Beyond PSA: The Next Generation of Prostate Cancer Biomarkers

Prostate cancer biomarkers that improve upon the PSA test should address unmet clinical needs. Next-Gen Biomarkers For decades, the prostate-specific antigen (PSA) test has been used to assist in the diagnosis of prostate cancer. It has also become more prevalent in early cancer screening. Although the number of deaths related to prostate cancer has decreased, it is not clear that the PSA test has been the major factor. As Prensner and co-authors point out, the PSA test may “do more harm than good.” This Review focuses on new ways to address unmet clinical needs in the area of biomarkers, to hopefully add to the armamentarium of diagnostic, prognostic, and predictive tools for prostate cancer, including PSA. Since the introduction of serum prostate-specific antigen (PSA) screening 25 years ago, prostate cancer diagnosis and management have been guided by this biomarker. Yet, PSA has proven controversial as a screening assay owing to several inherent limitations. The next wave of prostate cancer biomarkers has emerged, introducing new assays in serum and urine that may supplement or, in time, replace PSA because of their higher cancer specificity. This expanding universe of biomarkers has been facilitated, in large part, by new genomic technologies that have enabled an unbiased look at cancer biology. Such efforts have produced several notable success stories that involve rapidly moving biomarkers from the bench to the clinic. However, biomarker research has centered on disease diagnostics, rather than prognosis and prediction, which would address disease management. The development of biomarkers to stratify risk of prostate cancer aggressiveness at the time of screening remains the greatest unmet clinical need in prostate cancer. We review the current state of prostate cancer biomarker research, including the PSA revolution, its impact on early cancer detection, the recent advances in biomarker discovery, and the future efforts that promise to improve clinical management of this disease.

[1]  Graham A. Colditz,et al.  Applying What We Know to Accelerate Cancer Prevention , 2012, Science Translational Medicine.

[2]  J. Carpten,et al.  Germline mutations in HOXB13 and prostate-cancer risk. , 2012, The New England journal of medicine.

[3]  L. Tanoue,et al.  Reduced lung cancer mortality with low-dose computed tomographic screening , 2011 .

[4]  Christina Bougatsos,et al.  Screening for Prostate Cancer: A Review of the Evidence for the U.S. Preventive Services Task Force , 2011, Annals of Internal Medicine.

[5]  Lee T. Sam,et al.  Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study , 2011, Science Translational Medicine.

[6]  Jean-Pierre Gillet,et al.  Redefining the relevance of established cancer cell lines to the study of mechanisms of clinical anti-cancer drug resistance , 2011, Proceedings of the National Academy of Sciences.

[7]  D. Kerr,et al.  Predictive biomarkers: a paradigm shift towards personalized cancer medicine , 2011, Nature Reviews Clinical Oncology.

[8]  C. Gatsonis,et al.  Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening , 2012 .

[9]  Nallasivam Palanisamy,et al.  Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA , 2011, Science Translational Medicine.

[10]  John T. Wei,et al.  Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression , 2011, Nature Biotechnology.

[11]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[12]  Wei Yan,et al.  Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. , 2011, Cancer cell.

[13]  Sarat Chandarlapaty,et al.  Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. , 2011, Cancer cell.

[14]  U. Landegren,et al.  Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer , 2011, Proceedings of the National Academy of Sciences.

[15]  Dan Stoianovici,et al.  Advancements in MR imaging of the prostate: from diagnosis to interventions. , 2011, Radiographics : a review publication of the Radiological Society of North America, Inc.

[16]  Guido Jenster,et al.  Exosomes as biomarker treasure chests for prostate cancer. , 2011, European urology.

[17]  D. Ransohoff,et al.  Biomarker studies: a call for a comprehensive biomarker study registry , 2011, Nature Reviews Clinical Oncology.

[18]  Yousef Mazaheri,et al.  MRI of the prostate: Clinical relevance and emerging applications , 2011, Journal of magnetic resonance imaging : JMRI.

