Download De Bono JS et al. Circulating Tumor Cells Predict

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




Longer life expectancy
Widespread use of PSA leading to early
detection
15% present with advanced disease
20-30% of localized disease eventually
progress to metastatic disease
Clinical States of Prostate
Cancer
Androgen
Deprivation
Death
Therapies After
LHRH Agonists
and AA
Local
Therapy
Chemotherapy
Symptomatic
Under
the care of
ONCOLOGIST
Asymptomatic
Non Metastatic
Castrate Sensitive
Metastatic
Castrate Resistant
• Typical presentation of patient as they move through the different stages.
The line represents level burden of disease. Time is not proportional
Abbreviations: AA = antiandrogen; LHRH=luteinizing hormone-releasing hormone.
Postchemo
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.
The CellSearch® System
Sample Collection &
Preservation
Standardized CTC Capture
Sample Analysis
CellTracks®
AutoPrep® System
CellTracks Analyzer II®
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 in
Metastatic 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 in
Metastatic 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 in
Metastatic 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
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; 22:963-9
Morris 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
Bone Scan
Pre-Rx
PSA 432
Post-Rx
PSA < 1
Courtesy of Evan Yu
and Dave Mankoff
FDG PET
Acetate PET
Novel Tracers for PET
Sscans
 18F-1-(2'-deoxy-2'-fluoro-ß-D-
arabinofuranosyl)thymine (FMAU)
 (1-(2'-Deoxy-2'-Fluoro-β-Darabinofuranosyl) 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