Zengliu (Leo) Su Clinical Chemistry Postdoctoral Fellow Department of Pathology & Laboratory Medicine Medical University of South Carolina

Charleston, SC 29425 E-mail: suzze@musc.edu

 Ihavenorelevantfinancialrelationships todisclose

 Introduction Biomarkers ClinicalApplicationofCA125

Aclinicaltrialstirscontroversy

ClinicalApplicationofHE4 AlgorithmsfortheEstimationoftheriskof ovariancancerinwomenwithpelvicmass

ROMA OVA1

Introduction
Ovarian cancer are developed from three categories of cells
1. Epithelial Cells (90%)
a) b) c) d) e) Serous (50%) Mucinous (5-10%) Endometrioid (10-25%) Clear: 4-5% Transitional: rare

2. Sex Cord Cells 3. Germ Cells

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Introduction
OvarianCanceristheFifthMostfrequentcause ofdeathfromCancerinwomen
EstimatedNewCases EstimatedDeath

Siegel et al. CA CANCER J CLIN 2012

Introduction
Because Ovarian cancer cause few specific symptoms, >70% of patients are diagnosed with advanced disease. 5 year survival rates < 30% 25% are diagnosed with stage I: 5 year survival rate up to 90% Stage II: 5 year survival rate up to 70% Early detection has great promise to improve clinical outcome
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DiagnosisofOvarianCancer
Earlydetectionisnotaneasytask. Images:Transvaginal Ultrasound,MRI,CT,PET TumorMarkers.CA125andHE4areonlytwo markersapprovedbyFDAformonitoringthe diseaseprogression. HistologicalExamination Atpresent,noscreeningtestarerecommendedfor earlydetectionofovariancanceringeneral population.
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TumorMarkersassociatedwithOC

Cramer et al. Cancer Prev Res; 2011

UseofMultipleBiomarkersintheEarly DiagnosisofOvarianCancer
Panels CA125, Eotaxin-1, CEA, HE4 CA 125, HE4, CEA, and VCAM-1 CA 125, OVX1, LASA, CA15-3, CA 72-4 CA 125, TT, Apo A1, ITIH4 CA 125, CA 72-4, CA 15-3, M-CSF IL-6, IL-8, VEGF, EGF, CA-125 CA-125, Prolactin, Osteopontin, CA 125 Sensitivity Specificity 96.10% 95.7 85.40% 74% 71% 84% 90% 95% 95% 83.10% 97% 98% 95% 95% 95% 95% 95% 98% References
[Yurkovetsky et al] [Yurkovetsky et al] [Rosen et al.] [Fujiwaki et al.] [Levina et al] [Gorelik et al] [Visintin et al] [Visintin etal] [Mooreetal] [Mooreetal] [Clarkeetal]

CA-125, Prolactin, Osteopontin, CA 125, Leptin, MIF 90% CA125, HE4, CA 72-4, SMRP CA125, HE4, CA 72-4, SMRP, Osteopontin TT, ApoA1, ITIH4, CTAPIII 38.4% 38.5% 88%

ClinicalapplicationofCA125
Introduction
Discoveredwithamousemonoclonalantibody (OC125)producedbyimmunizingamousewitha serousovariancancercellline Glycoproteinwithahighmolecularweight(>200kD) Increasedinmostovariancancers. Alsoincreasedin~0.25.9%healthywomenand2.2 27.8%patientswithbenignovariandiseases.

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ClinicalapplicationofCA125

Markowska et al. Eur J Gynaecol Oncol; 1992

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ClinicalapplicationofCA125
MonitoringTreatmentResponse GCIG(GynecologicalCancerIntergroup) criterion:
Atleast50%ofCA125decreasecomparedwith thepretreatedsample Completeresponder:CA125concentrationsfall withinthereferencerangeaftertreatment.

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ClinicalapplicationofCA125
MonitoringRecurrence GCIGrecurrencecriteria:
ForpatientswithnormalizedCA125levelafter treatment:CA1252timesoftheupperlimitof thereferenceontwooccasionsatleast1week apart. ForpatientswhoseelevatedCA125levelnever normalizeaftertreatment:CA1251252times ofthenadirvalueontwooccasionsatleast1 weekapart.
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Arandomizedclinicaltrial
Completeremissionafterfirstlinechemotherapy NormalCA125concentrations Every3months Physicalexamination Qualityoflifeassessment CA125 IfCA1252timesofthenormalupperlimit, patientswererandomlyassignedto 1) Earlytreatment:ASAPwithin28days. 2) Delayedtreatment:untilclinicalrecurrence

Rustinetal.thelancet;2010.

