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C4Protocol Prospective,randomizednon-inferioritytrialofstreamlinedgeneticeducationand testingforhigh-gradeepithelialovarian,fallopianandperitonealcancerpatients PrincipalInvestigator:RebeccaPrevis,MD,MS OtherInvestigators: AndrewBerchuck,MD BrittanyDavidson,MD JinnyEun,MMSc LauraHavrilesky,MD,MHSc NoahKauff,MD PaulaLee,MD,MPH P.KellyMarcom,MD LeahMcNally,MD CarolynMenendez,MD MargaretPowell,MS JatinRoper,MD KeeliaRhoads,PhD,MS Angeles Secord,MD LindsaySoo,BA CatherineWatson,MD InstitutionalAffiliations:DukeUniversity,DukeCancerInstitute
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1.background genetictestinginovarianfallopianandperitonealcancers

Genetictestingforhereditarycancersusceptibilitygenemutationsisarapidly evolving science,complicatedbothbyanincreasingawarenessofitspertinenceandthe assumed risksassociatedwithgenetictestingandresultsdisclosure.Thedemand for testingincertainpopulationshasrisen incorrelation toanincreasingawarenessofthe geneticbackgroundofseveralcancers.Inthecaseof high-gradeepithelialovarian, fallopianandperitonealcancers,upto eighteen percent ofthesegynecologiccancersare secondarytoBRCA1and2mutations,and afurtherfivetotenpercentaresecondaryto otherassociatedpathogenicmutations[1,2].  
Resultsof genetic testingmayhaveprofoundimplications forfuturefamily members,whocanchoosetoundergo closer surveillanceorprophylacticmeasures shouldtheyalsocarryamutation [3]. Testing resultscanalso impactpatienttreatment, astherenowexistmultiple FDAapproved anticanceragentsfor BRCAmutationscarriers [4-7].Forthese reasons,currentnationalguidelines,includingthe2014SGOClinical PracticeStatement andtheNCCNguidelinesversion2.2019 thatallpatientswithovarian, fallopian,orperitonealcancershouldbeofferedgenetictesting[8,9].
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thetraditionalmodelofgeneticcounseling

