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 DEVELOPMENT More than 400 New Drugs are Being Developed for Clinical Trials Many Targeted D
2、rugs 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 CytostaticOBrien et al.Tumor Biology 2019CA 125 TO ACCELERATE PHASE II CLINICAL TRIALS Surrogate Marker for Respo
3、nse 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 o
4、f 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 TRIALS CA 125 as
5、 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 TrialsCompar
6、ison 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 DRUGS Monitor Response to New Cytostatic Drugs-Many Ta
7、rgeted 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 of 400 mg daily*Re
8、gimen 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 T
9、UBE,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 CA125FRONTIERS IN TUMOR MARKERS:PREDICTION OF REPONSE TO THERAPYBIOMARKER
10、S 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%Dont Benefit Difficult to Study These Drugs as Individual Agents Multiple Drugs a
11、re Also Active for SalvageBIOMARKERS 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-SurvivinBIOMARKERS TO PREDICT RESPONSE TO INDIVIDUAL D
12、RUGS IN OVARIAN CANCER Future 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 DETECTION OF OVAR
13、IAN 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 S
14、tage I Detection of Preclinical Disease at an Earlier Stage Might Improve SurvivalMINIMAL 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 U
15、ltrasonography Serum/Plasma/Urine Markers Two Stage StrategiesCA 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
16、 SpecificityCA 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
17、Sensitivity can be Improved by Sequential Monitoring Over TimeAnalysis 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 O
18、varian 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 THE CA125 ALGORITHM AND UL
19、TRASOUND 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 F
20、OR 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 80%of ovarian cancer patients(Kruk et al 2019)HE4 IS A BIOMARKER BOTH FOR OVARIAN AND ENDOMETRIAL CANCER HE4 is as Sensitive as CA 125 for detecting Ovarian
21、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 CancersPROTEOMIC ANALYSIS OF OVARIAN CANCER20002250250027502000225025002750NormalNormalOvarian Ovarian Cance
22、rCancer2000225025002750200022502500275020002250250027502000225025002750NormalNormalOvarian Ovarian CancerCancerApplication 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 Assay
23、s that can 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 a
24、l)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 UsedSTUDY DESIGN AND PATIENT FLOW FOR SAMPLES FROM FIVE ACADEMIC ME
25、DICAL CENTERSIdentification 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-Apolipop
26、rotein A1-Truncated Transthyretin-CTAPIIILuminexLuminex Assay AssayMultiplex Assay of Multiple Antigens and Antibodies(Gorelik,2019)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 8
27、6%Sensitivity and 93%Specificity for Early Stage Disease Recently,they have analyzed some 40 biomarkers with increased Sensitivity and SpecificityFRONTIERS IN TUMOR MARKERS CA 125 could facilitate and accelerate Drug Evaluation by serving as a Surrogate Endpoint for Response in Phase II Clinical Tri
28、als 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
