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

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 CombinationLess than 4%of Cancer Patients Enter Clinical TrialsLess than Half of Ovarian Cancer Patients meet RECIST CriteriaMany 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 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 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 above Normal or above Nadir-84-94%Sensitive and 98%Specific-80%precede or coincide with RECISTCombine 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 125Definitions,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,RANDOMIZED,Regimen IThalidomide200 mg PO daily qhs with weekly doseEscalation to a maximum dose of 400 mg daily*,Regimen IITamoxifen20 mg PO BID to 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 CARCINOMA AFTER FIRST LINE CHEMOTHERAPY,Epithelial ovarian,fallopian tube or peritoneal carcinomaComplete clinical regression following front-line chemotherapyBiochemical recurrence based on rising CA125,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 TreatmentTaxanes-50%Response Rate-Additive Not Synergistic-50%Dont BenefitDifficult to Study These Drugs as Individual AgentsMultiple Drugs are Also Active for Salvage,BIOMARKERS TO PREDICT RESPONSE TO INDIVIDUAL DRUGS IN OVARIAN CANCER,Clonogenic AssaysBiomarkers for Platinum Resistance-p53-ERCC1-Lack of Transporters-XIAPBiomarkers 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 TherapyDisease that has Spread from the Pelvis(Stage III-IV)can be Cured in only 20%or LessOnly 25%of Ovarian Cancers are Currently Diagnosed in Stage IDetection of Preclinical Disease at an Earlier Stage Might Improve Survival,MINIMAL REQUIREMENTS FOR OVARIAN CANCER SCREENING,Postmenopausal Prevalence:40/100,000High Sensitivity:75%Very High Specificity:99.6%Positive Predictive Value:10%,APPROACHES TO SCREENING FOR EPITHELIAL OVARIAN CANCER,UltrasonographySerum/Plasma/Urine MarkersTwo Stage Strategies,CA 125 FOR EARLY DETECTION OF OVARIAN CANCER,Elevated 10-60 Months Prior to DiagnosisDetects 50-60%of Stage I DiseaseSpecificity of a Single Determination is 99%,but This is Still InadequateCombination 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 DetectedSpecificity can be Improved by Combining CA 125 with Ultrasound SequentiallySpecificity 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 CancerStable CA 125 Values,Even when Elevated,are Associated with Benign ConditionsA 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 GroupsControl(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 CancerUsing 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 SectionsGreater Sensitivity Might be Achieved with Multiple Markers,Provided that Specificity is not Compromised,OTHER ANTIGENIC MARKERS FOR EPITHELIAL OVARIAN CANCER,CEACA 19-9CA 15-3TAG 72HMFG-2GalactosyltransferasePlacental alkaline phosphataseTissue peptide antigenNB/70K,erbB-2(HER-2-neu)CASALASACYFRA 21-1TAT1IL-2 receptorCathepsin 1Urinary gonadotropin peptideMatrix metalloproteinasesOVX1M-CSF,APPROACHES TO IDENTIFYING NOVEL MARKERS FOR EPITHELIAL OVARIAN CANCER,Murine Monoclonal AntibodiesMesothelinLipid Analysis-LPAExpression Array AnalysisHE4KallikreinsProstasinOsteopontinVEGFIL-8Proteomics,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 CancerWhen corrected for GFR,Urine SMRP detects 39%of Stage I Ovarian CancersBcl-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 MassesHE4 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 Distinctive Pattern of Peptide Expression in Serum or UrineIdentify 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 EvolvedIn Published Studies,Relatively Few Early Stage Patients have been ReportedOthers 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,Multiplex Assay of Multiple Antigens and Antibodies(Gorelik,2005),Lokshin and Colleagues at Pittsburgh Cancer Center have adapted Multiple Assays to a Luminex LabMAP FormatIn Published Studies,CA125,G-CSF,IL-6,EGF and VEGF produced 86%Sensitivity and 93%Specificity for Early Stage DiseaseRecently,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 CompoundsChanges in a Panel of Serum Markers may provide a First Step of a Two Phase Strategy for Early Detection of Ovarian CancerHE4 may provide an Effective Marker for Endometrial Cancer,