Transcript BIOMARKERS FOR MANAGEMENT OF EPITHELIAL OVARIAN …

FRONTIERS IN TUMOR MARKERS
Robert C. Bast, Jr., M.D.
U.T. M.D. Anderson Cancer Center
October 16, 2006
FRONTIERS IN TUMOR MARKERS:
CA 125 FOR ACCELERATING DRUG EVALUATION
IN OVARIAN CANCER
THE CHALLENGE OF TARGETED
DRUG DEVELOPMENT
• More than 400 New Drugs are Being Developed
for Clinical Trials
• Many Targeted Drugs will be Effective Only in
Combination
• Less than 4% of Cancer Patients Enter Clinical
Trials
• Less than Half of Ovarian Cancer Patients
meet RECIST Criteria
• Many Targeted Drugs will be Cytostatic
O’Brien et al. Tumor Biology 2001
CA 125 TO ACCELERATE
PHASE II CLINICAL TRIALS
• Surrogate Marker for Response in Phase II
Trials
- A 50% and 75% Decrease in CA125 has
correlated with Response Rates in 19 Phase II
Trials of 14 Different Cytotoxic Drugs with
>1000 Patients (Rustin, et al)
- Use of CA125 could Double Accrual
- Discontinue Trials with Poor Response
- Expand Accrual to achieve RECIST Criteria
Selection of Active Drugs in Phase II
Trials for Ovarian Cancer According to
CA 125 Response Rates
Paclitaxel
Docetaxel
Etoposide
Fosquidone
Gemcitabine
Isotretinoin/Calcitriol
Altretamine
Platinum based
Rhizoxin
Tallimustine
Tomudex
Topotecan
Oxaliplatin
CA 125 TO ACCELERATE
PHASE III CLINICAL TRIALS
• CA 125 as an Endpoint for Time to Progression
in Phase III Trials
- Rise >2-fold above Normal or above Nadir
- 84-94% Sensitive and >98% Specific
- 80% precede or coincide with RECIST
• Combine with RECIST Criteria
- RECIST takes Precedence
- CA125 must be at the Same Time Points in
Both Arms
- Shorten Duration of Trials
Comparison of CA-125 and Standard Definitions of
Progression in the Intergroup Trial of Cisplatin and Paclitaxel
Versus Cisplatin and Cyclophosphamide (Rustin et al 2006)
Standard
Definitions
CA 125
Definitions
Combined
CA 125 TO EVALUATE NOVEL
CYTOSTATIC DRUGS
• Monitor Response to New Cytostatic Drugs
-
Many Targeted Therapies are
Cytostatic and Stabilize Disease
-
Effective Drugs could arrest A Rising
CA 125 in Recurrent Disease
-
Measure the Decreased Slope or Use
Doubling of CA125 as Progression
A RANDOMIZED STUDY OF TAMOXIFEN VERSUS THALIDOMIDE (NSC#66847) IN
PATIENTS WITH BIOCHEMICAL RECURRENCE ONLY OF EPITHELIAL OVARIAN
CANCER, CANCER OF THE FALLOPIAN TUBE, AND PRIMARY PERITONEAL
CARCINOMA AFTER FIRST LINE CHEMOTHERAPY
-Epithelial ovarian,
fallopian tube or
peritoneal carcinoma
-Complete clinical
regression following
front-line
chemotherapy
-Biochemical
recurrence based on
rising CA125
Regimen I
Thalidomide
200 mg PO daily qhs with weekly dose
Escalation to a maximum dose of 400 mg daily*
R
A
N
D
O
M
I
Z
E
D
Until disease
progression or
adverse effects
prohibit
further therapy
for one year
Regimen II
Tamoxifen
20 mg PO BID to a maximum dose of 40 mg
FRONTIERS IN TUMOR MARKERS:
PREDICTION OF REPONSE TO THERAPY
BIOMARKERS TO PREDICT RESPONSE TO
INDIVIDUAL DRUGS IN OVARIAN CANCER
• Platinum Compounds
70% Response Rate
Very High Negative Predictive Value (>95%)
Required to Forego Treatment
• Taxanes
50% Response Rate
Additive Not Synergistic
50% Don’t Benefit
• Difficult to Study These Drugs as Individual Agents
• Multiple Drugs are Also Active for Salvage
BIOMARKERS TO PREDICT RESPONSE TO
INDIVIDUAL DRUGS IN OVARIAN CANCER
• Clonogenic Assays
• Biomarkers for Platinum Resistance
p53
