PSA and the Future Axel Heidenreich, Department of Urology
PSA and Prostate Cancer EAU Guideline 2011 PSA is a continuous variable PSA value (ng/ml) risk of PCa, % 0 0.5 6.6 0.6 1 10.1 1.1 2 17.0 2.1 3 23.9 3.1 4 26.9 PCPT-Studie Heidenreich A et al., Eur Urol 2011
Improvements of PSA EAU Guideline 2011 Improvement of PSA Specificity PSA - Density, Age specific reference values molecular PSA - variants (%f-psa, pro-psa) Limited value for PSA velocity (PSAV) and PSA doubling time (PSA DT) Heidenreich A et al., Eur Urol 2011
PSA Dynamics PSA velocity in men with total PSA < 4 ng/ml 22.019 men with PSA <4 ng/ml Loeb et al.j Urol. 2007 501 men with PCa and PSA-Velocity (ng/ml/year)
PSA Dynamcs PSA velocity in men with total PSA < 4 ng/ml Loeb et al.j Urol. 2007 22.019 men with PSA <4 ng/ml 501 men with PCa and PSA-Velocity (ng/ml/year) PSAV %Sens %Spec %+pred %-pred 0,2 65% 70% 9% 98% 0,4 56% 83% 12% 98% 0,75 40% 92% 18% 97% 2% of men with PSAV <0,4ng/ml/year: PCa 13% of men with PSAV >0,4ng/ml/year: PCa
J Natl Cancer Inst 2011 AUC using multivariate model and analysis (age, PSA, DRE, family history, biopsy) with and w/o PSA velocity in 5519 men from PCPT PSA velocity improved area under the curve from 0.702 to 0.709. PSA velocity not helpful to identify patients with the need for a protate biopsy
J Natl Cancer Inst 2011 no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications PSA velocity should not be included in practice guidelines.
Free PSA Diagnostic Value of Free PSA among Men with PSA of <3 ng/ml. Finne et al. Eur Urol. 2007 17.680 men with PSA <3ng/ml (Screening trial) median Follow-up 5,8 years 327 men with Pca Men with %f-psa <14% (lowest quartile) 6,9fold increased risk to harbour PCa as compared to men in the highest quartil (>23,7%)
National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Sturgeon CM Clin Chem. 2008 Dec Recommendation to use %f-psa to differentiate between benign and malignant tissue if total PSA is <10 ng/ml. Recommendation to use %f-psa to differentiate between benign and malignant tissue if total PSA is <10 ng/ml CAVE: storing temperature
Prognostic Significance of PSA PSA serum concentration to predict the risk to develop metastases or to die from prostate cancer Catalona AUA 2008
Vickers et al. BMJ. 2010 Sep 14
Vickers et al. BMJ. 2010 Sep 14
Incidence and death from PCa in men with initial PSA <3.0 ng/ml: results from ERSPC Rotterdam (2) Bul M. Eur Urol Suppl 2011;10(2):145(abs.419) Hazard ratio of (aggressive) PCa and PCa death stratified by PSA group The risk of (aggressive) PCa and PCa-mortality in a screening population with initial PSA <3.0 ng/ml increases significantly with higher PSA levels
Biomarkers to detect PCA Pro PSA (Serum) PCA3 (Urin) prostate specific, non coding mrna EPCA-2 (Serum) nuclear structural protein measured by ELISA TMPRSS2-TTS Gen Fusion (Urine & tissue) Hypermethylation of gen (Urine) Genetische Risiko Varianten (Blut oder Abstrich) Catalona AUA 2008
PCA3 basic considerations Non-coding mrna Highly overexpressed in prostate cancer cells Can be isolated in urine after prostatic massage PSA mrna can also be isolated in urine after prostatic massage PCA3 score = PCA3 mrna PSA mrna x 1000