[19]  Chunsheng Han,et al.  The Prostate 71 : 209 ^ 224 ( 2011 ) Meta-Analysis ofGenome-Wide andReplication Association Studies on ProstateCancer , 2010 .

[20]  Eric S. Lander,et al.  The genomic complexity of primary human prostate cancer , 2010, Nature.

[21]  M. Kattan,et al.  Development and validation of a nomogram for predicting a positive repeat prostate biopsy in patients with a previous negative biopsy session in the era of extended prostate sampling , 2010, BJU international.

[22]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[23]  L. Santarpia,et al.  Breast cancer assessment tools and optimizing adjuvant therapy , 2010, Nature Reviews Clinical Oncology.

[24]  E. Diamandis,et al.  Cancer biomarkers: can we turn recent failures into success? , 2010, Journal of the National Cancer Institute.

[25]  C. Oeser,et al.  Open-label, randomised, parallel-group, multicentre study to evaluate the safety, tolerability and immunogenicity of an AS03(B)/oil-in-water emulsion-adjuvanted (AS03(B)) split-virion versus non-adjuvanted whole-virion H1N1 influenza vaccine in UK children 6 months to 12 years of age. , 2010, Health technology assessment.

[26]  R. V. D. van den Bergh,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. , 2010, European urology.

[27]  Jaya M Satagopan,et al.  TMPRSS2–ERG gene fusion is associated with low Gleason scores and not with high-grade morphological features , 2010, Modern Pathology.

[28]  J C Wyatt,et al.  Computerised decision support systems in order communication for diagnostic, screening or monitoring test ordering: systematic reviews of the effects and cost-effectiveness of systems. , 2010, Health technology assessment.

[29]  H. Welch,et al.  Overdiagnosis in cancer. , 2010, Journal of the National Cancer Institute.

[30]  Milton C Weinstein,et al.  Comparative effectiveness and health care spending--implications for reform. , 2010, The New England journal of medicine.

[31]  A. D'Amico,et al.  American Cancer Society Guideline for the Early Detection of Prostate Cancer: Update 2010 , 2010, CA: a cancer journal for clinicians.

[32]  Francisco M. De La Vega,et al.  Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing , 2010, Science Translational Medicine.

[33]  Boris Freidlin,et al.  Randomized clinical trials with biomarkers: design issues. , 2010, Journal of the National Cancer Institute.

[34]  F. Song,et al.  Dissemination and publication of research findings: an updated review of related biases. , 2010, Health technology assessment.

[35]  T. H. van der Kwast,et al.  False-negative Prostate Needle Biopsies: Frequency, Histopathologic Features, and Follow-up , 2010, The American journal of surgical pathology.

[36]  B. G. Blijenberg,et al.  Screening and prostate-cancer mortality in a randomized European study. , 2009, The New England journal of medicine.

[37]  David Chia,et al.  Mortality results from a randomized prostate-cancer screening trial. , 2009, The New England journal of medicine.

[38]  Laura Esserman,et al.  Rethinking screening for breast cancer and prostate cancer. , 2009, JAMA.

[39]  M. Stockler,et al.  Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling. , 2009, Cancer research.

[40]  John T. Wei,et al.  Rational approach to implementation of prostate cancer antigen 3 into clinical care , 2009, Cancer.

[41]  A. D'Amico,et al.  Hormonal therapy use for prostate cancer and mortality in men with coronary artery disease-induced congestive heart failure or myocardial infarction. , 2009, JAMA.

[42]  F. Saad,et al.  PTEN genomic deletion is associated with p‐Akt and AR signalling in poorer outcome, hormone refractory prostate cancer , 2009, The Journal of pathology.

[43]  R. Shah,et al.  Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression , 2009, Modern Pathology.

[44]  J. Schalken,et al.  The use of PCA3 in the diagnosis of prostate cancer , 2009, Nature Reviews Urology.

