ovarian cancer genecs€¢ trans-vaginal ultrasound and ca-125 level • consult with...

OvarianCancerGeneMcs

BriganyDeGreef,MS,CGCLeeShulman,MD

CancerGene:csProgramNorthwesternMedicineSeptember9,2017

98

Disclosure

•  IserveontheGene:cCounselingAdvisoryBoardforInvitaeLaboratories.

99

OvarianCancer

Non-GeneMc•  Age•  Nulliparity(neverbeingpregnant)•  Familyhistoryofovariancancer

RiskFactors

GeneMc•  BRCA1orBRCA2carrier•  Lynchsyndrome(HNPCC)•  Othersinglegenemuta:ons(rare)

OvarianCancerRiskinGeneralPopula:on

1outof72womenwilldevelopovariancancerintheirlife:me(1.4%)

OvarianCancerRisks

0

10

20

30

40

50 Rangesfrom5-50%

GeneralPopula:on

1.4%

Firstdegreerela:vewithovariancancer

Twofirstdegreerela:veswithovariancancer

GeneMuta:on

7%3-5%

OvarianCancer

Sporadic:~70%•  Canceroccursbychanceorrelatedto

environmentalfactors•  Generalpopula:oncancerrisk

Familial:~20%•  Mul:plegenesand

environmentalfactors•  Someincreaseincancerrisk

Hereditary:5-10%•  Genemuta:onisinheritedinfamily•  Significantincreasedcancerrisk

CausesofHereditarySuscep:bilitytoOvarianCancer

WalshTetal.Muta:onsin12genesforinheritedovarian,fallopiantube,andperitonealcarcinomaiden:fiedbymassivelyparallelsequencing.ProcNatlAcadSci2011;108:18032–7.

104

CluesforaHereditaryCancerSyndrome

•  Earlyageofdiagnosis-  Typicallydiagnosedundertheageof60

•  Mul:pleprimarycancersinoneindividual-  Suchasovariancancerandbreastcancer

•  Individualwithovariancancerandfamilyhistoryofovarianand/orbreastcancertypicallydiagnosedundertheageof50

•  Mul:plegenera:onsaffectedwithcancer•  Rarecancers(i.e.malebreastcancer)•  AshkenaziJewishancestry

HowCancerForms

SporadicCancer

HereditaryCancer

NormalCell Accumulatechangesormuta:onsover:me

TumorDevelopment

x x x xxx x xxx x

x xx xxx

PredisposedCell

Accumulatechangesormuta:onsover:me

TumorDevelopment

x xxxx

106

Whatarethese“genes”?

•  Tumorsuppressorgenes•  Carriedbybothmenandwomen•  Twocopiesofeverygeneinourbody(~25,000)

WhatdoesamutaMonmean?AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAA•  Onecopyofgenecannolongerperformnormalfunc:onof“tumorsuppressing”

•  Increasedriskofcancer

AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCA

Inheritance

50%chancetopassonthenon-workingcopyofthe

gene

50%chancetopassonthe

workingcopyofthegene

108

HereditaryCancerSyndromes

AssociatedwithanIncreasedRiskforOvarianCancer

HereditaryBreastandOvarianCancerSyndrome(HBOC) LynchSyndrome Other/ModerateRiskGenesfor

OvarianCancer

Genes BRCA1andBRCA2 MLH1,MSH2,MSH2,PMS2,EPCAM BRIP1,RAD51C,RAD51D

OvarianCancerRisk 20-40% 10-15% 5-15%

OtherCancerRisks

Female/MaleBreast(50-60%,upto6%)Prostate(15%)Melanoma(5%)

Pancrea:c

Colon(upto70%)Uterine(40-60%)Gastric(upto13%)

UrinaryTract(upto7%)Pancrea:c(upto6%)

Unknown?

ManagementRecommendaMons CurrentlynoGuidelines

BasedonNCCNGuidelines2017

109




OvarianCancer



OtherCancerRisks


Pancrea:c



Unknown?



110




OvarianCancer



OtherCancerRisks


Pancrea:c



Unknown?



111




OvarianCancer



OtherCancerRisks


Pancrea:c



Unknown?



112




OvarianCancer



OtherCancerRisks


Pancrea:c



Unknown?



OvarianCancerRiskReduc:on

•  Birthcontrolpills-  5yearsofuse:27%reduc:on-  15yearsofuse:60%reduc:on

•  Firstfull-termpregnancy<age25;numberofpregnancies•  Breast-feeding•  Bilateraltuballiga:on/hysterectomy•  Prophylac:coophorectomy-  Riskofprimaryperitonealcancerremains

113

HBOCandLynchSyndrome

114

OvarianCancerRiskReduc:on

•  Ovariancancer-  Approximately15%life:meriskofovariancancer

•  Currentlynoestablishedguidelines-  Recommendriskreducingoophorectomyfollowingnaturalmenopause

•  Othercancerrisks?-  TBD

BRIP1,RAD51C,RAD51D

Prophylac:cSalpingectomywithDelayedOophorectomy

•  RecentstudieshavesuggestedmajorityofovariancancerbeginsinfallopiantubesinwomenwithBRCA1/2muta:ons(~80%)

•  RESEARCHcurrentlyongoingtoevaluateforremovaloffallopiantubesfirst-  Delayssurgicalmenopausewhilehopefullyreducingovariancancerrisk-  Removeovariesfewyearslater

•  NOTSTANDARDOFCARE,onlybeingperformedonresearchbasisatthispoint

116

117

WhatifIalreadyhadnega:veBRCA1andBRCA2tes:ng?

AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTAGTCACT

•  SequencingAnalysis-  Readsthrougheachlegeronebyone-  Picksupapproximately95%ofmuta:onsinBRCA1/2

118



119



120



121


AGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAAAATGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAAAGCTGTTCAAGTCAGTCACTGCAGTCAGTCAGTACGTTGCACCGTGACAGTCAATTGCACCGTGACAGTCACGTGACT

•  Dele:on/Duplica:onAnalysis-  Looksforlargeamountsoflegersthataremissingoradded-  Picksupapproximately5%ofmuta:onsinBRCA1orBRCA2

122


•  Genepanels…-  Includesmorethanonegenerelatedtospecificindica:onsuchasovarian

cancer•  Highriskgenes:Lynchsyndrome(MLH1,MSH2,MSH6,PMS2,EPCAM)•  Moderateriskgenes:BRIP1,RAD51C,RAD51D•  Andmanymore…

•  Changingyearly,evenmonthly

Arethereothergenesrelatedtoovariancancer?

123

Gene:cTes:ng

•  Mul:-GenePanelvsSingleGeneTes:ng-  Mul:plecasesofcancerwithinafamily-  Isolatedcaseofovariancancerdiagnosedatanyage-  Iden:fiedfamilialmuta:on

•  Gene:cTes:ngResults:-  NoMuta:onFound-  Pathogenic-  Variantofuncertainsignificance(VUS)–inconclusive

124

Allofmygene:ctes:ngwasnega:ve,nowwhat?

•  Managementbasedonpersonalandfamilyhistoryofcancer•  Firstdegreefemalerela:ves(daughters,sisters,mothers):

•  Considerovariancancerscreeningaspartofaresearchprotocol•  NorthwesternOvarianCancerDetec:onandPreven:onProgram

•  Trans-vaginalultrasoundandCA-125level

•  Consultwithphysicians/gene:ccounselorsperiodicallyforupdatedgene:ctes:ngandrecommenda:ons

BenefitsofGene:cTes:ng

•  Provideanexplana:onforyourpersonalorfamilyhistoryofcancer•  Evaluateyourriskofdevelopingfuturecancers•  Makeinformedmedicaldecisions,includingtreatment,surveillance,andpreven:veop:ons

•  Poten:aluseofotherchemotherapyop:ons-  PARPinhibitorsforBRCA1/2individuals

•  Qualifyyouforpar:cipa:oninclinicaltrialsorresearchstudies•  Iden:fyotherat-riskrela:vesforwhomgene:ctes:ngisrecommended•  Alwayschangingandevolving–periodicallycheck-inwithgene:cs

125

DrawbackstoGene:cTes:ng

•  Willresultsmakeadifferenceinmycare?•  Maybeinconclusive•  Riskfordevelopingcancernotalwaysestablished•  Whatinterven:onsareavailable?•  Psychosocialimplica:ons

126

127

TumorDNATes:ng

•  Usesnextgenera:onsequencing(many,manygenes)•  Tes:ngperformedtolookforDNAmuta:onswithincancercells/tumoronly-  Differentfromgene:ctes:ng(tes:ngwejustreviewed)

•  Typicallyperformedtolookfortreatmenttargetsorresponsetotreatment•  Incidentallycanfindagene:cmuta:onthatyouwerebornwith(inheritedmuta:on)

•  “New-er”soworkinprogressandrapidlyevolving…(staytuned)

HowCancerForms

SporadicCancer

HereditaryCancer

NormalCell Accumulatechangesormuta:onsover:me

TumorDevelopment

x x x xxx x xxx x

x xx xxx

PredisposedCell

Accumulatechangesormuta:onsover:me

TumorDevelopment

x xxxx

131

OtherConsidera:ons…

•  Gene:cInforma:onNondiscrimina:onAct(GINA)passedin2008

•  Familyplanningop:ons•  Opennessorwillingnesstocommunicatewithfamilymembers-  Familyleger

•  PsychosocialImplica:ons

•  Pa:entadvocacygroups

132

FamilyLegerExample

Dearfamily:

Iamwri:ngthislegertoinformyouthatIrecentlyhadgene:ctes:ngandwasdiagnosedwithacondi:oncalledhereditarybreastandovariancancersyndrome(HBOC)whichaffectsfamilies.Thislegercontainsinforma:onaboutHBOC,howitmightaffectyou,andhowtofindoutifyouhavethiscondi:onalso.

PeoplewhohaveHBOChaveincreasedcancerrisks.Specificallywomenhaveincreasedrisksforbreastcancerandovariancancer,andmenhaveincreasedrisksforprostatecancerandmalebreastcancer.ItisrecommendedthatanyonewithHBOChaveincreasedscreeningforthesecancerswhichhelpsdetectcancersearlierwhentheyaremoreeasilytreated,andinsomecases,preventthemaltogether.

Hereditarybreastandovariancancersyndromeiscausedbyamuta:oninagenethatcanbeinheritedinfamilies.Thespecificmuta:oniden:fiedinmewasintheBRCA*gene(***).Gene:ctes:ngisavailableforyoutoseeifyoucarrythissamemuta:on.Youcantakethislegertoyourdoctor,orcontactthegene:csteamatNorthwesternCancerGene:cstodiscussthisfurtherandfindouthowtogettestedinyourarea.Youcanalsofindagene:ccounselornearyoubygoingtothefollowingwebsite:www.nsgc.organdusingthe“FindaGene:cCounselor”tool.

Ifyouoryourdoctorshaveaddi:onalques:ons,theNorthwesternCancerGene:csteamwouldbehappytodiscussthisfurther.YoucanreachamemberoftheCancerGene:csTeamat312-472-0518or312-472-0523.Sincerely,

133

FindaGene:cCounselorNearyouhgp://www.aboutgene:ccounselors.com/

ThankYouEmail:[email protected]:(312)695-0320

ovarian cancer genecs€¢ trans-vaginal ultrasound and ca-125 level • consult with...

Documents