Biomarkers in Prostate Cancer

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Biomarkers in Prostate Cancer

• Prostate Cancer Symposium
• The Prostate Net
• September 17, 2011
• Steven Lucas
• Wayne State University School of Medicine
• Karmanos Cancer Institute

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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.

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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

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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

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Clinical Nomogram Kattan Nomogram
Stephenson et al, J natl CI, 2006
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How can biomarkers improve management?
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Categories of biomarkers
Urine Based
Blood Based
Tissu Based
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Urine Based Biomarkers

• Proteins
• Urinary/serum psa ratio
• Annexin A3
• MMP9
• Proteomics

• DNA
• Glutathione-S-transferase P1
• Other methylation- specific PCR assays

• RNA
• PCA3
• TMPRSS2-ERG gene fusion

Roobol et al, Acta oncologica, 2011
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Urinary PCA3

• Developed from differential expression of
  noncoding RNAs 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

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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 PCA30.64 PSA0.58

Roobol et al, Eur Urol, 2010
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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
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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
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Blood Based biomarkers

• Diagnosis
• PSA
• PSA velocity
• Free PSA
• Pro-PSA
• BPH-associated PSA

• Prognosis
• Human Kallikrein 2
• Urokinase plasminogen activator
• Transforming Growth factor ß1
• Interleukin-6
• Endoglin

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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) Percent CaP ()
lt0.6 6.6
0.6-1.0 10.1
1.1-2.0 17.0
2.1-3.0 23.9
3.1-4.0 26.9
Thompson et al, NEJM, 2004
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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) Odds Ratio of CaP
0.50 1.00
0.51-1.0 2.51
1.01-2.0 7.02
2.01-3.0 19.01
Ulmert et al, BMC Med, 2008
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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. Damico et
al, NEJM, 2004 3. Carter et al, J NCI, 2006
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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
  4-10ng/ml
• fPSA lt 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

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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
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• Endoglin CD 105, a cell surface co-receptor for
  TGFß1 and 3
• Found on immature blood vessels Angiogenesis
• Pre-prostatectomy levels may predict higher
  gleason score and PSA recurrence

Svatek et al, CCR 2008
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Combining Panel of Markers and Nomogram

• Biomarkers used to supplement not replace
  clinical data to improve accuracy of prognosis
• Kattan nomogram biomarker panel
• TGF-ß1, 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
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Tissue Based Biomarkers

• 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

• Diagnostic
• High molecular weight cytokeratin
• p63
• AMACR

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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
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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
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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