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Nodifferencewereobservedinoverallsurvival benefitbetweenearlyanddelayedtreatment

Rustinetal.thelancet;2010.
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Asignificantnegativeeffectonthequalityof lifeintheearlytreatedgroupwasobserved

Rustinetal.thelancet;2010.

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LimitationsandCritics
1. CTscanwasnotperformedtoshowhowmuch residualcanerremainsafterfirstlinetreatment. 2. Patientsdidnotreceivethesametreatments afterrecurrence. 3. AdoublingofCA125upperlimit(GCIGcriteria) cannotbeassumedtobeoptimalcutofffor detection.

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ClinicalapplicationofCA125
OtherRecurrenceCriteria Liuetal.2010,JournalofClinicalOncology.
ForpatientswithCA125nadir10U/mL:CA 12520U/mL. ForpatientswithCA125nadir>10U/mL:CA 1252timesofthenadirvalue.

Prat etal.2009,AnnalsofOncology
AnabsoluteincreaseofCA125level5U/mL comparedwithitsnadirvaluewasastrong predictorofrecurrence.
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ClinicalapplicationofHE4
Humanepididymisprotein4,amemberofthestable4 disulfidefamily Theexactfunctionhavenotbeencharacterized. Overexpressedin93%ofserous,100%ofendometrioid and 50%ofclearcellovariancancer Notexpressedinmucinousandgermcellovariancancers. Lessfrequentlyexpressedinsomebenignovariandiseases comparedtoCA125

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ClinicalapplicationofHE4
Monitoringthediseaseprogression
HE4correlatedbetterwiththePET/CTresultsascompared toCA125. HE4increased58monthbeforeCA125inrelapsedovarian cancer.

Hynninen etal.InternationalJournalofGynecological2011

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Estimationoftheriskofovariancancer inwomenwithpelvicmass
ROMA(RiskofOvarianMalignancyAlgorithm)
AquantitativeserumtestthatcombinesHE4,CA125and

menopausalstatusintoanumericalscore. Toassesswhetherawomanwhopresentswithanovarianadnexal massisathighorlowlikelihoodoffindingmalignancyonsurgery Calculation:

Premenopausal: PredicativeIndex(PI)=12.0+2.38*LN[HE4]+0.0626*LN[CA125] Postmenopausal: PredicativeIndex(PI)= 8.09+1.04*LN[HE4]+0.732*LN[CA125] ROMA= exp(PI)[1+exp(PI)]*10

Acutoffof1.31and2.77wereusedforpre andpostmenopausal womenwithanovarianadnexalmass,respectively,toprovidea specificitylevelof75%.

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Estimationoftheriskofovariancancer inwomenwithpelvicmass
ROMA(RiskofOvarianMalignancyAlgorithm)

Mooreetal.GynecologicalOncology;2009

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Estimationoftheriskofovariancancer inwomenwithpelvicmass
OVA1 Combine5serummarkersCA125,transthyretin (prealbumin),
apolipoprotein A1,2microglobulin,transferrinandmenopausalstatusinto anumericalscore. Toassesswhetherawomanwhopresentswithanovarianadnexalmassisat highorlowlikelihoodoffindingmalignancyonsurgery Calculation: Theuserentersresultsofthefiveanalytes manuallyintoaExcelspreadsheet togetherwiththeheadersneededbyOvaCalc software.Thesoftwarewill generateanumericalscorefrom0.0to10.0. Acutoffof5.0and4.4wereusedforpre andpostmenopausalwomen withanovarianadnexalmass,respectively.

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Estimationoftheriskofovariancancer inwomenwithpelvicmass
OVA1

Specificity, % 95% CI

Abrahametal.CommunityOncology;2010

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Summary
Challengestillexistsfortheearlydiagnosisof ovariancancer. The use of multiple serum markers for the early diagnosis has not yet been established. CA125andHE4aretwomarkersapprovedbyFDA formonitoringovariancancerprogression. FDAapprovedtwoalgorithms,ROMAandOVA1, toestimatetheriskofovariancancerinwomen withpelvicmass.

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