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CancerBiomarkers: ClinicalAspectsand Laboratory Determination
ClinicalAspectsandLaboratoryDeterminationofBiomarkersSeries
SeriesEditor:AmitavaDasgupta
Volume1
AlcoholanditsBiomarkers:ClinicalAspectsandLaboratoryDetermination
Volume2
BiomarkersinInbornErrorsofMetabolism:ClinicalAspectsandLaboratory Determination
Volume3
EndocrineBiomarkers:ClinicalAspectsandLaboratoryDetermination
Volume4
KidneyBiomarkers:ClinicalAspectsandLaboratoryDetermination
Volume5
CancerBiomarkers:ClinicalAspectsandLaboratoryDetermination
CancerBiomarkers: ClinicalAspectsand Laboratory Determination
Editedby
LakshmiV.Ramanathan
DepartmentofPathologyandLaboratoryMedicine,MemorialSloan KetteringCancerCenter,NewYork,NY,UnitedStates
MartinFleisher
DepartmentofPathologyandLaboratoryMedicine,MemorialSloan KetteringCancerCenter,NewYork,NY,UnitedStates
MichaelJ.Duffy
UCDSchoolofMedicine,ConwayInstituteofBiomolecularand BiomedicalResearch,UniversityCollegeDublin,Dublin,Ireland; UCDClinicalResearchCentre,St.Vincent’sUniversityHospital, Dublin,Ireland
Elsevier
Radarweg29,POBox211,1000AEAmsterdam,Netherlands TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UnitedKingdom 50HampshireStreet,5thFloor,Cambridge,MA02139,UnitedStates
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Listofcontributors..................................................................................................xv
Preface....................................................................................................................xix
Acknowledgments..................................................................................................xxi
CHAPTER1Overviewoftraditionalandnontraditionaltumor markers.......................................................................... 1 JieliLi,QingH.MengandLakshmiV.Ramanathan Objectives......................................................................................1
1.1 Introduction....................................................................................1
1.2 Definitionandcharacteristicsoftumormarkers...........................2
1.3 Utilizationofserumtumormarkersinmalignantand benigntumors.................................................................................4
1.3.1Alphafetoprotein................................................................5
1.3.2CEA.....................................................................................5
1.3.3CA19-9................................................................................5
1.3.4CA15-3/CA27-29................................................................6
1.3.5CA125,HE4,ROMAscore(riskofovarian malignancyalgorithm)........................................................6
1.3.6Prostate-specificantigenandprostate-specific antigenderivatives..............................................................6
1.4 UnderstandFDAapprovedandnon-FDAapprovedtumor markers...........................................................................................7
1.5 Overviewofmethodologiesformeasurementof tumormarkers................................................................................8
1.5.1Clinicalsensitivityandspecificityoflaboratory tests....................................................................................12
1.6 Laboratorytechnologiesfortumormarkermeasurement...........14
1.6.1Immunoassaymethodologies............................................14
1.6.2Othertypesofimmunoassays...........................................15
1.7 Technicallimitationsofimmunoassays.......................................17
1.7.1Standardizationoftumormarkerassays..........................17
1.7.2Interferencesinimmunoassays.........................................19
1.8 High-pressureliquidchromatographymassspectrometry..........21
1.9 Methodsfordetectingnontraditionalandemergingtumor markers.........................................................................................23
1.9.1Metabolomicsandproteomics..........................................23
1.9.2Molecularandcompaniondiagnostics.............................24
3.3 Interferencesproducedbycancer................................................74
3.3.1Monoclonalproteins.........................................................74
3.3.2Choriogonadotropin..........................................................76
3.4 Physiologicchangesduetocancertreatment..............................78
3.4.1Menopause........................................................................78
3.4.2Stemcelltransplant...........................................................79
3.4.3Bonemarrowrecovery......................................................79
3.4.4Filgrastim..........................................................................80
3.5 Preanalyticalissues......................................................................81
3.5.1Pseudohyperkalemia.........................................................81
3.5.2Lactatedehydrogenase......................................................82
3.5.3Hemolysis..........................................................................83