ERCC1
Lack of Transporters
XIAP
• Biomarkers for Taxane Resistance
MDR1
Tubulin Mutations
HER-2
Survivin
BIOMARKERS TO PREDICT RESPONSE TO
INDIVIDUAL DRUGS IN OVARIAN CANCER
• Future Directions
- Expression Array Analysis
- Changes in Proteomic Profiles
- Circulating Tumor Cells
- New Therapies with Specific Targets
- Molecular Imaging
REVERSE PHASE PROTEIN LYSATE ARRAYS TO
IDENTIFY ACTIVATED SIGNALING PATHWAYS
FRONTIERS IN TUMOR MARKERS:
EARLY DETECTION OF OVARIAN CANCER
RATIONALE FOR OVARIAN CANCER
SCREENING
• Ovarian Cancer Limited to the Ovaries (Stage
I) can be Cured in 90% of Patients with
Currently Available Therapy
• Disease that has Spread from the Pelvis
(Stage III-IV) can be Cured in only 20% or
Less
• Only 25% of Ovarian Cancers are Currently
Diagnosed in Stage I
• Detection of Preclinical Disease at an Earlier
Stage Might Improve Survival
MINIMAL REQUIREMENTS FOR
OVARIAN CANCER SCREENING
• Postmenopausal Prevalence:
40/100,000
• High Sensitivity:  75%
• Very High Specificity: 99.6%
• Positive Predictive Value: 10%
APPROACHES TO SCREENING FOR
EPITHELIAL OVARIAN CANCER
• Ultrasonography
• Serum/Plasma/Urine Markers
• Two Stage Strategies
CA 125 FOR EARLY DETECTION
OF OVARIAN CANCER
• Elevated 10-60 Months Prior to
Diagnosis
• Detects 50 - 60% of Stage I Disease
• Specificity of a Single Determination
is 99%, but This is Still Inadequate
• Combination with Ultrasonography
can increase Specificity
CA 125 FOR EARLY DETECTION
OF OVARIAN CANCER
• In the PLCO Trial, CA125 alone had a PPV of
3.7%, TVS had a PPV of 1%, both together
had a PPV of 23.5%, but 60% of Invasive
Cancers would not be Detected
• Specificity can be Improved by Combining
CA 125 with Ultrasound Sequentially
• Specificity and Sensitivity can be Improved
by Sequential Monitoring Over Time
Analysis of Changes in
CA 125 Over time
• Rising CA 125 Values are Associated with
Ovarian Cancer
• Stable CA 125 Values, Even when
Elevated, are Associated with Benign
Conditions
• A Computer Algorithm has been
Developed that Estimates Risk of Ovarian
Cancer based on Change Point Analysis
During Sequential Monitoring Over Time
Analysis of Changes in CA 125 Over Time: 6,532
Women >50 Years Screened Producing a Specificity
of 99.8% and a Positive Predictive Value of 19%
(Menon, JCO, 2005)
RANDOMIZED TRIAL OF SCREENING WITH
THE CA125 ALGORITHM AND ULTRASOUND
OR WITH ULTRASOUND ALONE (UKCTOCS)
• Two Hundred Thousand Postmenopausal
Women will be Randomized to Three
Groups
– Control (100,000)
– Annual TVS (50,000)
– CA125 Algorithm Prompting TVS
(50,000)
• Women will be Screened and Followed for
7 Years
INCREASING THE SENSITIVITY OF TWO
STAGE SCREENING STRATEGIES FOR
OVARIAN CANCER
• CA125 Levels are >35 U/ml in 50-60% of
Patients with Stage I Ovarian Cancer
• Using an Algorithm that Detects Disease when
CA125 <35 U/ml, Sensitivity Could Exceed 60%
• In 20% of Ovarian Cancers CA125 Cannot Be
Detected in Tissue Sections
• Greater Sensitivity Might be Achieved with
Multiple Markers, Provided that Specificity is
not Compromised
OTHER ANTIGENIC MARKERS FOR
EPITHELIAL OVARIAN CANCER
•
•
•
•
•
•
•
CEA
CA 19-9
CA 15-3
TAG 72
HMFG-2
Galactosyltransferase
Placental alkaline
phosphatase
• Tissue peptide antigen
• NB/70K
•
•
•
•
•
•
•
•
erbB-2 (HER-2-neu)
CASA
LASA
CYFRA 21-1
TAT1
IL-2 receptor
Cathepsin 1
Urinary gonadotropin
peptide
