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

Current and Emerging Biomarkers for Disease Management

Elisabeth I. Heath, MDAssociate Professor of Medicine and OncologyWayne State University/Karmanos Cancer InstituteAugust 28, 2010

Prostate Cancer

Annual incidence in the USA slowly Annual incidence in the USA slowly increasing increasing Longer life expectancyLonger life expectancy Widespread use of PSA leading to early Widespread use of PSA leading to early

detectiondetection 15% present with advanced disease15% present with advanced disease 20-30% of localized disease eventually 20-30% of localized disease eventually

progress to metastatic diseaseprogress 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

Under the care of ONCOLOGIST

Castrate Sensitive

Asymptomatic

Non Metastatic

Castrate Resistant

Metastatic

Symptomatic

Local Therapy

Androgen Deprivation

Therapies After LHRH Agonists

and AA ChemotherapyChemotherapy 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); 6302-6309.

CellTracks® AutoPrep® System

Standardized CTC Capture

CellTracks Analyzer II®

Sample Analysis

The CellSearch® SystemSample 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< 0.0001)

Posttreatment CTC predicted shorter OS (median OS 6.7-9.5 versus 19.6-20.7 mos, P< 0.0001)

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 inMetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19); 6302-6309.

Predictive Value: OS of CRPC Patients with <5 or >5 CTC at Baseline

De Bono JS et al. Circulating Tumor Cells Predict Survival Benefit from Treatment inMetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19); 6302-6309.

Circulating Tumor Cells

De Bono JS et al. Circulating Tumor Cells Predict Survival Benefit from Treatment inMetastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 2008:14(19); 6302-6309.

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

18F-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; 22:963-9Morris MJ et al. Urology 2002; 59:913-8

11C-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; 43:181-6.Kotzerke et al. Eur J Nucl Med Mol Imag 2002; 29:1380-4.Fricke E et al. Eur J Nucl Med Mol Imag 2003; 30:607-11.Oyama N et al. J Nucl Med 2003; 44:549-55.

11C-acetate PET Imaging

Prostate and lymph nodes visualizable Quantitative More sensitive for CaP than 18F-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; 43:181-6.Kotzerke et al. Eur J Nucl Med Mol Imag 2002; 29:1380-4.Fricke E et al. Eur J Nucl Med Mol Imag 2003; 30:607-11.Oyama N et al. J Nucl Med 2003; 44:549-55.

Response to Androgen Deprivation Therapy

Post-Rx

PSA < 1

Pre-Rx

PSA 432

FDG PET Acetate PETBone 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