Biomarkers in Prostate Cancer, part II
Prostate Cancer Symposium
September 17, 2011
Clara Hwang, MD
Internal Medicine
Hematology/Oncology
Biomarkers – the holy grail of
personalized medicine?
• Advances in technology (genomics, proteomics)
have offered the promise of personalized
medicine, where therapies and medical decision
making can be finely tailored to patients.
• Potential benefits include improving clinical
efficacy and decreasing toxicity by better
treatment selection and patient selection.
Phases of biomarker development
• Discovery – ~Phase I
• Identify relationship between molecular marker and clinical
outcome; ideally identify causal relationship
• Analytic Validation – ~Phase II
• Develop lab SOP/QC, reliability in clinical samples
• Selectivity, sensitivity, CR, precision, accuracy
• Clinical Qualification – ~Phase III
• Confirm correlation with clinical outcomes
• Clinical implementation - ~Phase IV
Clinical utility of biomarkers
in prostate cancer
Clinical scenario
Example
Detection
PSA for early diagnosis
Prognosis
Gleason score
Prediction
ER positivity and hormone Rx;
none exist for prostate cancer
Pharmacodynamic
Testosterone for GnRH agonist
Clinical surrogate
PSA decline as tumor marker
Prostate cancer clinical states
and treatment decisions
Localized
disease
Metastatic
disease
Should I start treatment? (Prognostic biomarker)
Which treatment should I use? (Predictive biomarker)
Is my treatment working? (Pharmacodynamic biomarker)
Is my treatment helping the patient? (Surrogate biomarker)
Current landscape of treatments for castrateresistant metastatic prostate cancer
• Minimally symptomatic – sipuleucel-T
• 1st line – docetaxel
• 2nd line –
• Abiraterone
• Cabazitaxel
• 3rd line – mitoxantrone
Biomarkers to assess response to
systemic therapy
• Limitations of systemic therapy – all
patients will ultimately progress
• Some patients will not have an initial
response to therapy
• Are there predictive or surrogate
biomarkers to guide treatment decisions?
Response markers in prostate cancer
• In current clinical use
•
•
•
•
PSA
Pain
Bone scan
CT scan/ MRI scan (RECIST)
• Experimental
• Circulating tumor cells
The difficulty of assessing response to
therapy in mCRPC
“PCWG2 advises that, in the absence of
clinically compelling indicators of disease
progression, early changes (within 12
weeks) in indicators such as serum PSA,
patient-reported pain, and radionuclide
bone scan be ignored.”
Scher et al JCO 2008 v26(7) p 1148
Clinical examples of using PSA as
biomarker for treatment response
• On occasion, PSA will
rise prior to falling (PSA
flare response)
140
120
100
% baseline PSA
• PSA responses from
three patients started on
chemotherapy with
CRPC
80
60
40
20
0
0
3
6
9 12
weeks
15
18
PSA response as surrogate marker
• Retrospective analysis of patients on Ph III
comparision of D+E vs M+P (S9916)
• 3 month 30% PSA decline defined to have
occurred if lowest PSA within first three
months <=50% of baseline value
• By this definition – occurred in 76% in D+E
arm vs 40% in M+P
Petrylak 2006 JNCI 98:516
PSA decline as surrogate marker in
S9916
Original figure of MP vs. DE compared to OS curve of
patients with PSA decrease >=30% in 3 mo vs < 30%
Petrylak 2006 JNCI 98:516
Circulating tumor cells (CTC)
• In patients with solid tumors, circulating
tumor cells can be detected in circulation
• Rare (1 in 109 nucleated cells)
• Provide a source of tumor cells for
molecular profiling
• For Cellsearch assay, cutoff for favorable
vs unfavorable is 5 CTC per 7.5 mL blood
CTC detection with CellSearch
Only FDA approved, analytically validated CTC assay
Baseline CTC is prognostic in mCRPC
patients treated with cytotoxic therapy
de Bono J S et al. Clin Cancer Res 2008;14:6302-6309
Conversion of CTC as predictor of
overall survival
de Bono J S et al. Clin Cancer Res 2008;14:6302-6309
CTC enumeration vs PSA decline as
predictor of overall survival
Clinical utility of biomarkers
in prostate cancer, revisited
Clinical scenario
Example
Detection
PSA for early diagnosis
Prognosis
Gleason score
Prediction
ER positivity and hormone Rx;
none exist for prostate cancer
Pharmacodynamic
Testosterone for GnRH agonist
Clinical surrogate
PSA decline as tumor marker
Markers that correlate with docetaxelsensitivity
underexpressed in sensitive cell lines
overexpressed in sensitive cell lines
Causal relationship between SKP2 and
docetaxel response
Effect of SKP2 knockdown on docetaxel response
si-SKP2
100
0.8
0.6
0.4
0.2
0.0
LNCAP
Cell viability, % baseline
Relative Quantitation
si-nontarget
1.0
80
60
40
Actin
SKP2
1
10
docetaxel concentration (log scale)
100
Conclusions
• PSA decline may be used as a surrogate
marker for response (after 12 weeks)
• Baseline levels of CTC are prognostic for
OS
• Conversion of CTC correlates with OS but
have not yet been qualified for individual
patient use
• Further studies are needed to identify and
validate predictive markers