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Improving PSA as a Marker for Prostate Cancer Detection

This article discusses the limitations and controversy surrounding PSA as a marker for prostate cancer, and explores ways to make PSA a better indicator of clinically significant cancer. It also examines the need for a serum marker that reflects prostate cancer in the current PSA range of 2 to 10 ng/mL.

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Improving PSA as a Marker for Prostate Cancer Detection

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  1. The Next Generation of Prostate Cancer Detection:How to Make PSA a Better MarkerLinda C. Rogers, PhD, DABCC, FACBScientific AffairsBeckman Coulter, Inc.

  2. Introduction PSA Limitations & Controversy Elevated PSA may not indicate clinically significant cancer Low specificity results in high costs Result: Prostate cancer is over diagnosed and over treated. How can we make PSA a better marker?

  3. Prostate Cancer Most common type of cancer found in men Second most common cause of cancer mortality in men Now estimated that one in six men will have prostate cancer High cost to manage patients Approximately 1.6 million men in the US undergo prostate biopsies yields only a 20-40% positive cancer rate Estimates in the US alone over a million negative biopsies annually • Prostate cancer testing: (where did we start, where are we going?) • 1986: First FDA approved PSA assay with Hybritech Tandem-R • mid-1990’s: Moved from a monitoring claim to a detection claim – Hybritech established the 4 ng/mL cutoff • Late-1990’s: Free PSA helped to improve specificity for cancer – Hybritech established the 4 to 10 ng/mL PSA Range • Other derivatives of PSA utilized (e.g. velocity, density) • New biomarkers (p2PSA)

  4. We want to “see” what’s going on to make accurate clinical decisions regarding prostate disease Can PSA help us do that?

  5. Benign Prostate Prostate Cancer Cancer Easily Recognized Only way to confirm cancer is to look at prostate cells: Normal cells are differentiated; Cancer cells are undifferentiated

  6. The non-specificity of PSA • Prostate Cancer • Even if prostate cancer is there, PSA cannot distinguish indolent from aggressive cancers • Benign Prostatic Hyperplasia (BPH) • Present in 4% at 40 yr, 30% at 50 yr, 75% at 80 yr • Other Conditions Affecting PSA • Acute and chronic prostatitis • Physical trauma, inflammation

  7. Prostate Cancer Markers: Optimal Characteristics • Specificity • Must be able to differentiate cancerous from normal prostate • Separate prostate cancer from other cancers and disease types (e.g. BPH, prostatitis) • “Tumor Specific” • Sensitivity • Identify all individuals with prostate cancer • Early marker of disease • Easily Detectable with Non-Invasive Methods

  8. Sensitivity/Specificity Ideal Situation Specificity = 100% True Negative = 100% False Positive = 0% Sensitivity = 100% True Positive = 100% False Negative = 0% Healthy Individuals Cancer Patients Cut Off

  9. Sensitivity/Specificity Real World Healthy Individuals Cancer Patients False Negatives False Positives Cut Off We must choose a cut off that maximizes both sensitivity and specificity

  10. Seminal Vesicle Fluid Prostate Prostate luminal epithelial cell pPSA PSA Seminal Plasma PSA promotes sperm motility (keeps semen in its liquid form) Blood Normal Physiological Pathway pro Proenzyme secreted Active enzyme Why PSA is a good tumor marker

  11. PSA Improves Detection of Early Cancers Expected At this point, PSA screening had been done for about 4-5 years Clinically unimportant (80%) Clinically unimportant (80%) PSA screening results: detect more & earlier Cancers detected by physical examination Early stage (10%) Advanced stage (10%) Cancers to worry about Adapted from Scientific American,1996: 215(3):115. Illustration by Christiansen J in “Does Screening for Prostate Cancer Make Sense?” by Hanks GE and Scardino PT.

