PROSTATE CANCER

TUMOR MARKER
INTRODUCTION
• Prostate cancer biomarkers is currently in an era of rapid expansion
• The clinical question has changed from diagnosis to distinguishing
aggressive from indolent disease
• PSA -> organ specific and not cancer specific
• Four domain Prostate cancer biomarker :
• Screening
• Elevated PSA with prior negative biopsy
• Pretreatment in men with a new diagnosis
• Postprostatectomy
• A guiding principle of prostate cancer biomarker development is that
prostate cancer cells a priori are different in some molecular way
compared with their benign counterparts.
BIOMARKER
1. Blood-based Biomarker
2. Urine-based Biomarker
3. Tissue-based Biomarker
Blood Based Biomarker
• Prostate-Specific Antigen
• Prostate-Specific Mebrane Antigen
• Human Kallikrein 2
• Additional Kallikrein Tumor Markers
• Endoglin
• Circulating Tumor Cells
• Autoimmune Responses
Prostate-Specific Antigen (PSA)
• PSA is unique to the prostate gland
• Organ specific, not cancer specific
• Normal reference range is 0–4 ng/ml
• The cancer sensitivity and tissue specificity of PSA
makes it the most useful tumor marker available for
the screening and management of prostate cancer
• Lack of specificity in distinguishing prostate cancer and
nonmalignant prostate lesions
• Benign conditions such as BPH, acute prostatitis, and
infarction can also be correlated with elevated serum
PSA levels
PSA
• Annual PSA screening is recommended both by the American
Urological Association and the American Cancer Society for all men
over the age of 50
• Because of its tissue specificity, PSA is particularly useful for
monitoring the success of surgical prostatectomy
• Complete removal of the prostate should result in an undetectable
PSA level, while incomplete resection of the gland (not persistent
disease) might result in measurable levels of PSA
• However, it should remain unchanged on extended follow-up
• Any increase in measurable PSA after a successful radical
prostatectomy would indicate prostate cancer recurrence or metastasis
• A transient and modest increase of PSA may occur during radiation
therapy, which should not be misinterpreted as disease progression
PSA
• Multiple studies suggest that > 80% of pts with prostate
cancer are diagnosed from PSA > 4 ng/ml
• 50% of pts with PSA > 4 ng/ml do not have prostate cancer
on biopsy even at significantly elevated levels, i.e., over 10
ng/ml
• PSA has a sensitivity of a minimum of 80% and a specificity
of around 50%
• 20% of initially negative biopsies, when repeated over a 3-
year period, become positive
• Thus the specificity of PSA may be higher, assuming that
the biopsies missed a malignant lesion and that a new
malignancy did not occur over the 3 year time period
PSA
• The cutoff value of 4.0 ng/ml does not sufficiently
distinguish pts with and without prostate cancer
• There are several approaches that have been
developed both to increase the sensitivity and
specificity of PSA in detecting prostate cancer
• Free PSA
• Complex PSA
• Percentage of free PSA
Free PSA
• Serum PSA exists in the serum largely (up to 90% of total PSA)
in the form of a PSA-ACT (PSA–α1-antichymotrypsin) complex
• In prostate cancer  Increased complex PSA and decreased
free PSA
• Percentage of free PSA = (fPSA/total PSA)/100
• Inverse relationship with prostate cancer risk (<6%)
• Free PSA ratio improves the specificity for prostate cancer detection
in men with PSA between 4–10 ng/ml
• Free PSA >25% - usually associated with BPH
• Free PSA is subject to quick degradation at 4°C or above
• Time interval from sample collection and assay should be less than
3 hours and the sample should be stored and shipped at −70°C
PSA Doubling Time, Velocity and Density
• PSA doubling time
• can predict recurrence after radical prostatectomy in androgen-
independent prostate cancer patients
• PSA velocity – rate of PSA increase over time
• PSA difference divided by the number of year(s)
• PSA velocity of 0.75 ng/year or above is a strong predictor of cancer
with a specificity of 95%
• PSA velocity may be useful in predicting prostate cancer risk when PSA
levels are between 2.0 and 4.0 ng/ml
• This is especially useful in predicting the risk of cancer and guiding the
necessity of prostate biopsy in patients with low/normal PSA value
(2.0–4.0 ng/ml)
• PSA density – ratio of total PSA to prostate gland volume as
measured by transurethral ultrasonography
• PSA densities of greater than 0.15 indicate an increased probability of
prostate cancer as opposed to BPH
Conclusions and Directions for the Future

• In summary, a molecule, almost always a protein,

could be used as a tumor marker as long as its
changing concentration reflects tumor cell activity
• The assessment of clinical utility for an individual
tumor marker is based on its sensitivity and specificity
• There has been a clear trend towards improving the
test specificity and sensitivity by ordering multiple
tumor markers
• PSA is useful in screening, diagnosis, and therapeutic
monitoring
• Free PSA >25%  lower risk of cancer
Urine-Based Biomarkers
• Prostate Cancer Antigen 3
• Gene Fusions
• Metabolomics
• Annexin A3
• MicroRNA
Prostate Cancer Antigen 3
• To enhance the sensitivity of PCA3 detection, urine samples are collected
after an “attentive” DRE involving three firm strokes on each lobe of the
prostate toward the median sulcus
• The first 20 to 30 mL of voided urine should be collected within 1 hour
(Sokoll et al, 2008).
• The commercial PCA3 score is reported as the ratio of urine PCA3 mRNA to
urine PSA mRNA × 1000, nor- malizing PCA3 expression to PSA expression.
• Numerous clinical studies have been performed to evaluate the utility of
urine PCA3 to serve as a prostate cancer biomarker, and all have shown that
PCA3 scores are closely correlated with the likelihood of a positive biopsy
Prostate Cancer Antigen 3
Tissue-Based Biomarkers
• α-Methylacyl Coenzyme A Racemase
• Epigenetic Modifications
• Genomic Expression Profiles
Summary
• Early detection when cancer remains confined to the prostate not
only improves cure rates but also decreases mortality from pro- state
cancer.
• Innovations and new understanding in the field of molecular oncology
have provided a host of potential prostate cancer tumor markers.
•