Transcript Biomarkers in Prostate Cancer

Biomarkers in Prostate Cancer
Prostate Cancer Symposium
The Prostate Net
September 17, 2011
Steven Lucas
Wayne State University School of Medicine
Karmanos Cancer Institute
Why are Biomarkers Important
• Prostate Cancer diagnosed in 200,000
men annually in the united states
• 30,000 cancer specific deaths per year
• Yet, a substantial portion of cancers
diagnosed through PSA screening do not
progress to clinically significant disease.
Problem with PSA screening
• It is not specific, resulting in a negative
biopsy rate of up to 70% in some series
• European randomized trial: 1410 men
screened and 48 treated to prevent 1 death
from prostate cancer
• Sweedish Randomized trial of watchful
waiting:
– Relative risk for surgery: 0.62 (0.44-0.87)
– NNT 15 overall and 7 for men younger than 65y
How do we improve screening and
treatment decisions?
• Clinical nomograms
– Include Gleason Score, positive cores, percent
involvement of cores, and PSA
– Other risk factors: family history, age, race
• Biomarkers
– Supplement known clinical information
Clinical Nomogram: Kattan Nomogram
Stephenson et al, J natl CI, 2006
How can biomarkers improve management?
Prostate cancer screening
Elevated PSA
Prostate biopsy
Prostate Cancer
management
Additional therapy
after primary
treatment
F/u after treatment
Metastasis
Categories of biomarkers
Urine Based
Blood Based
Tissu Based
Urine Based Biomarkers
• Proteins
– Urinary/serum
psa ratio
– Annexin A3
– MMP9
– Proteomics
• DNA
• RNA
– Glutathione-Stransferase P1
– Other methylationspecific PCR
assays
– PCA3
– TMPRSS2-ERG
gene fusion
Roobol et al, Acta oncologica, 2011
Urinary PCA3
• Developed from differential expression of
noncoding RNA’s in prostate cancer versus
other prostate conditions
• Commercially available, approved diagnostic
test
• Collected from urine sample following a firm
DRE
• Could function as a first line screen or prognostic
indicator
Urinary PCA3: First line screen
• Several studies show superior overall specificity to PSA:
80-90%, but include only patients with elevated PSA
– In the REDUCE trial the placebo test characteristics for PSA
were: Se = 0.518
Sp = 0.629
• PCA3 in patients with PSA 4-10ng/ml:
– Specificity: 71-93%
Sensitivity: 53-84%
Is PCA3 Better than PSA for CaP diagnosis?
• ERSPC: prostate biopsy trigger:
PSA ≥ 3 or PCA3 ≥ 10
• In 721 biopsied, PCA3 performed only marginally
better:
AUC: PCA3=0.64
PSA=0.58
Roobol et al, Eur Urol, 2010
PCA3 and TMPRSS2-ERG fusion
• Fusion of a strong androgen promoter
(transmembrane serine protease) and an
oncogene
• Further improved diagnostic accuracy
(AUC)
– PCA3: 0.65
PCA3 + Fusion: 0.77
– PCA3 + gene-fusion + PSA: 0.80
Aubin et al, J Urol, 2008
PCA3: prognostic indicator
• Conflicting studies show a positive relationship1
with cancer aggressiveness or no relationship2
• Reduce Trial- chemoprevention of CaP with
Dutasteride3:
– Weak association of PCA3 with Gl 7 or higher cancer
– OR: 1.017 (CI95%: 1.01-1.03)
– Though low numbers of high grade prostate cancer
weakens the analysis
1. Hessels et al, Prostate, 2010 2. Whitman et al, J Urol, 2008
3. Aubin et al, Urology, 2011
Blood Based biomarkers
• Diagnosis
–
–
–
–
–
PSA
PSA velocity
Free PSA
Pro-PSA
BPH-associated PSA
• Prognosis
– Human Kallikrein 2
– Urokinase plasminogen
activator
– Transforming Growth
factor β1
– Interleukin-6
– Endoglin
Limitations of Total PSA
• Neoplastic cells produce varying levels of PSA
• Biologic variation:
– Oscillations of PSA up to 30% in range of 0.1-20ng/ml
• Different Assays (WHO standard)
• Sensitivity: 52%
Specificity: 63%
What Cut-off?