[45]  X. Breakefield,et al.  Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer , 2009, British Journal of Cancer.

[46]  D. Dearnaley,et al.  Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. , 2009, Cancer research.

[47]  Angela Mariotto,et al.  Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. , 2009, Journal of the National Cancer Institute.

[48]  Lori J Sokoll,et al.  Predicting prostate cancer biochemical recurrence using a panel of serum proteomic biomarkers. , 2009, The Journal of urology.

[49]  W. Gerald,et al.  TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. , 2009, Cancer research.

[50]  Pamela A Shaw,et al.  Methods for Assessing Improvement in Specificity When a Biomarker is Combined With a Standard Screening Test , 2009, Statistics in biopharmaceutical research.

[51]  A. Chinnaiyan,et al.  Oncogenic gene fusions in epithelial carcinomas. , 2009, Current opinion in genetics & development.

[52]  Michel Bolla,et al.  [EAU guidelines on prostate cancer]. , 2009, Actas urologicas espanolas.

[53]  H. Carter,et al.  Words of wisdom. Re: Long-term prediction of prostate cancer: prostate-specific antigen (PSA) velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. , 2009, European urology.

[54]  P. Schellhammer.  Words of wisdom. Re: Pathologic characteristics of cancers detected in the Prostate Cancer Prevention Trial: implications for prostate cancer detection and chemoprevention. , 2009, European urology.

[55]  John T. Wei,et al.  Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression , 2009, Nature.

[56]  Monique J. Roobol,et al.  Mortality Results from a Randomized ProstateCancer Screening Trial , 2009 .

[57]  O. Ludkovski,et al.  Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome , 2008, Modern Pathology.

[58]  Rebecca O Barnes,et al.  Influence of Evolution in Tumor Biobanking on the Interpretation of Translational Research , 2008, Cancer Epidemiology Biomarkers & Prevention.

[59]  E. Diamandis,et al.  Emerging biomarkers for the diagnosis and prognosis of prostate cancer. , 2008, Clinical chemistry.

[60]  Mesut Remzi,et al.  Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. , 2008, European urology.

[61]  Holly Janes,et al.  Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction: Standards for Study Design , 2008, Journal of the National Cancer Institute.

[62]  K. Pienta,et al.  Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer , 2008, Clinical Cancer Research.

[63]  I. Thompson,et al.  Pathologic Characteristics of Cancers Detected in the Prostate Cancer Prevention Trial: Implications for Prostate Cancer Detection and Chemoprevention , 2008, Cancer Prevention Research.

[64]  Wadih Arap,et al.  Quality of life and satisfaction with outcome among prostate-cancer survivors. , 2008, The New England journal of medicine.

[65]  C. Stephan,et al.  Proteomic analysis of conditioned media from the PC3, LNCaP, and 22Rv1 prostate cancer cell lines: discovery and validation of candidate prostate cancer biomarkers. , 2008, Journal of proteome research.

[66]  C. Sawyers.  The cancer biomarker problem , 2008, Nature.

[67]  Andrew J. Vickers,et al.  Prostate-specific antigen and prostate cancer: prediction, detection and monitoring , 2008, Nature Reviews Cancer.

[68]  H Ballentine Carter,et al.  Early detection of prostate cancer in 2007. Part 1: PSA and PSA kinetics. , 2008, European urology.

[69]  Pär Stattin,et al.  Cumulative association of five genetic variants with prostate cancer. , 2008, The New England journal of medicine.

[70]  P. Scardino,et al.  Long-term prediction of prostate cancer: prostate-specific antigen (PSA) velocity is predictive but does not improve the predictive accuracy of a single PSA measurement 15 years or more before cancer diagnosis in a large, representative, unscreened population. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  Jianjun Yu,et al.  A first-generation multiplex biomarker analysis of urine for the early detection of prostate cancer. , 2008, Cancer research.

