Prostate Biomarkers in 2010

James McKiernan M.D.

Director of Urologic Oncology
Given Associate Professor of Urology
Columbia University
Herbert Irving Comprehensive Cancer Center
 Outline

• PSA today, an oldy but a goody

• PSA derivatives
• “Novel” markers
– hK2
– PCA3
– EPCA 2
– pro PSA
• Molecular screening and risk stratification
 Prostate Cancer - 2009
• >192,000 new cases expected in 2009
– Could be 450,000 in 2015 if nothing changes
• 27,360 deaths expected
• Approximately 1.5 million TRUS biopsies/yr
• >20 million men with one negative biopsy
• Lifetime risk of prostate cancer in U.S.:
– Diagnosis: ~17%
– Death: ~3%

Jemal A. Cancer Statistics 2009. CA

Cancer J Clin 2009
 Cost effective health care ??
What is the future of screening?
 Annual Age-Adjusted Cancer Incidence Rates Among
Males for Selected Cancers, 1975-2002
260
240
220
Rate per 100,000 Population

200
180 Prostate
160
140
120
100
80 Lung and Bronchus
60 Colon and Rectum
40 Urinary Bladder
20 Non-Hodgkin Lymphoma
Melanoma of the Skin
0

2002
1987

1991

1997

2001
1975

1977

1979

1981

1983

1985

1989

1993

1995

1999
Year of Diagnosis

Adapted from Jemal A, et al. CA Cancer J Clin. 2006;56:106-130.

 Utility of Prostate Markers
• Population screening
• Elevated PSA and negative biopsy
• Risk stratificaton in newly diagnosed and ASDI

• Post therapy monitoring

Vocabulary of Prostate Marker Assays
• Sensitivity is the chance of
finding all the true positives
– Sens= TP/ (TP+FN)

• Specificity is the chance of

not finding false positives
– Spec=TN/ (TN+FP)
 Vocabulary of Prostate Marker Assays

•ROC curve first used during WW II for

analysis of radar signals

•Following attack on Pearl Harbor in

1941, US army began new ROC
research to increase accuracy of
prediction of Japanese aircraft from their
radar signals.
 The Ideal Screening Test. . .
• Sensitive
• Specific
• Non invasive and safe
• Detects a condition which is common
• Detects a condition which is harmful
• Detects a condition which has effective therapy
• Cost effective
• Must pass the K.I.S.S. test
 Is PSA the Ideal Screening Test?
• Sensitivity at ???? = varies widely from 2-10
• Specificity at ???? = varies widely from 2-10
• Non invasive and safe yes
• Detects condition which is common yes
• Detects condition which is harmful ?????
• Detects condition with effective therapy maybe
• Cost effective ????
NCCN Guideline For Prostate Cancer Screening
 NCI position statement 2009
• “The evidence is insufficient to determine
whether screening for prostate cancer with PSA or
DRE reduces mortality from prostate cancer.
Screening tests are able to detect prostate cancer
at an early stage, but it is not clear whether this
earlier detection and consequent earlier treatment
leads to any change in the natural history and
outcome of the disease.”
 American Academy of Family
Practitioners
• “The AAFP recommends that physicians counsel
men between the ages of 50 and 65 regarding the
known risks and uncertain benefits of PSA
screening. All men should be informed of the
known harms and uncertain benefits of screening
and make an informed choice, rather than
routinely screening men’s PSA levels.”
 American Cancer Society

• “The American Cancer Society (ACS) does not

support routine testing for prostate cancer at this
time. ACS does believe that health care
professionals should discuss the potential benefits
and limitations of prostate cancer early detection
testing with men before any testing begins. . . ”
 AUA policy statement
2009
• “Early detection of and risk assessment for
prostate cancer should be offered to asymptomatic
men 40 years of age or older who have a life
expectancy of at least 10 years.”
 Challenging the Norm
PCPT
• N = 18,882
• Age ≥55; PSA ≤3.0ng/mL
• Finasteride vs placebo
• End-point: CaP on 7-year SEXTANT prostate
biopsy
• 803/4368 (18.4%) CaP finasteride arm
• 1147/4692 (24.4%) CaP placebo arm
• 24.8% reduction in CaP prevalence

Thompson IM, et al. N Engl J Med. 2003

 Prostate Cancer Prevalence
PSA < 4.0 ng/ml

30 26.9
23.9
25
20 17.0
%
15
10.1
10 6.6
5
0
<0.5 0.6 - 1.0 1.1- 2.0 2.1 - 3.0 3.1 - 4.0