Several societies,includingASCOandtheNationalSocietyofGeneticsCounselors, haveprovidedguidelines forcomprehensivepatienteducationand informed consent priortoadministrationoftesting [10-14]. These recommendations originatefromthe conceptthattheprocessofcounselingandtestingcanbepsychologicallydetrimentalto patientsandtheirfamilymembers andaregrounded inapracticeofnon-directive counseling [12].Fulfillmentoftheserecommendationshas traditionallybeen accomplishedthrough face-to-faceconsultationwithageneticcounselorpriortotesting.  
Duringtheseconsultations,patientsreceiveapproximatelythirtytoninety minutesofin-deptheducationconcerningtheirhereditarycancerriskandthe implicationsoftesting.Thiseducationalcomponentofthisprocessisexhaustively definedbyASCO'selementsofinformedconsentforgeneticcounseling,whichuponlast updatecontainssixteenseparatediscussiontopicsformulti-genepaneltesting[14] [Figure1].  
Figure 1: Components of informed consent and pretest education in clinical cancer genetics [14]  
| Pretest Counseling for Multigene Panel Testing (same   |                                                                                             |
|--------------------------------------------------------|---------------------------------------------------------------------------------------------|
|                                                        | general components as traditional counseling, with                                          |
| following special considerations                       |                                                                                             |
| Information on specific ganetic mutation(s)            | Discussions of specific genes may need to be batched                                        |
| or genomic variant(s) boing tested                     | because it may not be feasible to review each go                                            |
| including whether range of risk
associated with variant will affect                                                        | individually, high-penetrance syndromes being evaluated should be described leg, hereditary |
| breast-ovary, Lynch, hereditary diffuse gastric, Li-
Fraument; patients should be aware of possible                                                        |                                                                                             |
| mdcol care                                             | detection of high-penetrance mutations not                                                  |
| suggested by personal or family history; genes of      |                                                                                             |
| uncertain clinical utility may need to be described    |                                                                                             |
| more generally                                         |                                                                                             |
| Implications of positive (mutation)                    | Particular attontion should be paid to implications of                                      |
| confirmed to be deleteriousl, negative                 | positive results in less well-understood or lesser                                          |
| (no identified change in genetic                       | penetrance genes and in findings of mutations is                                            |
| sequence), or uncertain (genetic                       | gones associated with syndromes not suggested by                                            |
| variant of unknown dinical                             | porsonal or family histon                                                                   |
| significance) result                                   |                                                                                             |
| Possibility test will not be informative               | Attention should be paid to current high rate of                                            |
| variants of uncertain significal                       |                                                                                             |
| Risk that children and/or other family                 | Highlight potential reproductive implications to family                                     |
| more than the control of the control.                  | of mutations in ganas linked to recessive disorders
(eg, ATM, Fanconi's (BRCA2, PALB2), NBN, BLM                                                                                             |
| condition                                              |                                                                                             |
| Fees involved in testing and counseling:               |                                                                                             |
| for DTC testing, whether counselor is                  |                                                                                             |
| omployed by testing company                            |                                                                                             |
| Psychological implications of test results             |                                                                                             |
| (benefits and risks)                                   |                                                                                             |
| Risks and protections against genetic                  |                                                                                             |
| discrimination by omployers o                          |                                                                                             |
| insurers                                               |                                                                                             |
| Confidentiality issues, including DTC                  |                                                                                             |
| tosting companies and policies related                 |                                                                                             |
| to privacy and data security                           |                                                                                             |
| Possible use of DNA samples for future                 |                                                                                             |
| Options and limitations of modical                     |                                                                                             |
| survoillance and strategies for                        |                                                                                             |
| prevention after genetic or genomic                    |                                                                                             |
| tosting                                                |                                                                                             |
| Importance of sharing genetic and                      |                                                                                             |
| genomic test results with at-risk
relatives so they may benefit from                                                        |                                                                                             |
| this information                                       |                                                                                             |
| Plans for disclosing tost results and                  |                                                                                             |
| providing follow up                                    |                                                                                             |
| Abbreviation: DTC, direct to consumer.                 |                                                                                             |  
*Changes from the 2010 version include the discussion of multigene panel result management, discussion of batched genes rather than individual genes and acknowledgement of uncertain results and the high rate of VUS in multigene panel results.  
The critical components of the genetic counseling process include a medical and family history evaluation, cancer risk assessment, genetic education, discussion of testing, and arrangement of follow-up.  
Failure of the traditional model in ovarian, fallopian and peritoneal cancer patients Dependence on this model in the setting of universal testing recommendation, however, has several flaws.  The mutation rate is high enough and the implications of a positive mutation great enough to tip the risk and benefit ratio clearly to the side of testing. Thus, genetic counseling for the ovarian cancer population has undergone an implicitshiftfromnon-directivetodirective.While thefullASCOpre-testcounseling guidelinesmaystillbeappropriateincertainpopulationsforwhomuniversaltestinghas notbeenrecommendedbymultipleprofessionalsocieties,itseems reasonableto expedite theprocessforovariancancerpatients.  
Second,thelackofconsistentreferralandlimitedsupplyofcounselors associated withthe traditionalmodel,whencombinedwithnon-directive counseling,hasresultedin apersistentfailuretoachieveuniversaltesting,withapproximately25%ofpatients receivingBRCA1and2testing [15,16].The supplyanddemandissuewilllikelyworsen, asgenetictestingreferralsforothersolidtumorsarealsoincreasinginfrequency.In short,therecommendationforuniversal BRCA1/2testinginpatientswithhigh-grade epithelialovarian,fallopianorperitonealcarcinomahascreatedaneedforanalternate educationandtesting process.
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alternativemodelsofservicedelivery