3.5.4Contamination...................................................................83
3.6 Analyticalissues...........................................................................84
3.6.1Glucose-6-phosphatedehydrogenase................................84
3.6.2Therapeuticantibodies......................................................85
3.6.3Analyticsensitivitylowerrange.......................................86
3.6.4Analyticsensitivityhigherrange......................................87
3.7 Postanalyticalissues.....................................................................88
3.7.1Criticalvalues...................................................................88
3.8 Conclusionandfuturedirections.................................................89
3.9 Summarypoints............................................................................90 References....................................................................................90
CHAPTER4Thyroglobulinandthyroidcancer .............................. 93 WilliamS.Phipps,AndrewN.Hoofnagle, MaraY.RothandChristopherM.Shuford Objectives....................................................................................93
4.1 Introduction..................................................................................93
4.2 Thyroidnoduleevaluationandthelimitedroleof preoperativeserumthyroglobulinmeasurements........................94
4.3 Postoperativeevaluationofdifferentiatedthyroid cancer............................................................................................99
4.4 Thyroglobulininthemonitoringofdifferentiatedthyroid cancer..........................................................................................101
4.5 Utilizationofthyroglobulinautoantibodiesassurrogate marker.........................................................................................104
4.6 Themeasurementofthyroglobulinbyimmunoassaysand thechallengeofautoantibodies.................................................106
4.7 Thyroglobulinmeasurementbymassspectrometry usingpeptideimmunoaffinityenrichment.................................108
4.8 Thyroglobulinmeasurementbymassspectrometry—toward harmonization.............................................................................111
4.9 Thyroglobulinmeasurementbymassspectrometry—other challenges...................................................................................114
4.10 Practicalapplicationofthyroglobulinmeasurementbymass spectrometry:asuggestedapproach..........................................114
4.11 Thyroglobulinmeasurement—futuredirections........................117
4.12 Conclusion..................................................................................117
4.13 Summarypoints..........................................................................118
SigridV.Carlsson,KazunoriMurata,DanielC.Danila andHansLilja Objectives..................................................................................131
5.1 Introduction................................................................................132
5.2 PSA:physiologicalfunctionandanalyticalassay.....................132
5.3 PSAscreeningtrials...................................................................135
5.4 BaselinePSAstudiesandlong-termriskoflethalprostate cancer..........................................................................................139
5.4.1PSAvariation..................................................................139
5.4.2PSAasaprognosticmarker...........................................141
5.5 PSAasatumormarkerandscreeningtoolforprostate cancerandrecommendationsfromnationalguidelinegroups..146
5.6 PSA-relatedbloodbiomarkerstoimprovethespecificity ofPSAandruleouttheneedforprostatebiopsy.....................148
5.6.1PSAforms.......................................................................148
5.6.2BiomarkerstoimprovethespecificityofPSA..............149
5.6.34-Kallikreinpanel...........................................................150
5.7 MethodsofdetectingPSA.........................................................155
5.8 RoleofPSAinmonitoringdiseaserecurrenceand progression.................................................................................157
5.9 Conclusionsandfuturedirections..............................................159 Conflictofinterestdeclaration..................................................160 References..................................................................................160
CHAPTER6Monoclonalgammopathydetectionandcurrent technologies .............................................................. 173
ShelbyM.HutchersonandKatieL.Thoren Objectives..................................................................................173
6.1 Introduction................................................................................173
6.2 Monoclonalgammopathies........................................................174
6.3 CurrenttechnologiesforM-proteindetection...........................178