• Matrix
metalloproteinases
• OVX1
• M-CSF
APPROACHES TO IDENTIFYING NOVEL
MARKERS FOR EPITHELIAL OVARIAN CANCER
• Murine Monoclonal Antibodies
– Mesothelin
• Lipid Analysis - LPA
• Expression Array Analysis
– HE4
– Kallikreins
– Prostasin
– Osteopontin
– VEGF
– IL-8
• Proteomics
A COMBINATION OF SERUM SOLUBLE MESOTHELIN
RELATED PROTEIN (SMRP) AND CA125 IS SUPERIOR TO
EITHER ALONE FOR DISTINGUISHING OVARIAN CANCER
CASES FROM HEALTHY CONTROLS
Soluble Mesothelin Related Protein
(SMRP)
• Serum SMRP complements CA 125 in
detecting Ovarian Cancer
• When corrected for GFR, Urine SMRP
detects 39% of Stage I Ovarian Cancers
• Bcl-2 is also elevated in Urine from >80%
of ovarian cancer patients (Kruk et al
2005)
HE4 IS A BIOMARKER BOTH FOR
OVARIAN AND ENDOMETRIAL CANCER
• HE4 is as Sensitive as CA 125 for
detecting Ovarian Cancer, but has better
Specificity for distinguishing Malignant
and Benign Pelvic Masses
• HE4 is Twice as Sensitive as CA 125 for
Endometrial Cancer detecting 36% of All
Stages and 17% of Stage I Cancers
PROTEOMIC ANALYSIS OF
OVARIAN CANCER
2000
2250
2500
2750
Normal
2000
2250
2500
2750
Normal
2000
2250
2500
2750
2000
2250
2500
2750
Ovarian
Cancer
Ovarian
Cancer
2000
2000
2250
2250
2500
2500
2750
2750
Application of Proteomics to Early
Detection of Ovarian Cancer
• Identify a Distinctive Pattern of
Peptide Expression in Serum or
Urine
• Identify Specific Peptides and
Develop Individual Assays that can
be analyzed in Combination
USE OF PROTEOMIC PATTERNS TO IDENTIFY
OVARIAN CANCER
• SELDI and MALDI-TOF have been used to analyze
the Pattern of Peptides in Sera from Healthy Women
and Ovarian Cancer Patients (Petricoin, et al)
• Very High Sensitivity and Specificity have been
reported (Fishman, et al)
• Over the last 4 Years, the Computer Algorithm has
Evolved
•In Published Studies, Relatively Few Early Stage
Patients have been Reported
•Others have had difficulty in confirming the Analysis
and have identified Problems with the Methods Used
STUDY DESIGN AND PATIENT FLOW FOR SAMPLES FROM FIVE
ACADEMIC MEDICAL CENTERS
Identification of Biomarkers
from the Proteomic Profile
• Seven Biomarkers have been Identified that
Distinguish Benign from Malignant Pelvic Masses
(Zhang, et al)
• Of these, Downregulation of Three Biomarkers
Consistently Distinguishes Ovarian Cancer
Patients from Healthy Individuals
-
Apolipoprotein A1
-
Truncated Transthyretin
-
CTAPIII
Luminex Assay
Multiplex Assay of Multiple Antigens
and Antibodies (Gorelik, 2005)
• Lokshin and Colleagues at Pittsburgh Cancer
Center have adapted Multiple Assays to a
Luminex LabMAP Format
• In Published Studies, CA125, G-CSF, IL-6,
EGF and VEGF produced 86% Sensitivity and
93% Specificity for Early Stage Disease
• Recently, they have analyzed some 40
biomarkers with increased Sensitivity and
Specificity
FRONTIERS IN TUMOR MARKERS
• CA 125 could facilitate and accelerate Drug
Evaluation by serving as a Surrogate Endpoint for
Response in Phase II Clinical Trials and for
Recurrence in Phase III Trials in Ovarian Cancer
• New Technologies are providing Multiple
Candidates for Predictive Markers of Response to
Taxanes and Platinum Compounds
• Changes in a Panel of Serum Markers may
provide a First Step of a Two Phase Strategy for
Early Detection of Ovarian Cancer
• HE4 may provide an Effective Marker for
Endometrial Cancer