MeasurementofSerumLevelsofMacrophageInhibitory Cytokine1CombinedwithProstate-Specific Antigen ImprovesProstateCancerDiagnosis David A.Brown, 1,2 CarstenStephan, 5 RobynL.Ward, 2 MathewLaw, 3 MarkHunter, 1,2 AsneR.Bauskin, 1,2 Janaki Amin, 3 Klaus Jung, 5 EleftheriosP.Diamandis, 6 GarretM.Hampton, 7 Pamela J.Russell, 4 GrahamG.Giles, 8 andSamuelN.Breit 1,2 Abstract Purpose: Current serum testing for the detectionof prostate cancer (PCa) lacks specificity. Ondiagnosis,theoptimaltherapeuticpathwayisnotclearandtoolsforadequateriskassessment oflocalizedPCaprogressionarenotavailable.Thisleadstoasignificantnumberofmenhaving unnecessarydiagnosticbiopsiesandsurgery.Asearchfornoveltumormarkersidentifiedmacro- phageinhibitorycytokine1(MIC-1)asapotentiallyusefulmarker.Follow-upstudiesrevealed MIC-1overexpressioninlocalandmetastaticPCawhereasperitumoralinterstitialstainingfor MIC-1identifiedlower-gradetumorsdestinedforrecurrence.Consequently,wesoughttoassess serumMIC-1measurementasadiagnostictool. Experimental Design: UsingimmunoassaydeterminationofserumMIC-1concentrationin 1,000men,538ofwhomhadPCa,wedefinedtherelationshipofMIC-1todiseasevariables. A diagnostic algorithm (MIC-PSA score)basedonserumlevelsofMIC-1,totalserumprostate- specificantigen,andpercentageoffreeprostate-specificantigenwasdeveloped. Results: SerumMIC-1wasfoundtobeanindependentpredictorofthepresenceofPCaand tumorswithaGleasonsum z7.We validated the MIC-PSA score in a separate population andshowedanimprovedspecificityfordiagnosticbloodtestingforPCaoverpercentageoffree prostate-specificantigen,potentiallyreducingunnecessarybiopsiesby27%. Conclusions: SerumMIC-1isanindependentmarkerofthepresenceofPCaandtumorswitha Gleasonsumof z7.TheuseofserumMIC-1significantlyincreasesdiagnosticspecificityandmay beafuturetoolinthemanagementofPCa. Prostate cancer (PCa) is the most common male noncutaneous malignancy in the Western world, with 232,090 estimated new cases and 30,350 estimated deaths in the United States annually (1). However, cross-sectional postmortem studies estimate that PCa will spread in only 25% of men with histologically defined disease (2). Reliable tools for diagnosis and prediction of cancer progression are desirable but have been elusive to date. Currently, measurement of total serum prostate-specific antigen is the most widely used tool for early detection, sta- ging, and monitoring of PCa (3). Although total serum prostate-specific antigen is almost organ specific, it is not cancer specific, with elevated serum levels found in benign prostatic diseases. Approaches have been developed to improve the specificity of total serum prostate-specific antigen for the detection of PCa (4). The most successful of these, measurement of alternative molecular forms of prostate- specific antigen, expressed as the percentage of free prostate- specific antigen, improves the diagnostic specificity of prostate-specific antigen testing (5, 6) and can decrease the number of negative prostatic biopsies by 20% to 25% (7, 8). In an attempt to improve the specificity of PCa diagnostics, microarray technology has been used to identify a number of mRNA species modulated in PCa. Notable among these is macrophage inhibitory cytokine 1 (MIC-1; ref. 9), a divergent member of the transforming growth factor-h superfamily. MIC-1 was originally identified by some members of our group on the basis of increased mRNA expression associated with macrophage activation (10, 11). It has subsequently been Imaging, Diagnosis, Prognosis Authors’Affiliations: 1 CentreforImmunologyat 2 St.Vincent’sHospital, 3 National Centrein HIVEpidemiologyand ClinicalResearch, 4 OncologyResearchCentre, Prince ofWales Hospital and Department of Clinical Medicine, Cancer Epidemiology Centre, University of New SouthWales, Sydney, Australia; 5 DepartmentofUrology,UniversityHospitalCharite¤,HumboldtUniversity,Berlin, Germany; 6 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital,Toronto,Ontario,Canada; 7 GenomicsInstituteof theNovartisResearch Foundation, San Diego, California; and 8 The Cancer Council-Victoria, Carlton, Victoria,Australia Received6/20/05;revised10/4/05;accepted10/5/05. Grant support: St.Vincent’s Hospital, Sydney; Meriton Apartments Pty Ltd. throughanR&DsyndicatearrangedbyMacquarieBankLtd.;NewSouthWales Health Research and Development Infrastructure grant; National Health and MedicalResearch Council, Australia; andthe Mildred-Scheel-Foundation, grant 70-3295-ST1. Conflictofintereststatement: D.A.BrownandS.N.Breitareco-inventorson patentsfiledbySt.Vincent’sHospital,whichpertaintouseofMIC-1measurementin diagnosisofdisease. Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Requests forreprints: Samuel N. Breit, Centre for Immunology, St.Vincent’s Hospital,VictoriaStreet,Sydney,NSW2010,Australia.Phone: 61-2-8382-3700; Fax:61-2-8382-2830;E-mail:s.breit@cfi.unsw.edu.au. F 2006AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-05-1331 www.aacrjournals.org ClinCancerRes2006;12(1)January1,2006 89