  12. PSA Improves Detection of Early Cancers Real World Clinically unimportant (80%) PSA screening results Cancers detected by physical examination Early stage (10%) Advanced stage (10%) (not to scale) BPH We are detecting a lot more cancers that don’t need to be treated Adapted from Scientific American,1996: 215(3):115. Illustration by Christiansen J in “Does Screening for Prostate Cancer Make Sense?” by Hanks GE and Scardino PT.

  13. Applications of PSA Testing Screening for cancer Monitoring for recurrence Follow-up for suspected cancer Monitoring progression Managing BPH therapy Am J Clin Pathol 2000;113:421-428

  14. Prostate Cancer Detection:Clinical Dilemma Comparison: Cancer rate for general population of men >50 yr= 4% Grey Zone: The area that creates concern over “false positive” results Adapted from Catalona, JAMA, 1998

  15. The Chance of Finding Prostate Cancer Increases with PSA Levels (ng/mL) (Adapted from Dr. Alan Partin)

  16. Circulating Forms of PSA From: Rev Urol. 2004 Spring; 6(2): 58–72.

  17. PSA-ACT PSA-MAC f-PSA 1-Antichymotrypsin 2-Macroglobulin 5-50 % 50-95 % MAC ACT PSA PSA PSA Major PSA Forms in Serum Not measured No binding sites Next: Measuring free PSA. Complexed PSA Total PSA

  18. Probability of CancerBased on PSA and % fPSA Results(Men with Non-Suspicious DRE Results, Any Age) Free PSA helps us gain some specificity, but not enough to significantly affect the clinical decision-making process.

  19. “PSA has reached the end!” “We urgently need a serum marker that reflects prostate cancer in the current PSA range of 2 to 10 ng/mL.” - Dr. Thomas Stamey, Stanford University “Using the 2 to 10 ng/mL PSA range is the contemporary era of PSA screening” - Dr. William Catalona, Northwestern University

  20. Getting More Out of PSA:How can we increase its specificity? Free PSA • Catalona WJ (1998) JAMA PSA Velocity (Δ over time) • Smith DS (1994) J Urology PSA Density (ng/mL/cm3) • Zlotta (1997) J Urology • Beduschi (1997) Urology Clinical NA Age-Specific Reference Ranges • Battikhi (2006) Intl Urology Nephrology Novel Biomarkers • PSA Isoforms • EPCA-2 • PCA-3 • TMPRSS2-ERG • EN-2 (Engrailed-2) ACCEPTED UNDER INVESTIGATION (or currently in practice)

  21. Novel Biomarkers • [-2]proPSA (p2PSA) • EPCA-2 • PCA3 • TMPRSS2-ERG • EN-2 (Engrailed-2)

  22. Disease-Associated Forms of PSA pro pro This inactive precursor of PSA is associated with PCa Mikolajczyk, Urology 2002

  23. PSA-ACT PSA-MAC f-PSA 1-Antichymotrypsin 2-Macroglobulin 5-50 % 50-95 % MAC ACT PSA PSA PSA Major PSA Forms in Serum Not measured No binding sites Next: Measuring free PSA. Complexed PSA Total PSA

  24. Molecular Forms of PSA in Serum [-2]pro PSA 6% intact non-native PSA 39% Complexed PSA [-4]pro PSA 10% Free PSA 15% proPSA 32% [-5/7]pro PSA 17% BPH-A 28% Mikolajczyk, Urology 2002

  25. Receiver Operating Characteristic (ROC) Curve • True Positive rate vs. False Positive rate for different cut-off points • The closer the ROC is the upper left corner, the higher the overall accuracy of the test. • Relate two or more biomarkers to each other. Area Under the Curve > 0.500 Significant

  26. 2005, NCI formed the EDRN (independent investigators to identify and validate new cancer biomarkers) • Subjects • 566 men, in a prospective PCa detection study at four National Cancer Institute Early Detection Research Network clinical validation centers • Inclusion criteria • 40 years and older, no prior prostate surgery, biopsy or history of PCa, no use of 5-α reductase inhibitors, and at least a 10 core template biopsy (post-enrollment) • Results • Calclulated %[-2]proPSA ([-2]proPSA/free PSA) – found this had value • In the 2 to 10 ng/mL PSA range, %[−2]proPSA outperformed %fPSA (AUC 0.76 vs. 0.66) Sokoll, Cancer Epidemiol Biomarkers Prev, 2010