Severalalternativemodelshavebeensuggested,includinggroupcounseling, teleconferencing,telephonecounselingandpost-testcounselingonly[17,18]. More recently,thestreamlinedmodelhasbeensuccessfullyincorporatedintoseveral institutionsthroughqualityimprovementinitiatives[19,20].Inthismodel,thepatients arecounseledandtestingattheirprimaryoncologicappointment,eitherbytheproviders themselvesorbyembeddedgeneticcounselors. Thesemodifications havebeenshownto beeasilyimplementedandtoincreasetheinstitutions'counselingandtestingratesby significantmargins.
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safetyofalternativemodels

Whileexpeditedmodelsmayincreaseefficiencyandgenetictestinguptake,it mustbeestablishedthatthesemethodsarenotdetrimentaltopatients. ASCO andNSGC's originalpolicies regardingpre-testeducationoriginatefromaneffort tominimize patient distress.Asreportedinitspolicystatementongeneticcounselingforcancer susceptibilitymutationsin2003,"adefinitivegenetictestmayhaveconsiderablemedical andpsychologicalimplications,"anditscounselingframeworkintendstopreparethe patientforthese [12].  
Thisassumption maynotholdtrue, however, inthesettingofmoredirective counseling,whenthestakesforpatientsandfamilymembersaremoresignificant.A positiveBRCA1or2result,logically,hasbeenshowntohaveatleastatemporaryimpact on psychological well-being,butthisispresentevenaftertraditionalpre-testcounseling [21].Multiplestudies,however,havedemonstratedthatBRCA1and2testing inhigh-risk populationsdoesnotgenerallyincreasepatientdistress[22,23].Furthermore,theuseof certainalternatemodels toprovidepre-testeducation,suchastelephonecounseling and teleconferencing, didnotincrease patientdistresswhencomparedtothetraditional model [17,24]. Unfortunately, uptakeoftestingviatelephonecounselingwasshownto belowerthanthatachievedbythetraditionalmethod inaprospectivenon-inferiority trial[17],andvideoconferencingstillrequirespossibleover-utilizationofgenetic counselorsinapre-testsetting.
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purposeofstudy

Asevidencedbythisdiscussion,amodelthatachievesthegoalofincreasing uptakeanddecreasingresourceutilizationwhilenotsignificantlyincreasingpatient distresshasyettobeestablished.Wehypothesizethatastreamlined modelofservice deliverywill nothaveadetrimentaleffectonpatientdistress withthecounselingand testingprocess.Wealsohypothesizethatthismodelwilladheretonear-universaltesting uptakewithoutincreasingcostburdenonthehealthcare system.Thiswouldbethefirst randomizedtrialtoinvestigatethesafetyandnon-inferiorityofthispromisingnew geneticservicedeliverymodel,providinganalternate,resource-effectivemethodofpretesteducationthatcouldimprovegenetictesting uptakewithoutincreasingadverse psychologicaleffects.
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2.study objectives primaryobjective

a.Todetermineif implementationofastreamlinedmodelofgeneticservicedelivery increasespatientdistressasmeasuredbytheMultidimensionalImpactofCancerRisk AssessmentScale whencomparedtothetraditionalmodelofcounseling [25]. Hypothesis:Anexpeditededucationandtestingmodelinthispatientpopulationwillnot decreasepatientsatisfactionwithgeneticcounselingorincreasepatientanxiety. SecondaryObjectives a.Tocomparecost betweenthetraditionalgeneticcounselingmodelandthestreamlined model. Hypothesis:Anexpeditededucationandtestingmodelinthispatient populationwillbeless expensive *comparedtothetraditionalmodel.* b.Tocomparegenetictestinguptakebetweenthestreamlinedandtraditionalmodels. Hypothesis:Inthisstudysetting,bothgroupswillhaveclosetouniversaltestinguptake. c.Toobservedifferencesindistress throughoutthegeneticeducationandtesting process,includingpre-education,post-education,andpost-resultsdisclosure. Hypothesis:Theprocessofgeneticeducation,testingandresultsreviewcausesminimal distressinpatients.
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4.studyprocedure 4.1subjectselection andenrollment

