Degradation of Prostatic Acid Phosphatase. Biochemistry 2001; 40: 15341-15348
• 125 Planque C, Li L, Zheng Y et al. A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma. Clin Cancer Res 2008; 14: 1355-1362
• 126 Ewan KL, Li X, Cheikh Saad BK et al. Human kallikrein 10 ELISA development and validation in breast cancer sera. Clin Biochem 2007; 40: 1057-1062
• 127 Nakamura T, Scorilas A, Stephan C et al. The usefulness of serum human kallikrein 11 for discriminating between prostate cancer and benign prostatic hyperplasia. Cancer Res 2003; 63: 6543-6546
• 128 Stephan C, Meyer HA, Cammann H et al. Improved prostate cancer detection with a human kallikrein 11 and percentage free PSA-based artificial neural network. Biol Chem 2006; 387: 801-805
• 129 Mavridis K, Stravodimos K, Scorilas A. Quantified KLK15 gene expression levels discriminate prostate cancer from benign tumors and constitute a novel independent predictor of disease progression. Prostate 2013; 73: 1191-1201
• 130 Rabien A, Fritzsche FR, Jung M et al. KLK15 is a prognostic marker for progression-free survival in patients with radical prostatectomy. Int J Cancer 2010; 127: 2386-2394
• 131 Shaw JL, Grass L, Sotiropoulou G et al. Development of an immunofluorometric assay for human kallikrein 15 (KLK15) and identification of KLK15 in tissues and biological fluids. Clin Biochem 2007; 40: 104-110
• 132 Diamandis EP. EPCA-2: a highly specific serum marker for prostate cancer. Clin Biochem 2012; 45: 600
• 133 Brown DA, Stephan C, Ward RL et al. Measurement of serum levels of macrophage inhibitory cytokine 1 combined with prostate-specific antigen improves prostate cancer diagnosis. Clin Cancer Res 2006; 12: 89-96
• 134 Brown DA, Lindmark F, Stattin P et al. Macrophage inhibitory cytokine 1: a new prognostic marker in prostate cancer. Clin Cancer Res 2009; 15: 6658-6664
• 135 Meyer-Siegler KL, Bellino MA, Tannenbaum M. Macrophage migration inhibitory factor evaluation compared with prostate specific antigen as a biomarker in patients with prostate carcinoma. Cancer 2002; 94: 1449-1456
• 136 Michael A, Stephan C, Kristiansen G et al. Diagnostic validity of macrophage migration inhibitory factor in serum of patients with prostate cancer: a re-evaluation. Prostate 2005; 62: 34-39
• 137 Stephan C, Xu C, Brown DA et al. Three new serum markers for prostate cancer detection within a percent free PSA-based artificial neural network. Prostate 2006; 66: 651-659
• 138 Lucarelli G, Rutigliano M, Bettocchi C et al. Spondin-2, a Secreted Extracellular Matrix Protein, Is a Novel Diagnostic Biomarker for Prostate Cancer. J Urol 2013; 190: 2271-2277
• 139 Qian X, Li C, Pang B et al. Spondin-2 (SPON2), a more prostate-cancer-specific diagnostic biomarker. PLoS One 2012; 7: e37225
• 140 Balan V, Wang Y, Nangia-Makker P et al. Galectin-3: a possible complementary marker to the PSA blood test. Oncotarget 2013; 4: 542-549
• 141 Hermani A, Hess J, De Servi B et al. Calcium-binding proteins S100A8 and S100A9 as novel diagnostic markers in human prostate cancer. Clin Cancer Res 2005; 11: 5146-5152
• 142 Ludwig S, Stephan C, Lein M et al. S100A9, and the S100A8/A9 complex in circulating blood are not associated with prostate cancer risk-A re-evaluation study. Prostate 2007; 67: 1301-1307
• 143 Koutros S, Meyer TE, Fox SD et al. Prospective evaluation of serum sarcosine and risk of prostate cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Carcinogenesis 2013; 34: 2281-2285
