Current and Emerging Biomarkers for Disease Management Elisabeth I. Heath, MD Associate Professor of Medicine and Oncology Wayne State University/Karmanos Cancer Institute August 28, 2010

Prostate Cancer Annual incidence in the USA slowly increasing Annual incidence in the USA slowly increasing Longer life expectancy Longer life expectancy Widespread use of PSA leading to early detection Widespread use of PSA leading to early detection 15% present with advanced disease 15% present with advanced disease 20-30% of localized disease eventually progress to metastatic disease 20-30% of localized disease eventually progress to metastatic disease

Abbreviations: AA = antiandrogen; LHRH=luteinizing hormone-releasing hormone. Typical presentation of patient as they move through the different stages. The line represents level burden of disease. Time is not proportional Under the care of ONCOLOGIST Castrate Sensitive Asymptomatic Non Metastatic Castrate Resistant Metastatic Symptomatic Local Therapy Androgen Deprivation Therapies After LHRH Agonists and AA Chemotherapy Postchemo Death Clinical States of Prostate Cancer

Prostate Cancer and Biomarkers  Pubmed search of prostate cancer and biomarkers resulted in 18, 909 publications  Clinicaltrials.gov search resulted in 129 studies actively recruiting participants  Yahoo.com search resulted in 589, 000 sites with prostate cancer and biomarkers

Prostate Specific Antigen  PSA is a protein produced by cells of the prostate gland  FDA approved along with digital rectal exam to help detect prostate cancer in men age 50 or older  Also approved for monitoring of patients with history of prostate cancer to determine if disease has recurred  Medicare covered

Prostate Specific Antigen Uses  PSA velocity: change in PSA level over time  PSA density: considers the relationship between level of PSA and prostate size  Free versus attached PSA: free PSA more helpful in high PSA values, free PSA higher in BPH, attached PSA associated with cancer

Challenges with PSA  Screening recommendations controversial  AUA  American Cancer Society Discussion regarding screening, informed decision  US Preventive Task Force Insufficient evidence to endorse screening Against screening > 75 years

Circulating Tumor Cells  CellSearch cleared by the FDA as prognostic indicator for patients with metastatic breast, colorectal and prostate cancer  CTC most accurate and independent predictor of overall survival (OS) in castrate resistant prostate cancer (CRPC) De Bono JS et al. Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19);

CellTracks ® AutoPrep ® System Standardized CTC Capture CellTracks Analyzer II ® Sample Analysis The CellSearch ® System Sample Collection & Preservation MagNest ® VX10320C

Circulating Tumor Cells  231 patients had CTCs measured  Unfavorable CTC (>5 CTCs/7.5 mL) Pretreatment CTC (57%) had shorter OS (median OS 11.5 vs 21.7 mos, P< ) Posttreatment CTC predicted shorter OS (median OS versus mos, P< )  Prognosis for unfavorable to favorable conversion improved (6.8 to 21.3 mos)  Prognosis for favorable to unfavorable conversion worsened (> 26 mos to 9.3 mos) De Bono JS et al. Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19);

Predictive Value: OS of CRPC Patients with 5 CTC at Baseline De Bono JS et al. Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19);

Circulating Tumor Cells De Bono JS et al. Circulating Tumor Cells Predict Survival Benefit from Treatment in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19);

Additional Methods to Detect Prostate Cancer  MicroRNA patterns Different patterns in early versus late stage  DNA methylation changes Epigenetic changes to identify early PC  Gene fusions Role of ETS family of oncogones

Additional Methods to Detect Prostate Cancer  PCA3 Prostate-specific RNA expressed at high levels in PC. Urine test being developed  Metabolomics Sarcosine as marker of aggressiveness  Proteomics Patterns of proteins in blood to determine agggressiveness

Additional Methods to Detect Prostate Cancer  Dog sniffing prostate cancer  Urine samples with volatile organic compounds

Imaging as a Biomarker  Bone scan  CT scan  MRI  Xray

Detecting Bone Metastases: Bone Scan Anterior Posterior  Images increased bone formation due to tumor Blastic mets: excess bone formation Lytic mets: blastic reaction to bone lysis  “Purely lytic” mets not well seen - myeloma, thyroid Courtesy of Evan Yu and Dave Mankoff

18 F-FDG PET Imaging  Differential glucose uptake in cancer cells  Quantitative  Lacks sensitivity in CaP Low proliferation rate Urinary excretion obscures pelvis Mostly studied in PSA recurrence state  2 small studies that hint towards change in FDG uptake correlating with response to therapy Prostate Metastases PSA Oyama N et al. Nucl Med Comm 2001; 22:963-9 Morris MJ et al. Urology 2002; 59:913-8

11 C-acetate PET Imaging  Images abnormal oxidative metabolism in myocardium  In CaP, acetate uptake distributed to phospholipid membranes  Differential tumor uptake Acetate channeled to CO2 in normal tissue for energy production Oyama N et al. J Nucl Med 2002; 43: Kotzerke et al. Eur J Nucl Med Mol Imag 2002; 29: Fricke E et al. Eur J Nucl Med Mol Imag 2003; 30: Oyama N et al. J Nucl Med 2003; 44:

11 C-acetate PET Imaging  Prostate and lymph nodes visualizable  Quantitative  More sensitive for CaP than 18 F-FDG for the prostate, lymph nodes, and metastases PSA recurrent patients with goals of detection not treatment response Lack pathologic correlation Lack clinical correlation Oyama N et al. J Nucl Med 2002; 43: Kotzerke et al. Eur J Nucl Med Mol Imag 2002; 29: Fricke E et al. Eur J Nucl Med Mol Imag 2003; 30: Oyama N et al. J Nucl Med 2003; 44:

Response to Androgen Deprivation Therapy Post-Rx PSA < 1 Pre-Rx PSA 432 FDG PET Acetate PET Bone Scan Courtesy of Evan Yu and Dave Mankoff

Novel Tracers for PET Sscans  18F-1-(2'-deoxy-2'-fluoro-ß-D- arabinofuranosyl)thymine (FMAU)  (1-(2'-Deoxy-2'-Fluoro-β-D- arabinofuranosyl) Uracil (FAU)  3-Deoxy-3[18]Fluorothymidine (FLT)

Summary  PSA remains gold standard in screening and disease management  CTC technology approved by FDA helpful in prognosis  Tremendous amount of new technology emerging  Imaging emerging as biomarker  Encourage your patients to enroll in clinical trials