BIOMARKERS FOR MANAGEMENT OF EPITHELIAL 管理上皮细胞标志物-精选文档.ppt
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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
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