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1、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 Tr
2、ials Less than Half of Ovarian Cancer Patients meet RECIST Criteria Many Targeted Drugs will be Cytostatic,OBrien 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 Ra
3、tes 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 Res
4、ponse Rates,Paclitaxel Platinum based Docetaxel Rhizoxin Etoposide Tallimustine Fosquidone Tomudex Gemcitabine Topotecan Isotretinoin/Calcitriol Oxaliplatin Altretamine,CA 125 TO ACCELERATE PHASE III CLINICAL TRIALS,CA 125 as an Endpoint for Time to Progression in Phase III Trials - Rise 2-fold abov
5、e 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 t
6、he 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
7、 - Effective Drugs could arrest A Rising CA 125 in Recurrent Disease - Measure the Decreased Slope or Use Doubling of CA125 as Progression,R A N D O M I Z E D,Regimen I Thalidomide 200 mg PO daily qhs with weekly dose Escalation to a maximum dose of 400 mg daily*,Regimen II Tamoxifen 20 mg PO BID to
8、 a maximum dose of 40 mg,Until disease progression or adverse effects prohibit further therapy for one year,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 C
9、ARCINOMA AFTER FIRST LINE CHEMOTHERAPY,Epithelial ovarian, fallopian tube or peritoneal carcinoma Complete clinical regression following front-line chemotherapy Biochemical recurrence based on rising CA125,FRONTIERS IN TUMOR MARKERS: PREDICTION OF REPONSE TO THERAPY,BIOMARKERS TO PREDICT RESPONSE TO
10、 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% Dont Benefit Difficult to Study These Drugs as Individual Agents Multiple Drugs are Also Ac
11、tive 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 INDI
12、VIDUAL 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: EA
13、RLY 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
14、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 SCREE
15、NING 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 Comb
16、ination 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 12
17、5 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 Alg
18、orithm 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),RAND
19、OMIZED 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 Yea
20、rs,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
21、 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
22、 (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 Kallikre
23、ins 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 Ova
24、rian 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 b
25、etter 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,Application of Proteomics to Early Detection of Ovarian Cancer,Identify a Dis
26、tinctive 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
27、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
28、 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)
29、Of these, Downregulation of Three Biomarkers Consistently Distinguishes Ovarian Cancer Patients from Healthy Individuals - Apolipoprotein A1 - Truncated Transthyretin - CTAPIII,Multiplex Assay of Multiple Antigens and Antibodies (Gorelik, 2005),Lokshin and Colleagues at Pittsburgh Cancer Center have
30、 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
31、 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,