6.3.1Serumproteinelectrophoresis........................................178
6.3.2Immunofixationandimmunosubtraction.......................180
6.3.3Urineproteinelectrophoresisandimmunofixation........182
6.3.4Freelightchainquantitation...........................................185
6.3.5Testingguidelines...........................................................186
6.4 NewandemergingtechnologiesforM-proteindetection.........187
6.4.1Shiftassays......................................................................189
6.4.2Massspectrometry..........................................................191
6.4.3Currentstatusandpotentialroleofmass spectrometryforM-proteindetection.............................195
6.5 SummaryPoints.........................................................................197
6.6 Futuredirections.........................................................................197 References..................................................................................198
CHAPTER7Liquidbiopsyasacancerbiomarker-potential, andchallenges .......................................................... 203
DanielC.Danila
Objectives..................................................................................203
7.1 Introduction................................................................................203
7.2 Clinicalutilityofliquidbiomarkers..........................................204
7.3 Clinicaldevelopmentandvalidationofliquidbiomarkers.......205
7.3.1Contextofuse.................................................................205
7.3.2Analyticalvalidation.......................................................206
7.3.3Clinicalqualification.......................................................206
7.4 Circulatingtumorcells...............................................................207
7.4.1Themorphologyandcharacteristicsofcirculating tumorcells.......................................................................208
7.4.2Detectionmethods..........................................................210
7.5 CirculatingtumorDNA.............................................................221
7.6 Conclusion..................................................................................229
7.7 Summarypointsandfuturedirections.......................................229 Furtherreadings.........................................................................230 References..................................................................................230
CHAPTER8ChimericantigenreceptorTcellsand managementoftoxicities:implicationsof biomarkers ................................................................ 245 KitsadaWudhikarn,AnaAlarco´nToma ´ s, KazunoriMurataandMiguel-AngelPerales Objectives..................................................................................245
8.1 Introduction................................................................................246
8.2 ConstructandmanufacturingprocessofCD19chimeric antigenreceptorTcells..............................................................247
8.2.1Relapsed/refractorylargeB-celllymphoma...................247
8.2.2Relapsed/refractoryB-cellacutelymphoblastic leukemia..........................................................................249
8.2.3Relapsed/refractorymantlecelllymphoma....................249
8.2.4Relapsed/refractoryfollicularlymphoma.......................250
8.2.5Relapsed/refractorychroniclymphocytic leukemia..........................................................................250
8.3 Immune-mediatedtoxicitiesofCD19chimericantigen receptorT-celltherapy...............................................................250
8.3.1Cytokinereleasesyndrome.............................................251
8.3.2Immuneeffectorcell-associatedneurotoxicity syndrome.........................................................................254
8.3.3OtherchimericantigenreceptorTcell-associated toxicities..........................................................................255
8.4 ClinicalapplicationofbiomarkersinCD19chimeric antigenreceptorT-celltherapy..................................................255
8.5 Predictivebiomarkersofseverechimericantigen receptorandimmuneeffectorcell-associatedneurotoxicity syndrome....................................................................................256
8.5.1ChimericantigenreceptorT-celldose...........................256
8.5.2Tumorburden..................................................................257
8.5.3Inflammatorycytokines..................................................258
8.5.4SeruminflammatorymarkersincludingC-reactive proteinandferritin..........................................................260
8.5.5Preexistingendothelialactivation...................................261
8.6 Predictivebiomarkersforhematologictoxicities......................261
8.7 Predictivebiomarkersforhemophagocytic lymphohistiocytosisandmacrophageactivation syndrome....................................................................................262
8.8 Predictivemodelsforchimericantigenreceptorand immuneeffectorcell-associatedneurotoxicitysyndrome.........263