PCA3 molecular urine assay for PCa in men undergoing repeat biopsy. Marks et al. Urology. 2007 Cells in prostatic urethra Digital Rectal Exam (DRE) First Catch Urine Specimen (20 30mL)
PCA3 score PCA3 can help to predict tumour volume 100 90 80 70 60 50 40 30 20 10 0 P = 0.002; <0.5 cc vs. 0.5 2.0 cc <0.5 cc 0.5 2.0 cc >2.0 cc Total tumor volume in prostatectomy specimens Nakanishi J Urol 179:1804,2008
PCA3 score better than other prognostic factors to predict small tumour volume Total Tumor Volume < 0.5 cc Variables AUC Asymptotic significance PCA3 score 0.757 <0.001 PSA 0.632 0.051 % positive cores 0.733 0.001 Maximum tumor length 0.700 0.003 Abbreviations: AUC, area under the curve; PSA, prostate specific antigen Nakanishi J Urol 179:1804,2008 18
PCA3 score PCA3 can help to predict tumor aggressiveness 100 90 80 70 60 50 40 30 20 10 0 p = 0.005 3+3 7 or greater Prostatectomy Gleason score Nakanishi J Urol 179:1804,2008 19
Clinical utility of the PCA3 urine assay in European men scheduled for repeat biopsy. Haese et al. Eur Urol. 2008 463 men examined: PCA3 Score did correlate with detection of prostate cancer in men who were scheduled for rebiopsies Score Sensitivity Specificity PCa3 Cut-off 35 47 % 72 % PCa3 Cut-off 50 35 % 82 %
Eur Urology2010
Critical Assessment of Preoperative Urinary PCA3 on the Accuracy of Prostate Cancer Staging no improvement to predict locally advanced prostate cancer Auprich et al. Eur. Urology 2010 Oct
Critical Assessment of Preoperative Urinary PCA3 on the Accuracy of Prostate Cancer Staging Improvement to predict insignificant prostate cancer Auprich et al. Eur. Urology 2011
1rst repeat Bx cohort, n = 48 (19 PCA, 29 no PCA) PCA score < 44 avoids 73% of unnecessary biopsies Auprich et al. BJU Int 2011
2nd repeat Bx cohort, n = 40 (13 PCA, 27 no PCA) %f PSA < 12% avoids 67% of unnecessary biopsies Auprich et al. BJU Int 2011
3rd repeat Bx cohort, n = 39 (12 PCA, 27 no PCA) %f PSA < 14% avoids 45% of unnecessary biopsies Auprich et al. BJU Int 2011
Prostate health index (phi): diagnostic accuracy (1) Catalona WJ. J Urol 2011:185(4 Suppl):e396(abs.982)» Multi-centre prospective case-control study» N=892 men 50 yr with PSA 2-10 ng/ml, non-suspicious DRE and biopsyconfirmed PCa diagnosis» tpsa, fpsa, [-2]proPSA determined using Beckman Coulter Access 2 Immunoassay Analyser; phi =([-2]proPSA/fPSA) x tpsa» Receiver operating characteristics (ROC) curve: Phi has higher clinical specificity than tpsa and %fpsa and may be used for aiding biopsy decisions in men with PSA 2-10 ng/ml and negative DRE
Prostate health index (phi): diagnostic accuracy (2) Nava L. J Urol 2011:185(4 Suppl):e919-0(abs.2293)» Single-centre prospective study; N=289 men undergoing TRUS-guided prostate biopsy (18-22 cores); PCa detected in 108 patients (37.3%)» phi =([-2]proPSA/fPSA) x tpsa (Beckman Coulter Access 2 Immunoassay Analyser)» Gleason score correlated with %[-2]proPSA (P<0.001) and phi (P<0.0001) Phi and %[-2]proPSA have higher specificity, sensitivity and diagnostic accuracy than reference standard tests and correlate with Gleason score
Summary for daily routine There is no PSA threshold levels which excludes PCA PSA remains a significant predictor for the presence and the biological aggressiveness of PCA Pro-PSA seems to be promising Use of PSA Dynamics highly controverial PCA3 to identify insignificant cancer?