4.1.2InclusionandExclusionCriteria Inclusion:
- Agegreaterthan18 years - Female - Eithera)pathologically confirmeddiagnosisofhigh-gradeepithelialovarian, fallopianorperitonealcancer viabiopsyorsurgicalpathology orb) cytologic diagnosisconsistentwithhigh-gradeepithelialovariancancer.  
- PresentingtoDukegynecologiconcologyclinicorcollaboratinginstitutionfor firstoutpatientvisitfollowing pathologicorcytologicdiagnosis.Iflogistic constraintspreventthepatient frombeingenrolledatherinitialvisit,shewillbe eligibleforenrollmentuptoinitiationofherfourthcycleofchemotherapy.  
- Knownfamilyorpersonalhistoryofaninheritedcancersusceptibilitymutation
- Previouslyreceivedgeneticcounselingortesting for aninheritedcancer susceptibilitymutation
- Insuranceprovidedbyaninsurancecompanythat requires face-to-facegenetic consultationpriortotesting
- UnabletoreadorspeakEnglish asstudydesignincludesvideoassisted educationalmaterialsinEnglish
- Blindordeafasstudydesignincludesvideoassistededucationalmaterialsin English 4.1.3RecruitmentProcedures Recruitment Exclusion:
- RecruitmentwilloccurinthegynecologiconcologyclinicsatDukeCancerInstitute andcollaboratinginstitutions.  
- Potentialsubjectswillbeidentifiedbytheprimaryresearchcoordinatorpriorto theirclinicvisitandwillbeflaggedfortheprimaryprovider,fellows,residents andAPPstomaketheirpotentialeligibilityforthetrialknown.  
EligibilityDeterminationandIntroductionofTrial
- Oncethepatientarrivesinclinic,boththeresearchcoordinatorandprimary providerwillreviewhereligibilityforthetrialbasedontheabovestatedcriteria.  
- Ifeligible,eithertheprimaryresearchcoordinatororproviderwillgiveabrief explanationofthetrialandassesspatient'swillingnesstoenroll.  
- Ifthepatientagreestoenroll,theprocessofconsentwillbegin.Ifthepatientdoes notagreetoenroll,anotestatingthatthepatientwasapproachedandthen declinedenrollmentwillbeplacedintheEMRsothatsheisnotapproachedagain. Thepatient'sbasicdemographicinformationwillalsoberecordedinthesecure onlinedatabaseforlatercomparisonofdemographicinformationbetweenthose whowereamenabletoalternativeformsofservicedeliveryandthosewhodidnot wishtoparticipate.
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4.2processofconsent 4.2.1consentprocess

- Ifthepatientisamenabletoenrollment,shewillbeconsentedinoneoftheclinic roomsinthegynecologiconcologyclinicduringherprimaryappointmentby eithertheclinicalresearchcoordinatororherprimaryprovider.  
- TheIRBapprovedconsentwillbereviewedinfull,includingtrialpurpose,stated objectives,studyprocedures,risks,benefits,andcosts.Theconsentprocesswill takeplaceinaclinicexamroomwithacloseddoortoensureprivacy.  
- Patientswillhaveampletimewhileinclinictoaskquestionsoftheresearch coordinatororgynecologiconcologyprovider.Uptothirtyminuteswillbeallotted forreviewofconsentform. Iftheyhavequestionsaftertheirconsentissigned,the contactinformation oftheprimaryinvestigatorwillbelistedintheconsentform. Subjectswillbeemailedacopyoftheconsentformonceitissigned.Iftheydonot haveanactiveemailaccount,apapercopywiththeirsignaturewillbeprintedfor themaftertheyhavesignedtheconsent.  
4.2.2LegalCapacitytoGiveConsent
- Thesubjectmusthavefullcapacitytoconsent.
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4.3riskandbenefitassessment 4.3.1risk