8.9 BiomarkersofchimericantigenreceptorT-cellresponse, outcome,andtreatmentfailure..................................................265
8.9.1ChimericantigenreceptorTcelland host-immune-basedbiomarkers......................................265
8.9.2Tumor-basedbiomarkers................................................267
8.10 Summarypointsandfuturedirections.......................................269 Disclosures.................................................................................270
Acknowledgment.......................................................................271 References..................................................................................271
CHAPTER9Cerebrospinalfluidcirculatingtumorcellsfor diagnosis,responseevaluation,andmolecular profilingofleptomeningealmetastasesfrom solidtumors .............................................................. 283 MariaDiaz,MartinFleisherandElenaI.Pentsova
Objective....................................................................................283
9.1 Introduction................................................................................283
9.2 Rarecellcapturetechnologyasadiagnostictoolfor leptomeningealmetastases.........................................................285
9.3 ClinicalLaboratoryImprovementActcertification..................288
9.3.1Definitionofacirculatingtumorcellusing theCellSearchcirculatingtumorcelltest......................289
9.3.2Specimenneededforcirculatingtumorcells enumerationincerebrospinalfluid.................................290
9.3.3Interpretationofresults...................................................290
9.3.4Qualitycontrolofcirculatingtumorcellsin cerebrospinalfluid..........................................................290
9.3.5Reportingresults.............................................................291
9.3.6Referencerange..............................................................291
9.4 Additionalapplicationsofcerebrospinalfluidcirculating tumorcellsandothertechniques...............................................291
9.5 LimitationsoftheCellSearchplatform.....................................293
9.6 SummaryPoints.........................................................................293
9.7 Futuredirections.........................................................................294 References..................................................................................294
CHAPTER10Salivaasamatrixformeasurementofcancer biomarkers ................................................................ 297 LucasTrevisanFranc¸adeLima,JulianaMu¨llerBark, MohammadRasheduzzaman,ChameeraEkanayake WeeramangeandChamindiePunyadeera
Objective....................................................................................297
10.1 Introduction................................................................................297
10.2 Salivaproductionandsecretion.................................................300
10.3 Transportofbiomoleculesfromthebloodintosaliva..............301
10.4 Salivacollectionmethodsandsalivatypes...............................303
10.5 Salivarybiomarkersforcancer..................................................305
10.5.1Saliva-basednucleicacidbiomarkersforcancer detection........................................................................305
10.5.2Protein-basedcancerbiomarkersinsaliva...................313
10.5.3Glycansandglycoproteomicbiomarkersforcancer....317
CHAPTER11Emergingtechnologiesincancerdetection
ZviYaari,ChristopherP.Horoszko, MeravAntman-Passig,MijinKim,FreddyT.Nguyen andDanielA.Heller
11.2.4Transducertrends:low-costpaperdevices..................358
11.5.2Precisionmedicine........................................................369
11.7 Dataanalytics.............................................................................375
11.7.1Facilitatingconventionalbiomarkerdiscovery............375 11.7.2Artificialintelligenceincancerdiagnosis....................376
11.7.3Potentialpitfallsinartificialintelligence based sensortechnology..........................................................377
11.8 SummaryPoints.........................................................................378
11.9 Conclusionsandfuturedirections..............................................378 References..................................................................................379
CHAPTER12Oncometabolitesandtheirroleincancer ............... 393 EmilyL.Gill,KhushbuPatelandDineshRakheja
Objective....................................................................................393
12.1 Introduction................................................................................393
12.2 Oncometabolitesandtheirassociatedcancers..........................395
12.3 Invitroprofilingandmeasurementofoncometabolites...........396
12.4 Omicsapproachestometaboliteprofilingincancers...............397
12.5 Imagingforoncometabolites.....................................................399
12.6 Recentinnovationsinoncometabolomics.................................400
