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Zin en onzin PSA bepaling en prostaatbehandeling

L. Denis

Oncologisch Centrum Antwerpen

25 april 2005

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

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

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

Remarks:

1. April results Helsinki not taken into account (extreme outliers)

Prior to any treatment (repeat once).

After treatment with curative intent.

After treatment hormones/medication.

OCA, 2005

• 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

NPCP 1994

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

BPSA

(degraded PSA)

BPH

Transition Zone

Central

Zone

Prostate

Peripheral Zone

cancer

pPSA

(precursor PSA)

• 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

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

The final pathology or predictive value by t PSA or symptomatic biopsy is not improved by % f/t PSA.

Miyake H., 2005

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

Based on cysto-prostatectomy specimen it appears that the biologic activity appears to be independent of serum PSA.

Ward et al, 2004

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

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

• 91 molecular markers under investigation
• Chromogranin A
• GSTP
• Prostate Stem Cell Antigen
• Prostate-specific Membrane Antigen
• DD3PCA3
• SELDI-TOF MS
• Proteomics

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

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

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%!

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