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Minimally Invasive Techniques in
Screening and Management of
Prostate Cancer:
Urine Markers and Active
Surveillance
William C. DeWolf, MD
Chief, Division of Urology
Beth Israel Deaconess Medical Center
PSA Limitations
 Prostate cancer can exist at any low
value
 Most elevated PSA values are due to
a large prostate
 PSA can’t differentiate insignificant
from aggressive disease
 Interference with age, infection,
prostate volume, 5-alpha reductase
inhibitors, sexual activity
Main urine biomarkers under current
investigation
DNA markers
RNA markers
Protein markers
 Hypermethylation
 PCA3
 Urinary PSA
 ETS gene
fusions
 Annexin-3
 GSTP1
 Other genes
(RASSF, ARF)
 AMACR
 Metalloproteinase
 GOLM1
 Sarcosine
 Telomerase
activity
 Telomerase
activity
Ploussard G, de la Taille A. Nat Rev Urol 2010; 7:102
PCA3
 Non-coding mRNA
 Expression is restricted to the
prostate
 Highly over expressed in tumors
(20-60x) and PIN (x11)
 Measured as a ratio:
PCA3 mRNA / PSA (mRNA) x 1000
 Measured in prostate tissue
specimens and in urine
Biopsy decision making
 The higher the PCA3 score the
greater the probability of a positive
biopsy
Percent of subjects with positive biopsy
findings by PCA3 score range
P<0.0001
Aubin SM et al. J Urol 2010; 184:1949
PCA3 out performs PSA in
predictive value and specificity
for predicting biopsy outcomes
Diagnostic accuracy of PCA3 score is
statistically significantly better than for tPSA,
PSAD and % free PSA
de laTaille et al. J Urol 2011; 185:2121
Impact of Clinical Variables on
PCA3 Score:
PCA3 independent of:
 Age
 Prostate volume
 Total PSA
 Inflammation
 Palpable vs non-palpable
 5-alpha reductase use
 Previous biopsies
PCA 3 increases with
 Gleason score
 Percent number of positive biopsies
 Significant vs indolent cancers
Sensitivity and specificity of the PCA3 assay,
tPSA, PSAD and % free PSA
% Sensitivity
(95% CI)
% Specificity
(95% CI)
PCA3 score cutoff 20
84 (78-88)
55 (50-61)
PCA3 score cutoff 35
64 (57-71)
76 (71-81)
PCA3 score cutoff 50
50 (43-57)
83 (79-87)
tPSA cutoff 4 ng/ml
91 (86-94)
16 (12-20)
PSAD cutoff 0.15
ng/ml/cc
50 (43-57)
75 (69-80)
%free PSA cutoff 25%
90 (83-94)
18 (12-24)
de laTaille et al. J Urol 2011; 185:2121
Main urine biomarkers under current
investigation
DNA markers
RNA markers
Protein markers
 Hypermethylation
 PCA3
 Urinary PSA
 ETS gene
fusions
 Annexin-3
 GSTP1
 Other genes
(RASSF, ARF)
 AMACR
 Metalloproteinase
 GOLM1
 Sarcosine
 Telomerase
activity
 Telomerase
activity
Ploussard G, de la Taille A. Nat Rev Urol 2010; 7:102
TMPRSS2-ERG Fusion Gene
Nat Rev Urol 2009; 6:429-439
TMPRSS2
androgen-regulated transmembrane
protease serine 2 gene
ETS
E Twenty-Six transcription factors
TMPRSS2-ERG Fusion Gene
Nat Rev Urol 2009; 6:429-439
Urinary TMPRSS2: ERG fusion
 Sensitivity 37%
 Specificity 93%
 Most common specific gene
rearrangement in solid tumors
 50-70% prevalence
 Correlates with stage & grade
 Not yet available for commercial use
Main urine biomarkers under current
investigation
DNA markers
RNA markers
Protein markers
 Hypermethylation
 PCA3
 Urinary PSA
 ETS gene
fusions
 Annexin-3
 GSTP1
 Other genes
(RASSF, ARF)
 AMACR
 Metalloproteinase
 GOLM1
 Sarcosine
 Telomerase
activity
 Telomerase
activity
Ploussard G, de la Taille A. Nat Rev Urol 2010; 7:102
GSTP1 Loss
 Promotor hypermethylation
 The most common molecular
alteration reported in prostate cancer
 Important role in protecting DNA from
toxic ions
 Urinary GSTP1 loss
Specificity 93-100%
Sensitivity 21-39%
 Not commercially available
Conclusion: Main urine biomarkers
under current investigation
DNA markers
RNA markers
Protein markers
 Hypermethylation
 PCA3
 Urinary PSA
 ETS gene
fusions
 Annexin-3
 GSTP1
 Other genes
(RASSF, ARF)
 AMACR
 Metalloproteinase
 GOLM1
 Sarcosine
 Telomerase
activity
 Telomerase
activity
Ploussard G, de la Taille A. Nat Rev Urol 2010; 7:102
Active Surveillance:
an option for low risk
prostate cancer
Problem
 Overtreatment of low risk prostate
cancer is common and preventable
Background - Definitions
 Active Surveillance is a management
option of delayed treatment for
“insignificant” cancers (which is
based on size and grade of tumor)
Prostate cancer risk stratification
Carter HB. BJUI 2011; 108:1686
Background - Definitions
 Radical prostatectomy specimens on
patients with low risk disease reveal
insignificant disease in 27-56% of
cases
Risk assessment for progression
San Francisco IF et al. J Urol 2011; 185:471
Patients and Methods
 Criteria for entering into the protocol






Clinically localized cancer (T1c-T2)
Less than 3 positive cores
Gleason score 6 or less
No more than 50% of single core involved
Any age
Any PSA
 Criteria for progression (at re-biopsy)
 > 3 positive cores
 Increase in grade (Gleason score >7)
 More than 50% of single core involved
Progresion of patients on AS
San Francisco IF et al. J Urol 2011; 185:471
Factors which may predict
progression vs non-progression
 Age
 Family history
 BMI
 PSAV prior to
diagnosis biopsy
 PSA
 Prostate size
 PSA density
 Free and total
testosterone
 Chronic prostatitis
 Number of positive
cores
 % of cancer per cores
 Atypia
 Location of positive
cores
 PSAV between
diagnosis biopsy and
1st rebiopsy
Time to progression on rebiopsy by
number of risk factors
San Francisco IF et al. J Urol 2011; 185:471
Time to progression on rebiopsy by
number of risk factors
San Francisco IF et al. J Urol 2011; 185:471
Pathologic Outcomes
Modeling
(other) (%)
AS (other)
(%)
AS (WCD)
(%) (n=22)
Modeling
(WCD)
(n=201)
ECE
7-19
24-35
4
2
UP Grade
29-51
32-34
32*
19
SVI
0-9
0-2.1
4
<1 (1)
Margin (+)
4.4-35
15-32
0
12
Node (+)
-
0-4.2
0
0
5 year PSA
cure rate
90
62-96
91
98
*no Gleason pattern 8 or 9
Minimally Invasive Techniques in
Screening and Management of
Prostate Cancer:
Urine Markers and Active
Surveillance
William C. DeWolf, MD
Chief, Division of Urology
Beth Israel Deaconess Medical Center