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Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma.doc

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Clinical implications of novel activating EGFR mutations in malignant peritoneal mesothelioma

Fosteretal.WorldJournalofSurgicalOncology2010,8:88 /content/8/1/88 WORLD JOURNAL OF SURGICAL ONCOLOGY RESEARCH OpenAccess ClinicalimplicationsofnovelactivatingEGFR mutationsinmalignantperitonealmesothelioma JasonMFoster1,4*,UppalaRadhakrishna,VenkateshGovindarajan ,JosephHCarreau ,ZoranGatalica2, 1 1 1 PoonamSharma ,SwapanKNath,BrianWLoggie1 2 3 Abstract Background:ThereisapaucityofinformationaboutthemolecularperturbationsinvolvedinMPMtumor formation.WepreviouslyreportedthatEGFR-TKmutationsinMPMwerepredictiveofachievingoptimalsurgical cytoreduction,butthestatusofEGFRpathwayactivationpotentialofthesemutationswasnotknown.Herewe presentthemutantEGFRactivatingpotentialandthematuredsurvivaldataoftheEGFRmutant(mut+)relativeto wildtypeEGFR(mut-)mesothelioma. Methods:Twenty-ninepatientswereevaluatedandtheirtumorswereprobedformutationsinthecatalyticTK- domain.Twenty-fivepatientsweretreatedwithcytoreductivesurgeryandcompleteclinicaldatawasavailablefor comparisonofthemut+andmut-groups.ACOS-7cellexpressionmodelwasusedtodeterminemutation activatingprofilesandresponsetoerlotinib. Results:Functionalmutationswerefoundin31%(9/29)ofpatients;7ofthesemutationswerenovelandanother wastheL858Rmutation.Allmissensemutationswerefoundtobeactivatingmutationsandresponsiveto erlotinib.Ofthe25patientsmanagedsurgically,therewere7mut+and18mut-.Twoof7(29%)mut+developed progressivediseaseanddiedwithamedianfollow-uptimeof22months;while13/18(72%)mut-developed progressivediseaseand10/18(56%)diedwithmedianTTPof12monthsandmediansurvivalof14months. Conclusions:ThenovelEGFRmutationsidentifiedareactivatingmutationsresponsivetoerlotinib.Themut+ subsethavea‘relative’improvedoutcome.ErlotinibmayhavearoleinMPMandexplorationformutationsina largerpatientcohortiswarranted. Introduction therapyandcanceroutcome[5-8]. Thereported muta- Discovering the molecular pathways and mutations tionsinNSCLCaredeletionormissensemutationsthat active incancerhasresultedintheemergenceofnovel occur between exons 18-2