[72]  J Cuzick,et al.  Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer , 2008, Oncogene.

[73]  B. Trock,et al.  The natural history of men treated with deferred androgen deprivation therapy in whom metastatic prostate cancer developed following radical prostatectomy. , 2008, The Journal of urology.

[74]  David F Ransohoff,et al.  How to improve reliability and efficiency of research about molecular markers: roles of phases, guidelines, and study design. , 2007, Journal of clinical epidemiology.

[75]  Glenn Heller,et al.  Circulating Tumor Cell Number and Prognosis in Progressive Castration-Resistant Prostate Cancer , 2007, Clinical Cancer Research.

[76]  J. Witjes,et al.  Detection of TMPRSS2-ERG Fusion Transcripts and Prostate Cancer Antigen 3 in Urinary Sediments May Improve Diagnosis of Prostate Cancer , 2007, Clinical Cancer Research.

[77]  P. Walsh.  The discovery of the cavernous nerves and development of nerve sparing radical retropubic prostatectomy. , 2007, The Journal of urology.

[78]  W. Catalona,et al.  Prostate specific antigen density correlates with features of prostate cancer aggressiveness. , 2007, The Journal of urology.

[79]  R. Millikan,et al.  Prostate cancer progression in the presence of undetectable or low serum prostate‐specific antigen level , 2007, Cancer.

[80]  P. Humphrey,et al.  Diagnosis of adenocarcinoma in prostate needle biopsy tissue , 2007, Journal of Clinical Pathology.

[81]  P. Kantoff,et al.  TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort , 2007, Oncogene.

[82]  L. Ferrucci,et al.  Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. , 2006, Journal of the National Cancer Institute.

[83]  Steven A Carr,et al.  Protein biomarker discovery and validation: the long and uncertain path to clinical utility , 2006, Nature Biotechnology.

[84]  D. Bates,et al.  The impact of a suspicious prostate biopsy on patients’ psychological, socio-behavioral, and medical care outcomes , 2006, Journal of General Internal Medicine.

[85]  W. Sauerbrei,et al.  Reporting recommendations for tumor marker prognostic studies (REMARK). , 2005, Journal of the National Cancer Institute.

[86]  John P A Ioannidis,et al.  Selective reporting biases in cancer prognostic factor studies. , 2005, Journal of the National Cancer Institute.

[87]  Debashis Ghosh,et al.  Decreased α-Methylacyl CoA Racemase Expression in Localized Prostate Cancer is Associated with an Increased Rate of Biochemical Recurrence and Cancer-Specific Death , 2005, Cancer Epidemiology Biomarkers & Prevention.

[88]  P. Walsh,et al.  Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. , 2005, The Journal of urology.

[89]  M Bolla,et al.  EAU guidelines on prostate cancer. , 2001, European urology.

[90]  S. Cadrin,et al.  A Preliminary Analysis , 2005 .

[91]  Ming-Hui Chen,et al.  Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. , 2004, The New England journal of medicine.

[92]  Georg Bartsch,et al.  Serum pro-prostate specific antigen preferentially detects aggressive prostate cancers in men with 2 to 4 ng/ml prostate specific antigen. , 2004, The Journal of urology.

[93]  J. Crowley,et al.  Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. , 2004, The New England journal of medicine.

[94]  G. Yousef,et al.  An update on human and mouse glandular kallikreins. , 2004, Clinical biochemistry.

[95]  K. Pettersson,et al.  Prostate-Specific Antigen in Serum Occurs Predominantly in Complex with a . 1-Antichymotrypsin , 2004 .

[96]  T. Stamey,et al.  Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. , 2003, The Journal of urology.

[97]  Zhong Jiang,et al.  Expression of α-methylacyl-coa racemase (p504s) in various malignant neoplasms and normal tissues: a study of 761 cases , 2003 .

[98]  H. Klocker,et al.  Proenzyme psa for the early detection of prostate cancer in the 2.5-4.0 ng/ml total psa range: preliminary analysis. , 2003, Urology.