  27. ROC analysis (n = 195) comparing PSA, %fPSA, %[−2]proPSA, and a logistic regression model (0.58) • Most labs can’t calculate • A regression model that is difficult to understand (0.66) (0.70) (0.76) Sokoll, 2010

  28. Prostate Health Index (phi)

  29. Subjects • 892 men with no history of prostate cancer, in a prospective multi-institutional trial • Inclusion criteria • Normal DRE, pre-study PSA 2.0–10 ng/mL and 6-core or greater prostate biopsy • Results • At 80% to 95% sensitivity, the AUC of phi exceeded PSA & fPSA • phi = 0.724; fPSA = 0.670 • 4.7-fold increased risk of PCa and a 1.61-fold increased risk of a Gleason score greater than or equal to 4+3=7 disease on biopsy • Suggests a detection of indolent vs. aggressive cancers….higher phi, higher Gleason score

  30. PSA, fPSA, [-2]proPSA, free-to-total PSA and phiROC curves in 2 to 10 ng/mL PSA range Specificities & Sensitivities phi = 0.724

  31. Novel Biomarkers • [-2]proPSA (p2PSA) • EPCA-2 • PCA3 • TMPRSS2-ERG • EN-2 (Engrailed-2)

  32. EPCA-2 Serum Marker • Early Prostate Cancer Antigen (EPCA) • Proteomic approach focused on nuclear structure • Changes in the cell nucleus are hallmarks of cancer • Highly specific and sensitive for prostate cancer Leman, Adult Urology 2007

  33. EPCA-2 Serum Marker Leman, Adult Urology 2007

  34. EPCA-2 early-ELISA assay by Dr Getzenberg Used a cut-off of 30 ng/mL 385 subjects Results were reported as: --92% specificity (CI 0.85 – 0.96) --94% sensitivity (CI 0.93 – 0.99) EPCA-2 Serum Marker Leman, Adult Urology 2007

  35. Novel Biomarkers • [-2]proPSA (p2PSA) • EPCA-2 • PCA3 • TMPRSS2-ERG • EN-2 (Engrailed-2)

  36. PCA3 Discovered by researchers in The Netherlands and Johns Hopkins University Prostate-specific non-coding RNA which is overexpressed in 95% of prostate cancers The PCA3 assay is a gene-based (mRNA) diagnostic test Urine test CE-marked (2006) and available as the PROGENSA PCA3 Assay in Europe Not available in the US

  37. Gen-Probe PCA3 Attentive DRE to release sufficient # of prostate cells into the urine Transport to PCA3 specialty lab where mRNA molecules are amplified (RT-PCR) and PCA3 score is calculated Both PCA3 & PSA mRNA separately quantified: the ratio of PCA3 to PSA mRNA is called the “PCA3 Score”

  38. Gen-Probe PCA3 ** PCA3’s clinical utility in the diagnostic “gray zone” of 2-10 ng/mL is not apparent due to their cohort’s high levels of PSA (PSA values ranged from 0.3 to 484 ng/mL PSA) Gen-Probe 501377EN Rev. A.1

  39. PCA3: AUA 2011 Presentation PCA3 AS A PREDICTOR OF UNFAVORABLE CONFIRMATORY BIOPSYPATHOLOGY IN CANDIDATES FOR ACTIVE SURVEILLANCE Objective: Assessed ability of PCA3 to predict unfavorable confirmatory biopsy pathology in comparison to both PSA and PSA density (PSAD) in men with prostate cancer being considered for active surveillance. Subjects: 71 candidates with clinical stage T1c, Gleason score 6 Method: Predictive ability of these parameters was determined by ROC analysis. Results: ROC AUC: 0.65 for PCA3 overall, 0.65 for PCA3>35, 0.63 for PSA and 0.72 for PSA density. Conclusions: These preliminary results suggest that PCA3 is no better than either PSA or PSAD in predicting the results of confirmatory biopsies in prostate cancer patients being considered for active surveillance.