12.7 MeasuringoncometabolitesD-2-hydroxyglutarateand L-2-hydroxyglutarateintheclinicallaboratory........................402
12.8 Conclusionandfuturedirections...............................................404
12.9 Summarypoints..........................................................................405 References..................................................................................405
CHAPTER13Circulatingcancerbiomarkers:currentstatusand futureprospects ........................................................ 409 MichaelJ.Duffy
Objectives..................................................................................409
13.1 Introduction................................................................................409
13.2 Clinicalusesofestablishedcirculatingproteinbiomarkers......410
13.2.1Screeningforearlycancer............................................410
13.2.2Evaluatingprognosisfollowingdiagnosisofa primarycancer..............................................................417
13.2.3Surveillancefollowingcurativesurgeryfor primarycancers.............................................................418
13.2.4Monitoringtheeffectivenessofsystemictherapyin advancedcancer............................................................420
13.3 Futuretrendsincancerbiomarkerapplicationsandongoing research.......................................................................................421
13.3.1CirculatingtumorDNA................................................422
13.3.2Circulatingtumorcells.................................................431
13.3.3Micro-RNA...................................................................433
Listofcontributors
MeravAntman-Passig
MemorialSloanKetteringCancerCenter,NewYork,NY,UnitedStates
SigridV.Carlsson
DepartmentsofSurgery(UrologyService)andEpidemiologyandBiostatistics, MemorialSloanKetteringCancerCenter,NewYork,NY,UnitedStates; DepartmentofUrology,InstituteofClinicalSciences,SahlgrenskaAcademyat UniversityofGothenburg,Gothenburg,Sweden
DanielC.Danila
DepartmentofMedicine,MemorialSloanKetteringCancerCenter,NewYork, NY,UnitedStates;DepartmentofMedicine,WeillCornellMedicalCollege, NewYork,NY,UnitedStates
MariaDiaz
DepartmentofNeurology,MemorialSloanKetteringCancerCenter,NewYork, NY,UnitedStates
MichaelJ.Duffy
UCDSchoolofMedicine,ConwayInstituteofBiomolecularandBiomedical Research,UniversityCollegeDublin,Dublin,Ireland;UCDClinicalResearch Centre,St.Vincent’sUniversityHospital,Dublin,Ireland
ChameeraEkanayakeWeeramange
SalivaandLiquidBiopsyTranslationalLaboratory,CentreforBiomedical Technologies,SchoolofBiomedicalSciences,FacultyofHealth,Queensland UniversityofTechnology,Brisbane,QLD,Australia;TranslationalResearch Institute,Brisbane,QLD,Australia;GriffithInstituteforDrugDiscovery (GRIDD),GriffithUniversity,Brisbane,Australia;DepartmentofMedical LaboratorySciences,FacultyofHealthSciences,TheOpenUniversityof SriLanka,Nugegoda,SriLanka
MartinFleisher
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
EmilyL.Gill
DepartmentofPathologyandLaboratoryMedicine,Children’sHospitalof Philadelphia,Philadelphia,PA,UnitedStates;DepartmentofPathologyand LaboratoryMedicine,UniversityofPennsylvania,Philadelphia,PA, UnitedStates
DanielA.Heller
MemorialSloanKetteringCancerCenter,NewYork,NY,UnitedStates; DepartmentofPharmacology,WeillCornellMedicine,NewYork,NY, UnitedStates;DepartmentofPhysiologyandBiophysics,WeillCornell Medicine,NewYork,NY,UnitedStates
AndrewN.Hoofnagle
DepartmentofLaboratoryMedicineandPathology,UniversityofWashington, Seattle,WA,UnitedStates;DepartmentofMedicine,UniversityofWashington, Seattle,WA,UnitedStates
ChristopherP.Horoszko
MemorialSloanKetteringCancerCenter,NewYork,NY,UnitedStates; DepartmentofPharmacology,WeillCornellMedicine,NewYork,NY,UnitedStates
ShelbyM.Hutcherson
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
MijinKim
MemorialSloanKetteringCancerCenter,NewYork,NY,UnitedStates
JieliLi
DepartmentofPathology,WexnerMedicalCenter,TheOhioStateUniversity, Columbus,OH,UnitedStates
HansLilja
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates;DepartmentsofSurgery(Urology Service)andMedicine,MemorialSloanKetteringCancerCenter,NewYork, NY,UnitedStates;DepartmentofTranslationalMedicine,LundUniversity, Malmo ¨ ,Sweden
HungS.Luu
Children’sHealthSystemofTexas,UniversityofTexasSouthwesternMedical Center,Dallas,TX,UnitedStates
SamuelI.McCash
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
QingH.Meng
DepartmentofLaboratoryMedicine,DivisionofPathologyandLaboratory Medicine,TheUniversityofTexasMDAndersonCancerCenter,Houston,TX, UnitedStates
JulianaMullerBark
SalivaandLiquidBiopsyTranslationalLaboratory,CentreforBiomedical Technologies,SchoolofBiomedicalSciences,FacultyofHealth,Queensland UniversityofTechnology,Brisbane,QLD,Australia;TranslationalResearch Institute,Brisbane,QLD,Australia;GriffithInstituteforDrugDiscovery (GRIDD),GriffithUniversity,Brisbane,Australia
KazunoriMurata
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
FreddyT.Nguyen
InstituteforMedicalEngineeringandScience,MassachusettsInstituteof Technology,Cambridge,MA,UnitedStates;DepartmentofPathology, MolecularandCell-BasedMedicine,IcahnSchoolofMedicineatMountSinai, NewYork,NY,UnitedStates
