prostate markers 2010

8/8/2019 Prostate Markers 2010

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Prostate Biomarkers in 2010

James McKiernan M.D.Director of Urologic OncologyGiven 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. CACancer J Clin 2009



Cost effective health care ??What is the future of screening?



Annual Age-Adjusted Cancer Incidence Rates AmongMales for Selected Cancers, 1975-2002

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

Year of Diagnosis

R a

t e p e r

1 0 0

, 0 0 0 P o p u

l a t i o n

2 0 0 2

260

140

160180

200

220

240

100

120

Lung and Bronchus

Colon and Rectum80

0

2040

60

1 9 9 3

1 9 7 5

1 9 8 5

1 9 8 3

1 9 8 1

1 9 7 9

1 9 7 7

1 9 9 1

1 9 8 9

1 9 8 7

1 9 9 9

1 9 9 7

1 9 9 5

2 0 0 1

Prostate

Urinary BladderNon-Hodgkin LymphomaMelanoma of the Skin



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 in1941, US army began new ROCresearch 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 determinewhether 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 thisearlier detection and consequent earlier treatmentleads to any change in the natural history andoutcome of the disease.”



American Academy of FamilyPractitioners

• “The AAFP recommends that physicians counsel

men between the ages of 50 and 65 regarding theknown risks and uncertain benefits of PSAscreening. All men should be informed of theknown harms and uncertain benefits of screening

and make an informed choice, rather thanroutinely screening men’s PSA levels.”



American Cancer Society

• “The American Cancer Society (ACS) does notsupport routine testing for prostate cancer at thistime. ACS does believe that health care

professionals should discuss the potential benefitsand limitations of prostate cancer early detectiontesting with men before any testing begins. . . ”



AUA policy statement2009

• “Early detection of and risk assessment for prostate cancer should be offered to asymptomaticmen 40 years of age or older who have a lifeexpectancy of at least 10 years.”



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

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



6.6

10.1

17.0

23.926.9

0

5

10

15

20

25

30

<0.5 0.6 - 1.0 1.1- 2.0 2.1 - 3.0 3.1 - 4.0

PSA

%

Prostate Cancer PrevalencePSA < 4.0 ng/ml

Thompson et al . NEJM 2004



PSA as a Marker for Prostate Cancer

PSA Sensitivity False positive rate

1.1 82.0 59.41.6 67.4 41.22.1 54.4 29.22.6 43.6 20.43.1 35.8 14.94.1 24.5 7.7

6.1 5.4 2.08.1 2.0 0.910.1 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 0.1ng/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% whenPSAV 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/mlover 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 prostatecancer and 20 with BPH)

• The mean PSAD for CaP 0.581; while that for BPH0.044 (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 wasevaluated 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 2-4ng/mL, 0.1 at tPSA 4-10 ng/mL, and 0.19 at 10-20ng/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 ratiosignificantly higher in CaP than BPH (1.18 v 0.53)

• Odds ratio for CaP in highest quartile of hK2 levelwas 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 catalonaJ Clin Chem 1999



Sokoll J Urol 2008

Proenzyme PSA• NCI EDRN

• JHU, Fred Hutch, NCI, Beth IsraelDeaconess, 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 bestscreening test AUC 0.69 vs %Free PSA (0.61)

• PSA usually 0.52



Marberger Eur Urol 2004Bussemakers Cancer Res 1999

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



Fradet Urology 2004

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



Hessels Eur Urol 2003

RNA Analysis of PCA3 Gene in UrinarySediments

• Ratio PCA3:PSA is usedas a quantitative measure

• AUC 0.717 with cutoff value of 35



Patients Sensitivity Specificity

Hessels 2003 108 67% 83%

Tinzl 2004158 82% 76%

Fradet 2004443 66% 89%

Groskopf 2006122 69% 79%

Hessels Eur Urol 2003Tinzl Eur Urol 2004Fradet Urology 2004Groskopf Clin Chem 2006

Summary of PCA 3 Studies



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

Deras Urol 2008

0%

10%

20%

30%

40%

50%

60%

70%

80%

< 5 5 - 19 20 - 34 35 - 49 50 - 100 > 100

% B

i o p s y P o s i t i v e

(58) (205) (101) (62) (90) (54)PCA3 Score

(n=570)



EPCA 2EPCA- 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 healthymen 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 2EPCA 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 areaunder 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 "wereand are imaginary,“

• "Notwithstanding the spectacular (and false) results

proclaimed by defendants, the assay was no more accuratein distinguishing cancerous tissue from normal tissue than

flipping a coin,”Pittsburgh Tribune Review Sept 2009



The future of US healthcare????



* Donovan, M. JCO 2008

KM classification of patients from the training cohortand validation cohort as being low risk (blue line) orhigh risk (yellow line) for experiencing clinical failure

↑ Analysis of AR and AMACR

Copyright© American Society of Clinical Oncology

Systems Pathology Approach for the Prediction of Progression After RPAureon Systems



GSTP1

• Tissue based• Quantitative DNA

Methylation of GST Pi incells developing into prostatecancer

• Urinary based assay indevelopment

TSP-1

• Thrombospondin-1 stronglyelevated in BPH andrepressed in CaP

• Differentiated benign frommalignant disease with 79%sensitivity and 81%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 simplediagnostic assay available

• The future is risk stratified screening to find onlycancers we need to find

prostate markers 2010

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