- The first riskassociatedwiththisproposedstudyincludestheuseofsecure medicalrecords. Toensurethatpatientconfidentialityismaintained,alldata retrievalwillbeperformedbytheprincipalinvestigatororassignedresearchers usingpassword-securedcomputers. EachsubjectwillbeassignedasubjectID codethatwillbelinkedtothemedicalrecordnumber. Thiswillbegenerated usingREDCapdatabaseandwillbestoredonastandalonedatabaseserverhosted byDukeHealthTechnologyServices(DHTS)andwillonlybeaccessibletothekey personnelofthisstudy. CollaboratingsiteswillsharethesameDukeREDCap.  
- Risksofgenetictestingwillalsobeassociatedwiththestudy,asamajorityof patientsinbotharmswilllikelyundergotesting.However,thisisariskassociated withaseparate,well-establishedstandardofcareinthispopulationratherthan withthestudyintervention.Thus,whileitwillbeaddressedwiththepatientwhen theycompletetheirseparate,standardconsentforgenetictesting,itisnot consideredtobeanincrementalriskofthisstudy.  
- Thestudyalsoincursapotentialincrementalriskofadversepsychological reactionstostreamlinedgeneticcounselingandtesting.Ourhypothesisisthatthe streamlinedmodelwillnotsignificantlyincreasepatientdistress withthegenetic counselingandtestingprocess.  
4.3.2*Benefit*
- Patientswillreceivegeneticriskassessment,whichiscurrentlyrecommendedfor everyoneinthispatientpopulation.Thereisno other directbenefitprovidedto subjectsincludedinthisstudy. However,wehopethatthefindingsofthisstudy willleadtoincreaseanalysisanduptakeofexpeditedmodelsofgeneticeducation andtesting,thuspotentially benefiting thispatientpopulationandtheirfamily members.
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5.2.2traditioncounselinggroup(tg)

a.FormalConsultationScheduling
- Aftercompletionofbaselinesurveys,theTG subjectswillbereferredtoaformal pre-testconsultationwithageneticcounselorthatwillbescheduledforadate approximately2-4weeksaftertheirprimaryappointment(forpatientsinwhom resultswilldeterminetreatment,appointmentswilllikelybeexpedited). They willbemadeawareofthedateandtimeofthisappointmentpriortoleavingtheir initialvisit.  
b.ElectronicFamilyHistoryQuestionnaire - TGsubjects willcompleteanelectronicfamilyhistoryquestionnaire(FHQ)within oneweekoftheprimaryvisit.Thisisasystemalreadyemployed bytheDuke ClinicalGeneticsDepartment.Anemailissenttothesubject'sprimaryemail account withalinktoasecure,HIPAAcompliantportal,inwhichthesubjectcan then enterherfamilycancerhistory.  
- Amemberofthegeneticsteam willcuratetheresultsbycontactingthesubjectto reviewcommonerrorsandclarifyanyambiguitiesinthepedigree.  
c.FormalConsultationandPost-CounselingDistressSurvey - TheTGsubjectswillthenmeetwiththegeneticcounseloratthepreviously scheduledappointmenttime.Duringthis visit,theywillreceiveapproximately thirtytosixtyminutesofcounselingregarding genetic testingandpotential results.ThediscussionisbasedontheASCOandNCCNguidelinesofinformed consentforgenetictesting.  
- Aftercounseling,participantswillbegiventheoptiontoundergo amulti-gene panelgenetictesteitherviasalivaorbloodsample. Thosewhoagreetotesting willalsocompletethestandardgenetictestingconsentform.Asperstandard practiceoftheclinicalgeneticserviceatDCI,patientswillalsobeaskedtoprovide consentforsomatictumortestingofsurgicalspecimen(non-cytologic).  
- Subjectswillcomplete apost-educationdistressandanxietysurvey(IES)viaan email linktoaconfidentialREDCapsurvey link withinoneweek offormal consultation.
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5.2.3 streamlinedgroup(sg)

