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WBA. Zin en onzin PSA bepaling en prostaatbehandeling L. Denis Oncologisch Centrum Antwerpen 25 april 2005. PSA: a serine protease enzyme secreted by epithelial cells of the prostate. In the serum as a free uncomplexed form ACT alpha-1-antichymotrypsin

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  1. WBA Zin en onzin PSA bepaling en prostaatbehandeling L. Denis Oncologisch Centrum Antwerpen 25 april 2005

  2. PSA: a serine protease enzymesecreted by epithelial cells of the prostate In the serum as a free uncomplexed form ACT alpha-1-antichymotrypsin alpha 2M alpha-2-macroglobulin other acute phase proteins Identified in 1982 as follow-up marker. in 1987 as diagnostic marker. in essence tissue marker Nakamura, 2002

  3. PSA validation of a tumour marker A marker produced by cancer cells, detectable in body fluids, easily measurable. A PCa marker, PSA is tissue specific becomes a tumour marker after diagnosis. Long evolution of disease in elderly patients (co-morbidity) make prognostic value (surrogate marker of survival) difficult. L. Boccon-Gibod, 2005

  4. PSA assay development Total PSA equimolar response for free and PSA ACT complexes. Free PSA in serum separated in 3 hours and assayed in 24 hours. Reference values to be established for each assay combination. ICUD, 2002

  5. Results internal surveys ERSPC 2004 Remarks: 1. April results Helsinki not taken into account (extreme outliers)

  6. PSA in clinical practice. Prior to any treatment (repeat once). After treatment with curative intent. After treatment hormones/medication. OCA, 2005

  7. PSA: A Non-Ideal Test for PCa Screening • Lack of sensitivity With a cut-off point of 4 ng/ml, 20-30% of cancers will be missed • Lack of specificity Only 1 in 4 men with a PSA level of 4-10 ng/ml will have PCa following needle biopsy

  8. PPV in a diagnostic cohort NPCP 1994

  9. PSA validation as a PCa tumour marker The optimal upper limit of normal for PSA for PCa screening is unknown. New biomarkers are needed linked to prognosis and prognostic validated trials. I. Thompson, 2004

  10. BPSA (degraded PSA) BPH Transition Zone Central Zone Prostate Peripheral Zone cancer pPSA (precursor PSA)

  11. Enhancing PSA As A Screening Test • PSA density • Age-related reference ranges • Serial assays (PSA velocity – doubling time) • PSA isoform assays • Free PSA • Complexed PSA • Precursor PSA • Pro-PSA • B-form PSA • Mature form PSA

  12. PSA gimmicks DUST study shows that PSA, PSA D, TZ.PSA D and% free PSA do not enhance specificity for PCa detection in PSA 3-15 ng/ml. Michielsen D. et al, 2005

  13. PSA diagnosis based on % free to total The final pathology or predictive value by t PSA or symptomatic biopsy is not improved by % f/t PSA. Miyake H., 2005

  14. A note of concern: f/t PSA for PCa detection. Using invalidated combinations of f and t assays may increase the number of unnecessary biopsies. Cut points need to be validated for each individual assay. Oberpenning F. et al, 2002

  15. PSA indicator of clinical significance Based on cysto-prostatectomy specimen it appears that the biologic activity appears to be independent of serum PSA. Ward et al, 2004

  16. PSA 2-12 ng/ml not predictive for Pca (Stamey) Schröder: PPV of PSA 3,0 ng/ml is 20% and correlation remains significant. Catalona: Correlation PSA & % Ca (.37-47) Cancer Volume (.43-48) Prostate Volume (.01-17) AAGUS, 2005

  17. PSA pitfalls in clinical practice. Serial measurements vs. tissue (BPH) specificity. After surgery o and other treatment’s nadir is a rise therapy failure (Biochemical relapse). Nadir with hormonal treatment predictive for response duration. HRPC a 50% reduction and slope show response (other markers needed). OCA, 2005

  18. ? Future Markers for CaPTricoli et al, Clin Cancer Res 2004;10:3943 • 91 molecular markers under investigation • Chromogranin A • GSTP • Prostate Stem Cell Antigen • Prostate-specific Membrane Antigen • DD3PCA3 • SELDI-TOF MS • Proteomics

  19. M M DD3...DD3PCA3…PCA3 • PCA3DD3 is a novel prostate-cancer-specific gene: • (Bussemakers et al., Cancer Res. 59: 5975-79, 1999) • Overexpressed in >95% of PrCa 1 2 3 4 5 6 T B N T N T N T N (kb) 4.0 DD3 2.0 0.6

  20. Results • 108 urine samples collected of 108 men with PSA > 3 ng/ml. • 24 men had PCa was biopsy proven • 84 men were negative for prostate cancer

  21. Results • 14/84 men without PCa had ratios above the cut off: i.e. specificity of 80% (vs PSA 20 %) • 16/24 men with PCa had ratios above the cut off; • i.e..sensitivity of 67% • Negative predictive value: 88%!

  22. PSA: a test for asymptomatic men? Discovered as a concept in 1970 and developed into the PSA test has never been specific enough to be a definitive test for Pca. The PSA related concepts are flawed and lead to unnecessary treatments. A more specific test is needed and PSA is more a smoke than a fire alarm. Richard J. Ablin, 2001

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