From CEA to Complexomics and How to Get There Mark A Watson MD PhD Assoc Professor Pathology and Immunology Div Of Laboratory and Genomic Medicine Washington University School of Medicine ID: 1006741
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1. The Arena of Liquid BiopsyFrom CEA to Complexomics, and How to Get ThereMark A. Watson, MD, PhDAssoc. Professor, Pathology and ImmunologyDiv. Of Laboratory and Genomic MedicineWashington University School of Medicine** No conflicts of interest to disclose
2. Liquid Biopsy in the Continuum of Cancer CareEarly detection decreases cancer mortalityTargeted (expensive) therapies require repeated companion diagnostic assays- often from inaccessible solid tumor sitesEffective primary treatment renders many malignancies a disease requiring on-going surveillance- for clinically occult progressionScreening and Early DetectionPrecision DiagnosisTherapeutic ResponseMonitoring RemissionRelapse Precision Diagnosis
3. Evolving Complexity in Liquid Biopsy AssaysSingle Biomarker AssaysCEACA14.3PSAHomotypic Biomarker Panels4KscorectDNA panelsMulticomponent Testing StrategiesctDNA + Protein (CancerSEEK)ctDNA + CTCCTC + ExosomesExpansive understanding of cancer biologyNew technologies for detecting rare analytesNovel bioinformatic (AI) approaches to synergize disparate data types Challenges to create integrative testing platforms
4. CTCs: Populations of complex packets of diagnostic information that mediate malignant progressionCapture / EnrichmentDissection or ReleaseIHC / ISH Multi-marker assessmentR. Core / S. Rawal / C. YangAI-guided image analysesSingle cell expression population profiling(Pre-Rx, DTC-enriched)Cytomorphology+Targeted Biomarkers+Molecular Profiles
5. EVs: Discrete, complex packets of diagnostic information that mediate tumor behaviorEVsSurface AntigensCD63CD81ErbB2EGFRvIIIEpCAMCD86miRNAs21200a,b,c141101124643064644DNA MutationMethylationKRASBRAFEGFRp16Whole Blood / PlasmaEV fractionationAntigen based capture / detectionLysismiRNA probesMethylation loci probesmutation probesDetection = f (Sa, Sb1-3, Sc1-3, Sd)Fractionation, Detection, Quantification in a Homogeneous Assay
6. Components of Neoplastic Progression as Liquid Biopsy Targets“SEEDS”CTCs / cCAFscfNAProteinsSoluble Biomarkers“FERTLIZER”EVs“SOIL”Metastatic NicheOccult ReservoirsA multi-component analysis may improve diagnostic utility
7. Multi-component AnalysesComparison and Synergy Between CTC and cfDNA analysesTNBC in neoadjuvant setting142 ctDNA ; 123 CTC analysesFoundationOne ctDNA assayEpCAM based CTC capture / enumerationRadovich, et al. JAMA Oncology, 2020. PMCID: PMC7349081Fewer Comparative Exosome <> CTC studies Unique opportunities for cross-platform comparisons using reference sets
8. The Evolution of Biospecimen- Based Biomarker Research 1971 FFPE Tumor BlockPathology ReviewSimpler trial designTissue and bloodLimited biomarkersLimited technologies 2021Peripheral Blood CellsPlasmaFFPE TissueFresh TissueStoolUrineBuffy CoatPBMCCTCDNA; GenotypingImmunoprofilingMRD AssessmentPK / PDProteomicsMetabolomicscfNAExosomesMRD AssessmentBiomarkersSerumIHCSpatial ProfilingGenomicsPDX ModelsSingle Cell / ExpressionMethylationcfNADigital Imaging / AIMetagenomicsTimepoint:Pre-RX - CNDX - Surgery - Post-RX - RelapseSpecialized collection tubesShipping kitsAdvanced biobanking proceduresExpanded StorageInformaticsComplex trial designsMultiple assay timepointsMultiple analytesMultiple biomarkersSophisticated technology platformsRequirement for viable specimensDemand for control of pre-analytical variabilityBiospecimen tracking and data integration over multiple laboratories and assay platforms
9. Resource Requirements to Advance the FieldProspective collection may require years of ‘clinical maturation’Robust- Abundant- Accessible- Annotated biospecimen resources needed for assay validationAppropriate control populationsRacial / ethnic / gender diversitySerial CollectionsWide variety of sample typesStandardized clinical data and follow upDocumenting pre-analytical variabilityCost, Time, Effort, Space
10. Documenting Pre-analytical VariabilitySPREC- (Standard PREanalytical Coding of Biospecimens)Cancer Epidemiol Biomarkers Prev 2010, 19; 1004BRISQ- (Biospecimen Reporting for Improved Study Quality)J Proteome Res., 2011; 10(8): 3429–3438.
11. WUSTL Women’s Health RepositoryPI: G. ColditzRecruited 12,288 women from 2008-2012Baseline collection of plasma and PBL121,166 sample aliquotsEHR clinical data follow-upRoutine screening mammogramsIncident benign biopsy and malignant tumor tissuesMedian Age 54.8 years26.7% African AmericanAverage 9.7 years follow-up272 (2.2%) incident malignancies at 10 years; 116 in situ lesions
12. NCI ResourcesEDRN Biospecimen Reference SetsMultiple Cancer Types100-900 patient cohortsSerum, Plasma, (Tissue)Specimen Resource LocatorNCTN Biospecimen Resource
13. ALLIANCE A212102ALLIANCE A212102Blinded Reference Set for Multicancer Early Detection Blood TestsM. Wood; M. LiuPrimary Objective- To provide a blinded reference set of cancer vs. non-cancer blood samples that will be used to validate assays for inclusion in a prospective clinical trial focused on utility of blood-based multi-cancer early detection.Utilizes existing NCTN infrastructure to manage recruitment, and sample and data collection across numerous network sites1,000 patients with a confirmed histological diagnosis of any 1 of 19 tumor types1,000 healthy controls with no history of malignancy6 x 10 ml of blood in Streck BCT tubes Collection at baseline and (optional) 12 monthsA model for future resource creation
14. SUMMARYLiquid biopsy is a critical tool for the long-term management of many cancer patients, akin to those used in other chronic health conditions.New technologies are creating increasingly sophisticated biomarker assay platforms; opportunities and challenges for controlled comparisons and integrations across multi-modal assays exist.Equally important to the biomarkers and the technologies that support their implementation, is robust access to biospecimens and data for statistically defensible validation studies.Academic, investigative consortiums are critical to realize opportunities for assay integration and creation of need validation resources.