a.Video-AssistedGeneticEducation - Aftercompletionofthebaselinesurveys,theSGsubjectswillwatchan approximatelyeight minutelonggeneticseducationvideo.Thisvideowillbe made withtheassistanceofDukeUniversitygeneticcounselorsandgynecologic oncologyproviders.Itwill consist ofadiscussionofgenesandmutations,the recommendationofuniversaltestingfor highgradeepithelialovariancancer,a reviewofgenesassociatedwithovariancancerpredisposition, thepossibilityof uncertainresultsincludingvariantsofundeterminedsignificance, thepotentialfor undetectedmutationsinknownorunknowncancersusceptibilitygenes, the potentialimpactonpersonaltreatmentandonfamilymembers, thepossibilityof geneticdiscrimination andthelegalprotectionofgeneticinformation.  
- Afterwatchingthevideo,theprimaryoncologicproviderwillthenoffermultigenepaneltesting.  
- Allsubjects willthenhavetheoptionto"optout"and receive formalgenetic counselingpriortomakingadecisionabouttesting.  
- Ifthesubjectelectstoundergogenetictesting,shewillfilloutthestandardgenetic testingconsentform. AsperstandardpracticeoftheclinicalgeneticserviceatDCI, patientswillalsobeaskedtoprovideconsentforsomatictumortestingofsurgical specimen(non-cytologic).  
b.ElectronicFamilyHistoryQuestionnaire - SGsubjectswillcompleteanelectronicfamilyhistoryquestionnaire(FHQ)within oneweekoftheprimaryvisit.ThisisasystemalreadyemployedbytheDuke ClinicalGeneticsDepartment.Anemailissenttothesubject'sprimaryemail accountwithalinktoasecure,HIPAAcompliantportal,inwhichthesubjectcan thenenterherfamilycancerhistory.  
- Amemberofthegeneticsteamwillcuratetheresultsbycontactingthesubjectto reviewcommonerrorsandclarifyanyambiguitiesinthepedigree.  
c.Post-educationdistressmeasurement
- Subjectswillcomplete apost-educationdistressandanxietysurvey(IES)viaan email linktoaconfidentialREDCapsurveylink withinoneweek offormal consultation.  
5.2.3ResultsDisclosure(Bothgroups)
- Subjects willbenotifiedoftheirresultsbythegeneticcounseloroverthephone andtriagedaccordingly.  
o Deleteriousmutation,VUS orhigh-riskfamilyhistory despitenegative genetictestingresults:Scheduledforformalpost-testingconsultation2-4 weeksafterresultreturn o NodeleteriousmutationorVUSidentifiedongenetictestingandlowrisk familyhistory:Nofurthergeneticsfollow-upneeded
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5.3outcomevariables

5.3.1Demographicinformation Measurementtime:Baseline Description: Demographicinformation,includingcancerhistory,age,race,maritalstatus, andincome willbecollectedfromeachparticipantuponenrollment. 5.3.2Numeracyassessment Measurementtime:Baseline Description: Numeracyandhealthliteracywillbeassessedusing theNewestVitalSign survey, asix-questionsurveythatasksquestionsaboutaprovidedicecreamnutrition label[26]. 5.3.3 Electronic familyhistory Measurementtime:Asecureemailsenttopatientimmediatelyafterfirstvisit;completedat homewithinoneweekofvisit Description: Thisis asystemalreadyemployedbytheDukeClinicalGeneticsDepartment. Anemailissenttothesubject'sprimaryemailaccountwithalinktoasecure,HIPAA compliantportal,inwhichthesubjectcanthenenterherfamilycancerhistoryforthree generations.Amemberofthegeneticsteamwillcuratetheseresults.
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5.3.6 resourceutilization

Wewillevaluatethecostofphysician,geneticcounselorandgeneticassistanttimebased onaveragebasewagesforthesepositionsandtotalmeantimespentbyeachofthese providers.Theseestimateswillbeobtainedforapproximatelyforty patients–twenty fromeacharm– enrolledmid-trialtoensurethattheprocesstimeinthestreamlined grouphasreached fullefficiency.Eachproviderwillrecordtimeforeachofthese parametersusingastopwatch,withtotaltimesenteredintotheREDCapdatabase. Timesmeasuredinbotharmswillinclude: FamilyHistoryCuration GCphonetime GCdocumentationorcomputerentry Staffphonetime Staffdocumentationorcomputerentry Pretestcounseling *(Anytimepriortoresultsdisclosure)*
GCphonetime GCdocumentationorcomputerentry GCface-to-facecounseling Staffphonetime Staffdocumentation orcomputerentry Posttest *(Fromtimeofresultsdisclosureon)*
GCresultsdisclosurephonetime GCface-to-face counseling GCotherphonetime(notincludingresultsdisclosure) GCdocumentationorcomputerentry Staffphonetime Staffdocumentation orcomputerentry Wewillevaluatethecostofphysician,geneticcounselorandgeneticassistanttime based onaveragebasewagesforthesepositionsandtotalmeantimespentbyeachofthese providers.
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5.4.2primaryendpoint