  40. Novel Biomarkers • [-2]proPSA (p2PSA) • EPCA-2 • PCA3 • TMPRSS2-ERG • EN-2 (Engrailed-2)

  41. Gene Fusion Product:TMPRSS2-ERG Gene fusions are genetic alterations – described in other types of tumors (e.g. BCR-ABL is present in 100% of chronic myelogenous leukemia) TMPRSS2: Androgen-related transmembrane serine protease preferentially expressed in normal prostate tissue. In PCa, TMPRSS2 may fuse with a transcription factor, ERG, which modulates the transcription of genes involved in cell growth, transformation and apoptosis. The result of gene fusion with ERG is a mechanism for neoplastic transformation (i.e. cancer). Rubio-Briones. Urology 2010

  42. TMPRSS2-ERG Tomlins, Neoplasia 2008, Salagierski, Cancers, 2010

  43. Gene Fusion Product:TMPRSS2-ERG Fusion genes may be detected in tissue or urine. >20 TMPRSS2-ERG fusion transcripts have been described Observed in 33% - 80% of PCa cases RT-PCR assay Current Status: Accurate gene fusion detection is complex, assays have not been standardized and once they are, larger studies will need to determine their clinical utility. Rubio-Briones. Urology 2010

  44. TMPRSS2-ERG Study – Survival Rates Kaplan-Meier plots byTMPRSS2-ERG gene fusion status • Results/Conclusions: • TMPRSS2-ERG detected in ~50% of subjects • Suggest possibility of using TMPRSS2-ERG status to classify different PCa prognostic groups. • May be relevant to refine therapeutic strategies Rubio-Briones. Urology 2010

  45. Novel Biomarkers • [-2]proPSA (p2PSA) • EPCA-2 • PCA3 • TMPRSS2-ERG • EN-2 (Engrailed-2)

  46. Engrailed-2 (EN2) A protein (transcription factor) expressed in prostate cancer (PC) cell lines and secreted into the urine Protein measurement via ELISA Results: EN2 was expressed and secreted by PC cell lines and PC tissue but not by normal prostate tissue. The presence of EN2 in urine was highly predictive of PC, with a sensitivity of 66% and a specificity of 88.2%. No correlation with PSA levels. Conclusions: Urinary EN2 is a highly specific and sensitive candidate biomarker of prostate cancer. Morgan et al, Clinical Cancer Research, 2011

  47. Engrailed-2 (EN2) RT-QPCR analysis of EN2 in biopsies that were found to be histologically positive ("PC") or negative ("Non PC") for prostate cancer. Morgan et al, Clinical Cancer Research, 2011

  48. Engrailed-2 (EN2) ROC analysis of urine EN2 concentrations in men with biopsy proven prostate cancer versus the men that were a biopsy did not find PC. Morgan et al, Clinical Cancer Research, 2011

  49. Engrailed-2 (EN2) EN2 can be detected in 100 mL of unprocessed urine, collected without DRE and uses a simple enzymatic detection method. A larger, multicenter study is planned to determine whether EN2 could be used as a monitoring tool and whether levels of urinary EN2 correlate with tumor stage and Gleason grade. Morgan et al, Clinical Cancer Research, 2011

  50. Summary of Biomarkers Engrailed-2 (EN2) Research stage, simple detection Larger studies needed to determine utility TMPRSS2-ERG Research stage, complex detection Larger studies needed to determine utility PCA3 CE Marked - Available in Europe Promising biomarker, mixed results, complex detection EPCA-2 Falsified data tainted this biomarker Continued research in process [-2]proPSA & phi CE Marked - Available in Europe Promising biomarker & index for PCa detection

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