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1、ClinicalReview&EducationReviewTheEvolvingLandscapeofHER2TargetinginBreastCancerMarkM.Moasser,MD;IanE.Krop,MD,PhDThedevelopmentofhumanepidermalgrowthfactorreceptor2(HER2)-targetingagentsforthetreatmentofHER2-amplifiedbreastcancerhasdramaticallyimprovedoutcomesforp
2、atientswiththisdisease.ThevalueofHER2asatherapeutictargetencompasses2entirelydifferentmechanisticdimensions.ThefirstapproachexploitsthefactthatHER2isclearlyadisease-drivingoncogenetodeliverHER2kinaseinhibitors,apparentlyahighlyrationalapproachtothetreatmentofHER2
3、-amplifiedcancers.However,thefunctionallyrelevantHER2-HER3complexhasprovenmuchmoredifficulttoinhibitthanhadbeenanticipated,andbecauseofitsmodestefficacy,theHER2inhibitorlapatinibiscurrentlyusedpredominantlyincombinationsandinveryadvancedstagesofdisease.Theseconda
4、pproachexploitsthemassivecellsurfaceexpressionofHER2anddeliversofavarietyofcytotoxicorimmunologiceffectorswithgreatselectivitytothesecancercells.Thisapproachhasproventransformative,with3suchdrugsintroducedintopracticetodate.TheHER2-specificantibodytrastuzumab,inc
5、ombinationwithchemotherapy,hasshownsubstantialeffectinthemanagementofHER2-amplifedbreastcanceratallstagesofdiseaseandlinesoftherapy—andtheadditionofthesecondHER2antibodypertuzumabsubstantiallyincreasesthemagnitudeofthiseffectinallofthecontextstestedthusfar.Whilet
6、heimmunologiceffectorsstimulatedbythesenakedHER2antibodiesprovideonlymodestactivityasAuthorAffiliations:HelenDillerFamilyComprehensiveCancermonotherapy,thetoxin-carryingantibodytrastuzumab-emtansineprovidessubstantialCenter,UniversityofCalifornia,Sansingle-agenta
7、ctivityandisbeingdevelopedforbothearly-andlate-stagedisease.TheFrancisco(Moasser);Dana-FarberdiversemechanisticlandscapeaffordedbythetargetHER2hasproventobefertilegroundCancerInstitute,HarvardMedicalfordrugdevelopment,butithasalsocreatedcomplexityandmisconception
8、inSchool,Boston,Massachusetts(Krop).understandingtheseagents’modesofaction,underminingthedevelopmentofclinicallyCorrespondingAuthors:MarkM.usefulpredictivebiom