• 144 Lucarelli G, Fanelli M, Larocca AM et al. Serum sarcosine increases the accuracy of prostate cancer detection in patients with total serum PSA less than 4.0 ng/ml. Prostate 2012; 72: 1611-1621
• 145 Lucarelli G, Ditonno P, Bettocchi C et al. Serum sarcosine is a risk factor for progression and survival in patients with metastatic castration-resistant prostate cancer. Future Oncol 2013; 9: 899-907
• 146 de Vogel S, Ulvik A, Meyer K et al. Sarcosine and other metabolites along the choline oxidation pathway in relation to prostate cancer-A large nested case-control study within the JANUS cohort in Norway. Int J Cancer 2014; 134: 197-206
• 147 Struys EA, Heijboer AC, van Moorselaar J et al. Serum sarcosine is not a marker for prostate cancer. Ann Clin Biochem 2010; 47: 282
• 148 Bohm L, Serafin AM, Fernandez P et al. Plasma sarcosine does not distinguish early and advanced stages of prostate cancer. S Afr Med J 2012; 102: 677-679
• 149 Jentzmik F, Stephan C, Lein M et al. Sarcosine in prostate cancer tissue is not a differential metabolite for prostate cancer aggressiveness and biochemical progression. J Urol 2011; 185: 706-711
• 150 Sokoll LJ, Ellis W, Lange P 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
• 151 Sreekumar A, Poisson LM, Rajendiran TM et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009; 457: 910-914
• 152 Jentzmik F, Stephan C, Miller K et al. Sarcosine in urine after digital rectal examination fails as a marker in prostate cancer detection and identification of aggressive tumours. Eur Urol 2010; 58: 12-18
• 153 Cernei N, Heger Z, Gumulec J et al. Sarcosine as a potential prostate cancer biomarker-a review. Int J Mol Sci 2013; 14: 13893-13908
• 154 de Kok JB, Verhaegh GW, Roelofs RW et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res 2002; 62: 2695-2698
• 155 Hessels D, Klein Gunnewiek JM, van Oort I et al. DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer. Eur Urol 2003; 44: 8-15
• 156 Filella X, Foj L, Mila M et al. PCA3 in the detection and management of early prostate cancer. Tumour Biol 2013; 34: 1337-1347
• 157 Groskopf J, Aubin SM, Deras IL 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
• 158 Haese A, de la Taille A, Van Poppel H et al. Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Eur Urol 2008; 54: 1081-1088
• 159 Deras IL, Aubin SM, Blase A et al. PCA3: a molecular urine assay for predicting prostate biopsy outcome. J Urol 2008; 179: 1587-1592
• 160 Roobol MJ, Schroder FH, van Leenders GL et al. Performance of prostate cancer antigen 3 (PCA3) and prostate-specific antigen in Prescreened men: reproducibility and detection characteristics for prostate cancer patients with high PCA3 scores (≥ 100). Eur Urol 2010; 58: 893-899
• 161 Bradley LA, Palomaki GE, Gutman S et al. Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer. J Urol 2013; 190: 389-398
• 162 Roobol MJ. Contemporary role of prostate cancer gene 3 in the management of prostate cancer. Curr Opin Urol 2011; 21: 225-229
• 163 Truong M, Yang B, Jarrard DF. Toward the detection of prostate cancer in urine: a critical analysis. J Urol 2013; 189: 422-429
• 164 Auprich M, Bjartell A, Chun FK et al. Contemporary role of prostate cancer antigen 3 in the management of prostate cancer. Eur Urol 2011; 60: 1045-1054
• 165 Auprich M, Haese A, Walz J et al. External validation of urinary PCA3-based nomograms to individually predict prostate biopsy outcome. Eur Urol 2010; 58: 727-732
• 166 Hessels D, van Gils MP, van Hooij O et al. Predictive value of PCA3 in urinary sediments in determining clinico-pathological characteristics of prostate cancer. Prostate 2010; 70: 10-16
