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Slide 1 - Biomarkers in Prostate Cancer Prostate Cancer Symposium The Prostate Net September 17, 2011 Steven Lucas Wayne State University School of Medicine Karmanos Cancer Institute
Slide 2 - 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.
Slide 3 - 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
Slide 4 - 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
Slide 5 - Clinical Nomogram: Kattan Nomogram Stephenson et al, J natl CI, 2006
Slide 6 - How can biomarkers improve management?
Slide 7 - Categories of biomarkers Urine Based Blood Based Tissu Based
Slide 8 - 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
Slide 9 - 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
Slide 10 - 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
Slide 11 - 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
Slide 12 - 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
Slide 13 - 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
Slide 14 - 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 Thompson et al, NEJM, 2004
Slide 15 - 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 Ulmert et al, BMC Med, 2008
Slide 16 - PSA Velocity 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) 1. Shariat et al, Acta Onc, 2011 2. D’amico et al, NEJM, 2004 3. Carter et al, J NCI, 2006 Diagnosis 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 Prognosis
Slide 17 - 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 < 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 Catalona et al, JAMA, 1998 Canto et al, J Urol, 2004
Slide 18 - 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
Slide 19 - 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
Slide 20 - 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
Slide 21 - 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
Slide 22 - 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
Slide 23 - 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
Slide 24 - 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