[99]  G. Bubley,et al.  Biology of prostate-specific antigen. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  N. Anderson,et al.  The Human Plasma Proteome: History, Character, and Diagnostic Prospects , 2003, Molecular & Cellular Proteomics.

[101]  G. Bubley,et al.  BIOLOGY OF PROSTATESPECIFIC ANTIGEN , 2003 .

[102]  Evert-Ben van Veen,et al.  Tumour banks: well-guarded treasures in the interest of patients , 2003, Nature Reviews Cancer.

[103]  L. Kiemeney,et al.  DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. , 2002, Cancer research.

[104]  Debashis Ghosh,et al.  alpha-Methylacyl coenzyme A racemase as a tissue biomarker for prostate cancer. , 2002, JAMA.

[105]  N. Anderson,et al.  HISTORY, CHARACTER, AND DIAGNOSTIC PROSPECTS* , 2002 .

[106]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[107]  M. Lukeš,et al.  Prostate-specific antigen: current status. , 2001, Folia biologica.

[108]  E. Feuer,et al.  Impact of screening on incidence and mortality of prostate cancer in the United States. , 2001, Epidemiologic reviews.

[109]  F. Zattoni,et al.  European Association of Urology GUIDELINES ON PROSTATE CANCER , 2001 .

[110]  C. Baird,et al.  The pilot study. , 2000, Orthopedic nursing.

[111]  H. Federrath,et al.  Design issues , 2008 .

[112]  W. Isaacs,et al.  DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. , 1999, Cancer research.

[113]  M. Brawer,et al.  Prostate‐specific antigen: Current status , 1999, CA: a cancer journal for clinicians.

[114]  A W Partin,et al.  Natural history of progression after PSA elevation following radical prostatectomy. , 1999, JAMA.

[115]  E. Feuer,et al.  Asymptomatic incidence and duration of prostate cancer. , 1998, American journal of epidemiology.

[116]  A S Whittemore,et al.  Prostate cancer incidence and mortality in the United States and the United Kingdom. , 1998, Journal of the National Cancer Institute.

[117]  A W Partin,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. , 1998, JAMA.

[118]  P. Walsh,et al.  Prospective evaluation of men with stage T1C adenocarcinoma of the prostate. , 1997, The Journal of urology.

[119]  D. Ornstein,et al.  Effect of digital rectal examination and needle biopsy on serum total and percentage of free prostate specific antigen levels. , 1997, The Journal of urology.

[120]  J. Oesterling,et al.  In vitro stability of free prostate-specific antigen (PSA) and prostate-specific antigen (PSA) complexed to alpha 1-antichymotrypsin in blood samples. , 1996, Urology.

[121]  T. Stamey,et al.  A comparison of the free fraction of serum prostate specific antigen in men with benign and cancerous prostates: the best case scenario. , 1996, The Journal of urology.

[122]  C Parkes,et al.  Prospective observational study to assess value of prostate specific antigen as screening test for prostate cancer , 1995, BMJ.

[123]  F C Lowe,et al.  Prostatic acid phosphatase in 1993. Its limited clinical utility. , 1993, The Urologic clinics of North America.

[124]  Dale McLerran,et al.  An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. , 1993, JAMA.

[125]  D. Chan,et al.  Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease. , 1992, Cancer research.

[126]  O. Nilsson,et al.  Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin. , 1991, Clinical chemistry.

[127]  W. Catalona,et al.  Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. , 1991, The New England journal of medicine.

[128]  T. Stamey,et al.  Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. , 1988, The New England journal of medicine.

[129]  R L Vessella,et al.  Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. , 1987, The Journal of urology.

[130]  I. Romslo.  Prostatic acid phosphatase. , 1971, British medical journal.

[131]  M. Uslenghi,et al.  The World Space Observatory (WSO-UV) - Current status , 2008, 0801.2080.