KhushbuPatel
DepartmentofPathologyandLaboratoryMedicine,Children’sHospitalof Philadelphia,Philadelphia,PA,UnitedStates;DepartmentofPathologyand LaboratoryMedicine,UniversityofPennsylvania,Philadelphia,PA,UnitedStates
ElenaI.Pentsova
DepartmentofNeurology,MemorialSloanKetteringCancerCenter,NewYork, NY,UnitedStates
Miguel-AngelPerales
AdultBoneMarrowTransplantation,DepartmentofMedicine,MemorialSloan KetteringCancerCenter,NewYork,NY,UnitedStates;Departmentof Medicine,WeilCornellCollegeofMedicine,NewYork,NY,UnitedStates
MelissaS.Pessin
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
WilliamS.Phipps
DepartmentofLaboratoryMedicineandPathology,UniversityofWashington, Seattle,WA,UnitedStates
ChamindiePunyadeera
SalivaandLiquidBiopsyTranslationalLaboratory,CentreforBiomedical Technologies,SchoolofBiomedicalSciences,FacultyofHealth,Queensland UniversityofTechnology,Brisbane,QLD,Australia;TranslationalResearch Institute,Brisbane,QLD,Australia;GriffithInstituteforDrugDiscovery (GRIDD),GriffithUniversity,Brisbane,Australia;MenziesHealthInstitute Queensland(MIHQ),GriffithUniversity,Queensland,Australia
DineshRakheja
DepartmentofPathologyandLaboratoryMedicine,Children’sHealth,Dallas, TX,UnitedStates;DepartmentofPathology,UniversityofTexasSouthwestern MedicalCenter,Dallas,TX,UnitedStates
LakshmiV.Ramanathan
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
MohammadRasheduzzaman
SalivaandLiquidBiopsyTranslationalLaboratory,CentreforBiomedical Technologies,SchoolofBiomedicalSciences,FacultyofHealth,Queensland UniversityofTechnology,Brisbane,QLD,Australia;TranslationalResearch Institute,Brisbane,QLD,Australia;GriffithInstituteforDrugDiscovery (GRIDD),GriffithUniversity,Brisbane,Australia
MaraY.Roth
DepartmentofMedicine,UniversityofWashington,Seattle,WA,UnitedStates
ChristopherM.Shuford
LaboratoryCorporationofAmericaHoldings,Burlington,NC,UnitedStates
KatieL.Thoren
DepartmentofPathologyandLaboratoryMedicine,MemorialSloanKettering CancerCenter,NewYork,NY,UnitedStates
AnaAlarco ´ nToma ´ s
AdultBoneMarrowTransplantation,DepartmentofMedicine,MemorialSloan KetteringCancerCenter,NewYork,NY,UnitedStates;PhDPrograminSignals IntegrationandModulationinBiomedicine,CellTherapyandTranslational Medicine,UniversityofMurcia,Murcia,Spain
LucasTrevisanFranc¸adeLima
SalivaandLiquidBiopsyTranslationalLaboratory,CentreforBiomedical Technologies,SchoolofBiomedicalSciences,FacultyofHealth,Queensland UniversityofTechnology,Brisbane,QLD,Australia;TranslationalResearch Institute,Brisbane,QLD,Australia;GriffithInstituteforDrugDiscovery (GRIDD),GriffithUniversity,Brisbane,Australia;GallipoliMedicalResearch Institute,GreenslopesPrivateHospital,Brisbane,QLD,Australia
KitsadaWudhikarn
AdultBoneMarrowTransplantation,DepartmentofMedicine,MemorialSloan KetteringCancerCenter,NewYork,NY,UnitedStates;DivisionofHematology andResearchUnitinTranslationalHematology,DepartmentofMedicine, ChulalongkornUniversity,Bangkok,Thailand
ZviYaari
MemorialSloanKetteringCancerCenter,NewYork,NY,UnitedStates;School ofPharmacy,FacultyofMedicine,TheHebrewUniversityofJerusalem,Israel
Preface
Cancerisaleadingcauseofdeathworldwidewithalmost10million casesin2020perestimatesoftheWHO.In2020themostcommon causesofcancerdeathswereattributedtomalignanciesofthelung, colonandrectum,liver,stomach,andbreast.Approximately, 400,000childrenarediagnosedeveryyear,worldwide.
Giventheenormousmagnitudeandcomplexityofthisdisease process,therehavebeenremarkableachievementsovertheyears fordetecting,monitoring,andtreatmentofcancer.Theearlierthe detection,thebetterarethechancesforsuccessfultreatment. However,despitedecadesofbasicresearchinvolvingbiomarkers, fewerthan25havebeenapprovedbytheUSFoodandDrug Administrationasthejourneyofabiomarkerfromthebenchtothe bedsideiscomplexandchallenging.Thereasonforthisisthat extensivevalidationstudiesarerequiredtobedoneforanybiomarkertobeclinicallyimplemented.
Inthisbook,thatispartoftheseriesonbiomarkerspublishedby Elsevier,thefocusisoncancerbiomarkers,clinicalaspects,and laboratorydetermination.Asthebookistargetedformedicalstudents,physicians,oncologists,pathologists,clinicalchemists,and medicaltechnologists,wehavefocusedonfourareas.Thefirstsection,Chapters1 3,discusstheoverviewoftraditionalandnontraditionalbiomarkersfollowedbylaboratorytestinginpediatricaswell asadultcancerpatients.Emphasisisplacedontheuniquechallengesinthemanagementofthesetwosegmentsofthecancer patientpopulation.ThisisfollowedbyChapters4 6thatfocuson prostate-specificantigen,thyroglobulin,andmonoclonalproteins. Chapters7 9discussliquidbiopsy,chimericantigenreceptorTcelltherapies,andthevalidationofcirculatingtumorcellsandcellfreeDNAincerebrospinalfluid.Thefourthsectionthatincludes Chapters10 12assessesemergingtechnologiesaswellasdifferent
platformsinbiomarkertestingwithsummary,conclusions,andfurtherdirection.Finally,Chapter13broadlysummarizesthecurrent statusofstandardcancerbiomarkersanddiscusseslikelyfuture developmentswithcirculatingtumorDNA,circulatingtumorcells, andextracellularvesicles.