Gene fusions and prostate cancer Gene fusions involving the prostate-specific gene transmembrane protease, serine 2 TMPRSS2 Gene fusions are only present in cancer cells or high grade PIN Morris et al BJU int 102:276, 2008
Gene Fusions in Prostate Cancer A Translocation ETV1 erythroblastosis virus transforming sequence Fusion Gene TMPRSS2:ETV1 Gene Fusion TMPRSS2 ERG (= oncogene) Chrom.21 Chrom.7 TMPRSS2 ERG (= oncogene) Occurs only in 1-10% of cases B Deletion Gene Fusion Fusion Gene TMPRSS2:ERG TMPRSS2 ERG (= oncogene) Deletion TMPRSS2 ERG (= oncogene) Occurs in 50% of cases Chrom.21 Tomlins et al., Science 310:644,2005 Chrom.21 31
Androgen Responsive Gene Fusions in Prostate Cancer TMPRSS2/GAPDH TMPRSS2/GAPDH TMPRSS2/GAPDH Fusion Structure Androgen Response Chromosome 21 Chromosome 7 TMPRSS2 ETV1 20 16 12 8 4 TMPRSS2:ETV1 R1881: + 20 TMPRSS2 ERG 16 12 8 4 TMPRSS2:ERG R1881: + 20 TMPRSS2 ETV4 16 12 8 4 TMPRSS2:ETV4 R1881: + 32
HNRPA2B/GAPDH C15orf21/GAPDH Androgen Resistent Gene Fusions in Prostate Cancer Fusion Structure Androgen Response C15orf21 C15orf21:ETV1 ETV1 2.0 1.5 1.0 0.5 R1881: + Stimulates cancer progression in the androgenablation state HNRPA2B1 ETV1 2.0 1.5 1.0 0.5 HNRPA2B1:ETV1 R1881: + 33
Combination of PCA3 and TMPRSS2:ERG gene fusion: diagnostic accuracy Robert G. J Urol 2011:185(4 Suppl):e648(abs.1616)» Comparison of PCA3 and TMPRSS2:ERG expression levels (quantitative real-time PCR, normalised for housekeeping gene HPRT) between tissue samples of PCa (N=48), BPH (N=48) and normal tissue adjacent to PCa (N=32) Combination of PCA3 and TMPRSS2:ERG has a higher sensitivity and better accuracy than either test alone
Medical Faculty RWTH Aachen University, Pathology Workflow Spot isolation Material 1mm 2 n = 10/group Tryptic digest DIGE-technology Mass spectrometry Reverse phase protein array Western blot Protein I.D. urine/serumbiomarker? validation 1 cm G C 1 cm D
Non-invasive diagnosis of PCa: proteome analysis of seminal plasma Neuhaus J. Eur Urol Suppl 2011;10(2):206-7(abs.638)» Biomarker discovery and validation study in seminal plasma of men aged 50-70 yrs with PSA 4-20 ng/ml or suspicious DRE» Discovery phase: accuracy of biomarker panel: 92%» Validation phase: Seminal plasma seems to be a suitable source for proteome based, non-invasive detection of PCa
The Belgian Shepherd Dog (Malinois) is a breed of dog, sometimes classified as a variety of the Belgian Shepherd Dog rather than as a separate breed. These dogs are popular in use of police departments, as are German Shepherds Eur Urol. 2010 Oct 15
Eur Urol. 2010 Oct 15
Correct identification of PCA in 30 of 33 cases 1/3 false negative patients was diagnosed with PCA on repeat biopsy Sensitivity and Specificity 91%. conclusion: urine contains PCA specific proteins => urine based screening potentially possible Eur Urol. 2010 Oct 15
Ratio of the finger length Ratio of length of index finger to ring finger appears to be hormone dependent (2D:4D) Finger length ratio correlates negatively with the ratio of fetal estradiol levels to fetal testosterone levels
1524 men with PCA and 3044 controls Men with index finger longer as ring finger (high 2D:4D) 33% risk reduction to develop PCA (OR) 0.67, risk reduction in men <60 years (OR 0.13, 95% CI 0.09 0.21). Finger length ration appears to be a simple biologic marker: 2D longer 4D: low risk