BIOMARKERS-FOR-MANAGEMENT-OF-EPITHELIAL-管理上皮细胞标志物课件

1、FRONTIERS IN TUMOR MARKERSRobert C. Bast, Jr., M.D.U.T. M.D. Anderson Cancer CenterOctober 16, 2019FRONTIERS IN TUMOR MARKERS:CA 125 FOR ACCELERATING DRUG EVALUATION IN OVARIAN CANCER THE CHALLENGE OF TARGETED DRUG DEVELOPMENTMore than 400 New Drugs are Being Developed for Clinical Trials Many Targe

2、ted 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 CytostaticOBrien et al. Tumor Biology 2019CA 125 TO ACCELERATE PHASE II CLINICAL TRIALSSurrogate Marker for Re

3、sponse 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

4、 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 AltretamineCA 125 TO ACCELERATE PHASE III CLINICAL TRIA

5、LSCA 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 o

6、f TrialsComparison of CA-125 and Standard Definitions of Progression in the Intergroup Trial of Cisplatin and Paclitaxel Versus Cisplatin and Cyclophosphamide (Rustin et al 2019) Standard DefinitionsCA 125DefinitionsCombined CA 125 TO EVALUATE NOVEL CYTOSTATIC DRUGSMonitor Response to New Cytostatic

7、 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 ProgressionRANDOMIZEDRegimen IThalidomide200 mg PO daily qhs with weekly doseEscalation to a maximum dose

8、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, CANC

9、ER OF THE FALLOPIAN TUBE, AND PRIMARY PERITONEAL CARCINOMA AFTER FIRST LINE CHEMOTHERAPYEpithelial ovarian, fallopian tube or peritoneal carcinomaComplete clinical regression following front-line chemotherapyBiochemical recurrence based on rising CA125FRONTIERS IN TUMOR MARKERS:PREDICTION OF REPONSE

10、 TO THERAPYBIOMARKERS TO PREDICT RESPONSE TO INDIVIDUAL DRUGS IN OVARIAN CANCERPlatinum 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

11、AgentsMultiple Drugs are Also Active for SalvageBIOMARKERS TO PREDICT RESPONSE TO INDIVIDUAL DRUGS IN OVARIAN CANCERClonogenic AssaysBiomarkers for Platinum Resistance-p53-ERCC1-Lack of Transporters-XIAPBiomarkers for Taxane Resistance-MDR1-Tubulin Mutations-HER-2-SurvivinBIOMARKERS TO PREDICT RESPO

12、NSE TO INDIVIDUAL DRUGS IN OVARIAN CANCERFuture Directions-Expression Array Analysis-Changes in Proteomic Profiles-Circulating Tumor Cells-New Therapies with Specific Targets-Molecular ImagingREVERSE PHASE PROTEIN LYSATE ARRAYS TO IDENTIFY ACTIVATED SIGNALING PATHWAYSFRONTIERS IN TUMOR MARKERS:EARLY

13、 DETECTION OF OVARIAN CANCER RATIONALE FOR OVARIAN CANCER SCREENINGOvarian 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 Cu

14、rrently Diagnosed in Stage IDetection of Preclinical Disease at an Earlier Stage Might Improve SurvivalMINIMAL REQUIREMENTS FOR OVARIAN CANCER SCREENINGPostmenopausal Prevalence: 40/100,000High Sensitivity: 75%Very High Specificity: 99.6%Positive Predictive Value: 10%APPROACHES TO SCREENING FOR EPIT

15、HELIAL OVARIAN CANCERUltrasonographySerum/Plasma/Urine MarkersTwo Stage StrategiesCA 125 FOR EARLY DETECTION OF OVARIAN CANCERElevated 10-60 Months Prior to DiagnosisDetects 50 - 60% of Stage I DiseaseSpecificity of a Single Determination is 99%, but This is Still InadequateCombination with Ultrason

16、ography can increase SpecificityCA 125 FOR EARLY DETECTION OF OVARIAN CANCERIn 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 Sequen

17、tiallySpecificity and Sensitivity can be Improved by Sequential Monitoring Over TimeAnalysis of Changes in CA 125 Over timeRising CA 125 Values are Associated with Ovarian CancerStable CA 125 Values, Even when Elevated, are Associated with Benign ConditionsA Computer Algorithm has been Developed tha

18、t Estimates Risk of Ovarian Cancer based on Change Point Analysis During Sequential Monitoring Over TimeAnalysis 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, 2019) RANDOMIZED TRIAL OF SCREENING WITH

19、 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 TW

20、O STAGE SCREENING STRATEGIES FOR OVARIAN CANCERCA125 Levels are 35 U/ml in 50-60% of Patients with Stage I Ovarian CancerUsing an Algorithm that Detects Disease when CA125 80% of ovarian cancer patients (Kruk et al 2019)HE4 IS A BIOMARKER BOTH FOR OVARIAN AND ENDOMETRIAL CANCERHE4 is as Sensitive as

21、 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 CancersPROTEOMIC ANALYSIS OF OVARIAN CANCER20002250250027502000225025002750N

22、ormalOvarian Cancer2000225025002750200022502500275020002250250027502000225025002750NormalOvarian CancerApplication 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 ca

23、n be analyzed in CombinationUSE 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) O

24、ver 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 UsedSTUDY DESIGN AND PATIENT FLOW FOR SAMPLES FROM FIVE ACADEMIC MED

25、ICAL CENTERSIdentification of Biomarkers from the Proteomic ProfileSeven 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-CTAPIIIMultiplex Assay of Multiple Antigens and Antibodies (Gore