PCPT
PSA (ng/ml)
<0.6
0.6-1.0
1.1-2.0
Percent CaP (%)
6.6
10.1
17.0
2.1-3.0
3.1-4.0
23.9
26.9
Thompson et al, NEJM, 2004
PSA: Long-term risk
• Malmo Preventative Medicine Study
– 462 CaP median f/u 18y matched to 1,222 controls
– Total PSA at age 44-50 was compared
Total PSA at age
44-50y (ng/ml)
≤ 0.50
0.51-1.0
1.01-2.0
2.01-3.0
Odds Ratio of CaP
1.00
2.51
7.02
19.01
Ulmert et al, BMC Med, 2008
PSA Velocity
Diagnosis
• Measurement of change in total PSA over time
• Two large prospective trials found no independent
predictive value beyond total PSA and other standard
variables (PCPT and ERSPC)
Prognosis
• Increase risk of death determined at PSAv levels
greater than 0.35 – 2.0 ng/ml per year
• May not predict early progression but an indication
of aggressive disease beyond treatment window
1. Shariat et al, Acta Onc, 2011 2. D’amico et al, NEJM, 2004
3. Carter et al, J NCI, 2006
Percent Free PSA
• Isoform of PSA that remains unbound in plasma
• Percent free PSA relative to the total PSA is FDA
approved as an adjunct to total PSA between 410ng/ml
– fPSA < 25% used as a trigger for biopsy
• Multicenter, prospective trial
– Specificity: 95%, Sensitivity: 20% over PSA
– AUC: %fPSA = 0.72
PSA: 0.53
– When use 10-12 core biopsy: efficiency
decreases
1. Catalona et al, JAMA, 1998
2. Canto et al, J Urol, 2004
Combined panel of PSA isoforms
• ERSPC: For every 1,000 unscreened men, the model, if
used to determine biopsy:
– Reduce biopsy rates by 573
– Miss 31/152 low grade CaP
3/40 high grade CaP
Vickers et al, BMC Med, 2008
• Endoglin: CD 105, a cell surface co-receptor for TGFβ1 and 3
– Found on immature blood vessels: Angiogenesis
– Pre-prostatectomy levels may predict higher gleason score
and PSA recurrence
Svatek et al, CCR 2008
Combining Panel of Markers and Nomogram
• Biomarkers used to supplement not replace
clinical data to improve accuracy of prognosis
• Kattan nomogram + biomarker panel:
– TGF-β1, IL-6R, IL-6, endoglin, VEGF, VCAM-1
• Predictive accuracy of the Kattan nomogram
improved by 15%
– 71.6% versus 86.6%
Shariat et al, Acta Onc, 2011
Tissue Based Biomarkers
• Diagnostic
– High molecular
weight cytokeratin
– p63
– AMACR
• Prognostic
– Human kallikrein type 2
– Prostate specific
membrane antigen
– Ki-67
– Androgen receptor
– Gene fusions
– PTEN
– P53
– SPINK1/TATI
– MSMB
– EZH2
– Heat shock proteins
– DNA methylation
– HER2
Prostate Specific Membrane Antigen
• Transmembrane glycoprotein negatively regulated by
androgens and overexpressed in androgen independent CaP
Increased expression associated with higher
grade and biochemical recurrence
Perner S, et al, Human Path, 2007
Translating biomarkers into therapeutic
Targets
• PSMA
– PSMA- antibody drug conjugate currently in
phase 1 trial
– Castration-resistent metastatic CaP
• Endoglin
– TRC105 is a human/murine chimeric
monoclonal antibody that binds to endoglin,
thus inhibiting angiogenesis
– Phase 1 / phase 2 trial for CRPC
www.nih.gov, 2011
Summary
• Biomarkers serve as a powerful adjunct to the
diagnosis and management of prostate cancer
• Biomarkers are testable in the urine, blood,
and prostate cancer tissue
• Further validation of these biomarkers and
research into potential therapeutic targets is
needed