• 167 Marks LS, Fradet Y, Deras IL et al. PCA3 molecular urine assay for prostate cancer in men undergoing repeat biopsy. Urology 2007; 69: 532-535
• 168 Ankerst DP, Groskopf J, Day JR et al. Predicting prostate cancer risk through incorporation of prostate cancer gene 3. J Urol 2008; 180: 1303-1308
• 169 Aubin SM, Reid J, Sarno MJ et al. Prostate cancer gene 3 score predicts prostate biopsy outcome in men receiving dutasteride for prevention of prostate cancer: results from the REDUCE trial. Urology 2011; 78: 380-385
• 170 Bollito E, De Luca S, Cicilano M et al. Prostate cancer gene 3 urine assay cutoff in diagnosis of prostate cancer: a validation study on an Italian patient population undergoing first and repeat biopsy. Anal Quant Cytol Histol 2012; 34: 96-104
• 171 Chun FK, de la Taille A, Van Poppel H et al. Prostate cancer gene 3 (PCA3): development and internal validation of a novel biopsy nomogram. Eur Urol 2009; 56: 659-668
• 172 Ferro M, Bruzzese D, Perdona S 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
• 173 Gittelman MC, Hertzman B, Bailen J et al. PCA3 molecular urine test as a predictor of repeat prostate biopsy outcome in men with previous negative biopsies: a prospective multicenter clinical study. J Urol 2013; 190: 64-69
• 174 Hansen J, Auprich M, Ahyai SA 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: 201-209
• 175 Ochiai A, Okihara K, Kamoi K et al. Clinical utility of the prostate cancer gene 3 (PCA3) urine assay in Japanese men undergoing prostate biopsy. BJU Int 2013; 111: 928-933
• 176 Perdona S, Cavadas V, Di Lorenzo G 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
• 177 Roobol MJ, Schroder FH, van Leeuwen P 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
• 178 Stephan C, Jung K, Semjonow A 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
• 179 Tombal B, Andriole GL, de la Taille A et al. Clinical judgment versus biomarker prostate cancer gene 3: which is best when determining the need for repeat prostate biopsy?. Urology 2013; 81: 998-1004
• 180 Goode RR, Marshall SJ, Duff M et al. Use of PCA3 in detecting prostate cancer in initial and repeat prostate biopsy patients. Prostate 2013; 73: 48-53
• 181 Ploussard G, Haese A, van Poppel H 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
• 182 Aubin SM, Reid J, Sarno MJ 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
• 183 de la Taille A, Irani J, Graefen M et al. Clinical evaluation of the PCA3 assay in guiding initial biopsy decisions. J Urol 2011; 185: 2119-2125
• 184 Ruffion A, Devonec M, Champetier D et al. PCA3 and PCA3-Based Nomograms Improve Diagnostic Accuracy in Patients Undergoing First Prostate Biopsy. Int J Mol Sci 2013; 14: 17767-17780
• 185 Scattoni V, Lazzeri M, Lughezzani G 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
• 186 Crawford ED, Rove KO, Trabulsi EJ 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: 1726-1731
• 187 Vlaeminck-Guillem V, Bandel M, Cottancin M et al. Chronic prostatitis does not influence urinary PCA3 score. Prostate 2012; 72: 549-554
• 188 Leyten GH, Wierenga EA, Sedelaar JP et al. Value of PCA3 to Predict Biopsy Outcome and Its Potential Role in Selecting Patients for Multiparametric MRI. Int J Mol Sci 2013; 14: 11347-11355
• 189 Perdona S, Bruzzese D, Ferro M 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
• 190 Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644-648
• 191 Esgueva R, Perner S, LaFargue J et al. Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort. Mod Pathol 2010; 23: 539-546