PSA
Thompson et al . NEJM 2004
PSA as a Marker for Prostate Cancer

PSA Sensitivity False positive rate

1.1 82.0 59.4
1.6 67.4 41.2
2.1 54.4 29.2
2.6 43.6 20.4
3.1 35.8 14.9
4.1 24.5 7.7
6.1 5.4 2.0
8.1 2.0 0.9
10.1 1.0 0.5

Thompson JAMA 2005

 PSA Derivatives
• PSA Velocity (PSAV)

• PSA Density (PSAD)

• Age specific PSA

• Free/Total PSA ratio

 PSA Velocity
• 89 males in Baltimore Longitudinal Study of Aging
with serial PSA from 2.0- 4.0 ng/mL

• Sensitivity and Specificity of a PSAV of 0.1

ng/mL/yr was 81% and 50%

• The RR of CaP 6.53 when PSAV > 0.1 ng/mL/yr

• At 10 yrs, freedom from CaP 97% and 35% when

PSAV below or above 0.1 ng/mL/yr
Carter Urology 2002
 PSA velocity
• 2,915 Austrian men 10 yrs of serial PSA testing

• Cancer, mean PSA increased from 2.28 ng/ml to

6.4 ng/ml over 10 yrs (PSAV: 0.41 ng/yr)

• BPH, mean PSA increased from 1.18 to 1.49 ng/ml

over 10 yrs (PSAV of 0.03 ng/yr)

Berger AP Prostate. 2005

 PSA Density
• Serum PSA/ prostate volume
• 61 patients with prostatic disease (41 with prostate
cancer and 20 with BPH)
• The mean PSAD for CaP 0.581; while that for BPH
0.044 (p<0.002)
• No patient with BPH had a PSAD> 0.12
• Of 34 patients with a PSAD of 0.1 or greater 33
had CaP

Benson J Urol 1992,1988

 PSA Density
• 1809 men 1996-2004
• Diagnostic validity of PSA and PSAD was
evaluated by ROC analysis
• PSAD differed significantly (p < 0.0001)
• PSAD at tPSA concentrations < 4 ng/mL for
detecting prostate carcinoma, with AUC for PSAD
(0.739)
• Different PSAD cut-off values of 0.05 at tPSA 2-4
ng/mL, 0.1 at tPSA 4-10 ng/mL, and 0.19 at 10-20
ng/mL necessary for 95% sensitivity
Stephan C Cancer 2005
 Novel Markers
• hK2

• PCA3

• pro PSA

• EPCA

• GSTP1, TSP 1, TMPRSS 2

 Human Kallikrein 2 (hK2)
• Glandular kallikrein 2 (hK2) and PSA members of a
multigene family of serine proteases
• Human Kallikrein 3 is PSA

• 324 men PSA and hK2 levels

• Mean hK2 levels and hK2:free PSA ratio
significantly higher in CaP than BPH (1.18 v 0.53)
• Odds ratio for CaP in highest quartile of hK2 level
was 5.83
• hK2 predictive capacity was higher than PSA
Nam RK JCO 2000
 Human Kallikrein 2 (hK2)
• Catalona 206 serum samples from men with known
BPH and cancer (100 BPH 106 cancer)
• Total PSA 2.5-10 ng/dl
• Total and free PSA and hK2 measured
• hK2 alone could not discriminate cancer from BPH
• hK2/free PSA (AUC = 0.69) better than free/total PSA
(AUC = 0.64).
•

Magklara and catalona

J Clin Chem 1999
 Proenzyme PSA
• NCI EDRN
• JHU, Fred Hutch, NCI, Beth Israel
Deaconess, Univ Texas San Antonio

• 123 subjects
• No difference in total PSA
between cancer and BPH groups
– 6.8 vs 6.94
• Proenzyme PSA was the best
screening test AUC 0.69 vs %
Free PSA (0.61)
• PSA usually 0.52
Sokoll J Urol 2008
 PCA3
• First described in 1999 as DD3
• Non-coding RNA, unknown function, no protein
• Highly specific for CaP and 60-100 times overexpressed
RNA in CaP
• Not detected in any other tissue or cancer
• Extracted from urine after prostatic massage
• Sensitivity 82% specificity 76%
• Compared to 98%, 5% for tPSA at cutoff of 2.5 ng/ml
• AUC (area under the curve) 0.87