Editors
LakshmiV.Ramanathan
MartinFleisher
MichaelJ.Duffy
Acknowledgments
Ourapproachtothisbookdedicatedtomedicalstudents,oncologists,physicians,clinicalchemists,andmedicaltechnologistsisto givethemanideaofchallengesfacedwithadultandpediatric patientsininterpretinglaboratorytestresults,stepsrequiredforthe completevalidationofabiomarkerbeforeitisintroducedinclinical practice,acomprehensivediscussiononselectedbiomarkersand emergingplatforms,andtestingforbiomarkers.
Keepingouroverallperspectivesofthebookinmind,ithasbeen asheerpleasureforustoworkwithourauthorsbothwithinand outsideMemorialSloanKetteringCancerCenter.Theirsupportand enthusiasmforourendeavorisreallyappreciatedaswellastheir timelysubmissionofchaptersandresponsetoourquestions.Weare gratefultoourpublisherswhohavebeenamazinglypatientand helpfulthroughoutthisjourney.
Notenoughcanbesaidregardingourcolleaguesinclinical chemistrywhohaveworkedinourlaboratoriesformanyyearsvalidatinglaboratorydevelopedtests,performingrequiredroutinetasks, andalwaysgivingtheir100%totheirwork.Theseincludeourlaboratoryassistants,benchtechnologists,supervisors,managers,and fellowclinicalchemists.Theirhardworkandsupportcannotbe measuredaswellastheirdedicationtoourcancerpatients.Ourclinicalcolleagueshavebeenamazingandsupportiveasisevidentfrom theircontributionstoourbook.Wewouldespeciallyliketo acknowledgeDrs.PeterMaslakandMikeTuttlewhoprovidedvaluablefeedbackandcommentsforChapters2and4.Aspecialvoteof thankstoouradministratorEvelinPoncewhoworkedwithour schedulesandarrangedourweeklyzoomcalls.
Finally,oursupportfromourfamiliesovertheyearscannotbe measuredandwearetrulygratefultothem.Thiswasatrulycollaborativeteameffortamongthethreeofus,anditwasanhonortobe associatedwiththisventure.
LakshmiV.Ramanathan MartinFleisher MichaelJ.Duffy
Overviewoftraditional andnontraditionaltumor markers
1
JieliLi1,QingH.Meng2 andLakshmiV.Ramanathan3
1DepartmentofPathology,WexnerMedicalCenter,TheOhioState University,Columbus,OH,UnitedStates
2DepartmentofLaboratoryMedicine,DivisionofPathologyand LaboratoryMedicine,TheUniversityofTexasMDAndersonCancer Center,Houston,TX,UnitedStates
3DepartmentofPathologyandLaboratoryMedicine,MemorialSloan KetteringCancerCenter,NewYork,NY,UnitedStates
Objectives
•Reviewlaboratorytestsusedincancerdiagnosis.
•Definecharacteristicsoftumormarkers.
•ListFDAapprovedversusnon-FDAapprovedtumormarkers.
•Understandoverviewofdifferentmethodologiesusedfortumor markermeasurement.
•Explainroleofnontraditionaltumormarkersandtheirpotential scope.
•Discussfuturedirections.
1.1 Introduction
About10milliondeathswerereportedin2020worldwidedueto cancerorcancer-relatedconditions [1].Ithasbeenshownthatearly diagnosiscandramaticallyimprove5-yearsurvivalfrom21%to 89%forallcancersand5%to56%forlungcancer [2].Thisis mainlyduetotechnologicaladvancementsinlaboratorymedicine
withthemeasurementofbiomarkers,inpathologywithexamination oftissueandinradiologywithimagingstudies.