• 192 Perner S, Demichelis F, Beroukhim R et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 2006; 66: 8337-8341
• 193 Salagierski M, Schalken JA. Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. J Urol 2012; 187: 795-801
• 194 Perner S. Dangerous liaisons in prostate cancer. Clinical and biological implications of recurrent gene fusions. Pathologe 2010; 31 (Suppl. 02) 121-125
• 195 Young A, Palanisamy N, Siddiqui J et al. Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden. Am J Clin Pathol 2012; 138: 685-696
• 196 Groskopf J, Siddiqui J, Aubin SMJ et al. Feasibility and clinical utility of a TMPRSS2:ERG gene fusion urine test [Abstract]. Eur Urol (Suppl 2009; 8: 195
• 197 Salami SS, Schmidt F, Laxman B 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
• 198 Cornu JN, Cancel-Tassin G, Egrot C et al. 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
• 199 Leyten GH, Hessels D, Jannink SA 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
• 200 Tomlins SA, Aubin SM, 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
• 201 Robert G, Jannink S, Smit F et al. Rational basis for the combination of PCA3 and TMPRSS2:ERG gene fusion for prostate cancer diagnosis. Prostate 2013; 73: 113-120
• 202 Dimitriadis E, Kalogeropoulos T, Velaeti S et al. Study of genetic and epigenetic alterations in urine samples as diagnostic markers for prostate cancer. Anticancer Res 2013; 33: 191-197
• 203 Rigau M, Ortega I, Mir MC et al. A three-gene panel on urine increases PSA specificity in the detection of prostate cancer. Prostate 2011; 71: 1736-1745
• 204 Cao DL, Ye DW, Zhang HL et al. A multiplex model of combining gene-based, protein-based, and metabolite-based with positive and negative markers in urine for the early diagnosis of prostate cancer. Prostate 2011; 71: 700-710
• 205 Katafigiotis I, Tyritzis SI, Stravodimos KG et al. Zinc alpha2-glycoprotein as a potential novel urine biomarker for the early diagnosis of prostate cancer. BJU Int 2012; 110: E688-E693
• 206 Jamaspishvili T, Kral M, Khomeriki I et al. Urine markers in monitoring for prostate cancer. Prostate Cancer Prostatic Dis 2010; 13: 12-19
• 207 Roobol MJ, Haese A, Bjartell A. Tumour markers in prostate cancer III: biomarkers in urine. Acta Oncol 2011; 50 (Suppl. 01) 85-89
• 208 Hessels D, Schalken JA. Urinary biomarkers for prostate cancer: a review. Asian J Androl 2013; 15: 333-339
• 209 Liang Y, Ankerst DP, Ketchum NS et al. Prospective evaluation of operating characteristics of prostate cancer detection biomarkers. J Urol 2011; 185: 104-110
• 210 Guazzoni G, Nava L, Lazzeri M 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
• 211 Lazzeri M, Briganti A, Scattoni V et al. Serum index test %[-2]proPSA and prostate health index are more accurate than prostate specific antigen and %fPSA in predicting a positive repeat prostate biopsy. J Urol 2012; 188: 1137-1143
• 212 Loeb S, Sokoll LJ, Broyles DL et al. Prospective multicenter evaluation of the Beckman Coulter Prostate Health Index using WHO calibration. J Urol 2013; 189: 1702-1706
• 213 Ito K, Miyakubo M, Sekine Y et al. Diagnostic significance of [-2]pro-PSA and prostate dimension-adjusted PSA-related indices in men with total PSA in the 2.0-10.0 ng/mL range. World J Urol 2013; 31: 305-311
• 214 Ng CF, Chiu PK, Lam NY et al. The Prostate Health Index in predicting initial prostate biopsy outcomes in Asian men with prostate-specific antigen levels of 4-10 ng/mL. Int Urol Nephrol 2014; 46: 711-717