Marberger Eur Urol 2004

Bussemakers Cancer Res 1999
 PCA3
• Multicenter 443 men
• Overall PCA 3 sensitivity and specificity was 66%
and 89%, respectively
• PSA < 4 ng/mL sens 74% and spec 91%
• PSA level 4-10 ng/mL, sens 58% and spec 91%

• Overall accuracy 81% vs 43% for total PSA

Fradet Urology 2004

 RNA Analysis of PCA3 Gene in Urinary
Sediments

• Ratio PCA3:PSA is used

as a quantitative measure

• AUC 0.717 with cutoff

value of 35

Hessels Eur Urol 2003

 Summary of PCA 3 Studies

Patients Sensitivity Specificity

Hessels 2003
108 67% 83%

Tinzl 2004
158 82% 76%

Fradet 2004
443 66% 89%

Groskopf 2006
122 69% 79%

Hessels Eur Urol 2003

Tinzl Eur Urol 2004
Fradet Urology 2004
Groskopf Clin Chem 2006
 PCA 3
• Cutoff at > 35

• 278 PCA3 tests 2006-2007 mostly prior negative biopsy

patients

• No correlation with PSA

• PCA3 test sensitivity 72.7% and specificity 84.2%

Shappell SB Urology 2009

 PCA3
• 570 men EDRN
• Equally effective in first and repeat biopsy groups AUC
0.70 and 0.68, respectively.
• Did not increase with prostate volume
• Accuracy equivalent at all PSA values
• Log reg using PCA3, PSA, prostate volume and DRE
increased the AUC to 0.75 (PSA alone 0.547)

Deras Urol 2008

 PCA3
80%

70%

60%
% Biopsy Positive

50%

40%

30%

20%

10%

0%
PCA3 Score < 5 5 - 19 20 - 34 35 - 49 50 - 100 > 100
(n=570) (58) (205) (101) (62) (90) (54)

Deras Urol 2008

 EPCA 2
EPCA- 2.22

• Nuclear matrix protein found in serum of men with CaP

• Serum samples from 385 men
• PSA <2.5 ng/mL, > 2.5 ng/mL with negative biopsies
findings, BPH, CaP

• Cutoff of 30 ng/mL, EPCA-2.22 92% specificity for healthy

men and men with benign prostatic hyperplasia and 94%
sensitivity to detect prostate cancer
• Also excellent in detecting organ confined vs extracapsular
Leman Urology 2007
 EPCA 2
EPCA 2.19

• Distinct epitope; EPCA-2.19.

• 328 samples
• Cut point of 0.5ng/ml
• Specificity of % and a sensitivity of 91% in distinguishing
normal from CaP !!

• ROC analyses of the EPCA-2.19 assay demonstrate an area

under the curve of 0.982 !!!

Leman Prostate 2009

• Onconome claims to have spent millions preparing to
produce and market tests based on the EPCA-2 — only to
find that it was based on scientific breakthroughs that "were
and are imaginary,“

• "Notwithstanding the spectacular (and false) results

proclaimed by defendants, the assay was no more accurate
in distinguishing cancerous tissue from normal tissue than
flipping a coin,”
Pittsburgh Tribune Review Sept 2009
The future of US healthcare????
 Systems Pathology Approach for the Prediction of Progression After RP
Aureon Systems

↑ Analysis of AR and AMACR

KM classification of patients from the training cohort

and validation cohort as being low risk (blue line) or
Copyright© American Society of Clinical Oncology
high risk (yellow line) for experiencing clinical failure
* Donovan, M. JCO 2008
 GSTP1 TSP-1
• Tissue based • Thrombospondin-1 strongly
• Quantitative DNA elevated in BPH and
Methylation of GST Pi in repressed in CaP
cells developing into prostate • Differentiated benign from
cancer malignant disease with 79%
• Urinary based assay in sensitivity and 81%
development specificity TMPRSS2

Shafer Prostate 2007

 Coming Soon
• TMPRSS2 ERG or ETV 1 Gene fusion
– Urinary marker

• Sarcosine
– Urinary
 Conclusions
• 25 years of criticism PSA is still the standard

• Hard to imagine we can’t do better

• PCA 3 is probably the most useful and simple

diagnostic assay available

• The future is risk stratified screening to find only

cancers we need to find