Cancerbiomarkersinvolvemeasurementofproteins,peptides,biochemicals,DNA,andRNA.Theycanbefurthercategorizedaspredictive,diagnostic,orprognostic.Theseincludegenetic,transcriptive, epigenetic,andproteomicbiomarkers.Theycanbedetectedinbiologicalfluidsincludingwholeblood,serum,plasma,fluids,urine,stool, sputum,andnippledischarge [3].Identifyingbiomarkerscanpredict responsetotreatmentthatisvitalforthesuccessofprecisionandtargetedtherapyincancerpatients.CurrentlytheUSFoodandDrug Administration(FDA)hasapproved23proteincancerbiomarkers,of whichonly16aredetectableinblood [4].However,thesebiomarkers donotdemonstratehighsensitivityandspecificityforclinicaldiagnosis whenemployedalone.
Diagnostictestingfortumorsi snotonlylimitedtoclinical chemistrybutalsoincludesimmunology;hematology;hematopathology;thepathologicaland histologicalexaminationof biopsy,genetic,genomic,andmolec ulartesting(liquidbiopsy); imagingtests(X-ray,computerizedtomography,ultrasound,magneticresonanceimaging,single-photonemissioncomputerized tomography,andpositronemissi ontomography);andmolecular imaging.Blood,tissues,andbodyfluidsarethemostcommon specimensinclinicallaboratorytesting.Bodyfluidsfortumor markertestingincludecerebrospin alfluid(CSF),saliva,effusions,andurine.
1.2 Definitionandcharacteristicsoftumormarkers
Tumormarkersaredefinedassubstancesfoundintissue,blood, bonemarrow,orotherbodyfluids thatmaybeindicativeofcancerorcertainbenign(noncance r)conditions.Manytumormarkersareproteinsmadebybothnormalcellsandcancercells,but theyaremadeinhigheramountsb ycancercells.Geneticchanges intumortissue,suchasgenemutations,patternsofgeneexpression,andotherchangesintumorDNAorRNA,arealsobeing usedastumormarkers.Atumormarkermaybeusedwithother teststohelpdiagnosecancer.Itmayalsobeusedtohelpplan
FIGURE1.1
100yearsoftumormarkerdevelopment. ACTH,adrenocorticotropic hormone; AFP,alphafetoprotein; CA,carbohydrateantigen; CEA, carcinoembryonicantigen; ct,circulatingtumor; EGFr,humanepidermal growthfactorreceptor; ER,estrogenreceptor; hCG,humanchorionic gonadotropin; NGS,nextgenerationsequencing; NSE,neuronspecific enolase; PAP,prostaticacidphosphatase; PR,progesteronereceptor; WGA,wholegenomeanalysis.
treatment,givealikely prognosis,andmonitorthepatient’s responsetotherapy.
Traditionaltumormarkerdevelopmentoverthelastfewdecades hasbeenrelativelyslowandchallengingwiththetimelineshownin Fig.1.1.
Tumormarkersinclude:
•Enzymes
•Hormonesandhormonemetabolites
•Oncofetalantigens
•Carbohydratemarkers
•Bloodgroupantigens
•Proteinssuchas β2-microglobulinandimmunoglobulins
•Receptors
•RNAs
•DNA
Table1.1 presentsasummaryoftumormarkersthathaveadequatespecificityandsensitivityforuseinprognosis,detectionof recurrence,andmonitoringresponsetotreatment.
Table1.1 Themajortumormarkersusedforprognosis, treatmentmonitoring,andrecurrencedetection.
UtilityTumormarkers
Prognosis
β2-Microglobulin
CA125
AFP,PSA,CEA
Lactatedehydrogenase
HER2/neu
Estrogenreceptor
Progesteronereceptor
MonitoringtreatmentCA125
CA19-9 CEA
AFP hCG PSA
DetectionofrecurrenceCA15-3 CA125 CEA
AFP hCG PSA
1.3 Utilizationofserumtumormarkersin malignantandbenigntumors
Despitethechallengesandinterferenceswithimmunoassaymethodologiesfortumormarkers,theirmeasurementsarereadilyavailableonautomatedplatformsthatarerelativelyinexpensiveand easytouse.Althoughtheirpotentialutilityinscreeningthegeneralpopulationislow,theyarewidelyusedforthedifferential diagnosisofsymptomaticpati entsandmonitoringtherapy. Overall,theyhavelimiteduseforearlydetection,clinicalstaging ofcancer,andestimatingtumorvolume.Althoughspecifictumor markersarediscussedindetailin otherchaptersinthisbook,we
