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OvarianCancerAustralia Webinar “Whatisovariancancer”? Ovariancancer–howwearege:ng toknowtheenemy ProfessorDavidBowtell PeterMacCallumCancerCentre,Melbourne GarvanInsGtuteandKinghornCancerCentre,Sydney [email protected];[email protected] Talkoutline • Recognizingthedifferenttypesofovariancancer • Genesthatinfluencetheriskofdevelopingovarian cancer • Genesthatinfluencetheresponseofthe cancertotreatment • Thedevelopmentofdrugresistant cancerswiththerapy Talkoutline • Recognizingthedifferenttypesofovariancancer • Genesthatinfluencetheriskofdevelopingovarian cancer • Genesthatinfluencetheresponseofthecancerto treatment • Thedevelopmentofdrugresistantcancerswith therapy CancerdiagnosishasbeenbasedonlocaGon inthebodyandpaSernsofcellgrowth Ovariancancerisacomplexdisease • Germcelleg. dysgerminoma • Sexcord–stromal/ carcinoma • Epithelial (90%) C.Kosary(2007)Cancersoftheovary(Chapter16:SEERSurvivalMonograph) ConvenGonalclassificaGonof epithelialovariancancer 6 10 12 15 60 Serous Mucinous Endometrioid Clearcell Other OvarianSurface Epithelium Themostcommontypesofovariancancerwere thoughttomostlyarisefromcellsonthesurface oftheovary OvariancancerisaseriesofdisGnct diseaseswithdifferentcellsoforigin –mostlynotfromtheovaryandallverydifferent! Vaughan et al (2011) Nature Reviews Cancer WhythereclassificaGonofovarian cancerisimportant: • Treatmentsneedtobespecific–notaonesizefitsall • GeneGcrisktrackswithspecifictypes–helpsdecidewho shouldbeofferedtesGng • Wecan’tfigureoutthebiologyiftheyare allmixedtogether • Knowingwheretheycomefrominfluences prevenGon(eg.removaloffallopiantubes) andearlydetecGonstrategies Refocusingriskreducingsurgeryin womenwithBRCA1orBRCA2 mutaGons • Removalofovariesandfallopian tubestogether? • Removaloffallopiantubesonlyas thisiswherecancersassociated withBRCAmutaGonsarise? • Fallopiantubesfirst andovarieslater? OvarianclearcellcancergeneGcmake upresemblesrenalclearcellcancer! sunitinib Surgery + Platinum - taxol SuniGnibisusedinrenalcancer Anglesio et al (2011) Clinical Cancer Research Talkoutline • Recognizing the different types of ovarian cancer • Genesthatinfluencetheriskofdevelopingovarian cancer • Genes that influence the response of the cancer to treatment • The development of drug resistant cancers with therapy First,whatexactlyisagene? OurgenomeismadeofDNApackaged intochromosomes chromosomes A G T T C DNA T G OvariancancergeneGcs TheBRCA1andBRCA2genesprovide theblueprintsforcomponentsofa nanomachinethatveryaccurately repairsDNA BRCA1andBRCA2mutaGonsincreasethe riskofbreastandovariancancerby10-20X BRCA1/2makeproteinsthatareinvolvedinDNArepair Lossofonecopy(mutaGon)increasestheriskofbreastandovarian cancer(alsosomeothercancers,eg.prostatecancerinmen) MutaGonfrequencywasthoughttobe5-10% TesGngwasofferedbasedonstrongfamilyhistory(andageof diagnosis) Studiesaroundtheworld,includingamajor Australianstudychangedthatview BRCAmutaGonsinovariancancer Whatwastherealfrequencyof mutaGon? 17%ofhighgradeserouscancers Almostonlyseeninthese cancers ShouldthegeneGctesGng guidelinesbechanged? Yes.Almosthalfofthecarriers didn't haveafamilyhistory–so wouldbemissed.Guidelines nowchanged DidcarryingamutaGoninfluence treatment? Yes.BeSerresponsetotreatment andbeSersurvival.Persistwith plaGnum. Isitusefultoknow? Yes.Riskof ovariancancer canbereduced by80-90% Alsop et al (2012) Journal of Clinical Oncology Talkoutline • Recognizing the different types of ovarian cancer • Genes that influence the risk of developing ovarian cancer • Genesthatinfluencetheresponseofthecancerto treatment • Thedevelopmentofdrugresistantcancerswiththerapy Nature May 2015 95 trillion bits of data Understanding excepGonalresponse • • • • InternaGonalconsorGum(US,Canada,UK,Australia,Scandinaviancountries) Australialeadsthegenomesequencinganalysis Womenwithadvancedhighgradeserousovariancancerwhosurvive>10years RecentlyfundedbyUSDepartmentofDefense Genetic (germline and in the cancer) Lifestyle Immune Summary WehaveamuchbeSerideaofhowthedifferenttypes sortout–specifictherapies,notonesizefitsall GeneGcsisclearer–changethetesGngguidelines CompleteblueprintofallthemutaGonsincommon (andrare)forms–knowwhatwearedealingwith andcanseenewtargets Recurrenceandacquiredresistance–criGcal weunderstandthis