Thestudyispoweredasanon-inferiorityanalysisof distressassociatedwith streamlined geneticeducation andtestingversustraditionalpre-testgeneticcounselingandtesting. Atwosampleone-sidedt-testisusedtocheckthenon-inferiorityfortheexperimental treatmentintermsoftheMICRA(MultidimensionalCancerRiskAssessment questionnaire).WeassumedthemeanMICRA scoresforbothexperimentalarmand controlarmwillbe thesameandequalto13.5,witha commonstandarddeviationof8.4. Thesevalueswereobtained fromastudythatassessedtheMICRA inasimilarpatient population[25].Usingtheseestimates, atotalsamplesizeof102(51patientseacharm) willprovide80%powertodetectthenon-inferiorityfortheexperimentaltreatmentwith asignificancelevelof0.05andanon-inferioritymarginof4.2(50%standard deviation). Thismarginwaschosenasa highgeneralMICRAscorehaspreviouslybeen consideredtobeonestandardofdeviationabovethemean; thus,wearetakingamore conservativeapproachbyusinganon-inferioritymarginof0.5theexpectedstandard deviation observedinCellaetal [28]. Whenincorporatingapotential10%attrition rate, thetotalsample sizewillbe112. 5.4.3Secondaryendpoints Resourceutilization Meanresourceutilizationwillalsobecomparedbetweenthetwomodelsusingsummary statistics. Genetictestinguptake Genetictestinguptakebetweenthetwogroupswillbecomparedusinglogistic regression. 5.4.4Exploratoryendpoints ImpactofEventsScale MeanchangesintheImpactofEventsScalescoresbetweeneachadministrationpoint willbecomparedbetweenthetwoarmsusingtheWilcoxonranksumstest.
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5.6theroleofexternalpersonnel

Noexternalpersonnelwillbeinvolvedinthisstudy.  
  
botharms)
consultation
Post-ResultsEvaluation completed within1weekafterconsultation
-ImpactofEventsScale
-MICRA
Post-ResultsEvaluationsentviaemail within1weekafterphonecall
-ImpactofEventsScale
-MICRA
References 1. Zhang etal.FrequenciesofBRCA1andBRCA2mutationsamong1.342unselectedpatientswith ovariancancer.GynecolOncol2011;121(2):353.  
2. Minionetal.Hereditarypredispositiontoovariancancer,lookingbeyondBRCA1/2.GynOnc127
(2015)86-92.  
3. Hartmannetal.Riskreducingsurgeryinhereditarybreastandovariancancer.NEJM2016; 374(24):2404.  
4. Mirzaetal.Niraparibmaintenancetherapyinplatinum-sensitive,recurrentovariancancer.NEJM
2016;375:2154-2164.  
5. Colemanetal.Rucaparibmaintenancetreatmentforrecurrentovariancarcinomaafterresponseto platinumtherapy(ARIEL3):Arandomized,double-blind,placebo-controlledphase3trial.Lancet 2017;390:1949-1961.  
6. Pujade-Lauraine.Etal.Olaparibtabletsasmaintenancetherapyinpatientswithplatinumsensitive, relapsedovariancancerandaBRCA1/2mutation(SOLO2/ENGOT-Ov21):Adouble-blind, randomized,placebo-controlled,phase 3trial.Lancet2017;18(9):1274-1284.  
7. Mooreetal.Maintenanceolaparibinpatientswithnewlydiagnosedadvancedovariancancer.  
NEJM.2018;379:2495-2505.  
8. SocietyofGynecologicOncology.SGOClinicalPracticeStatement;genetictestingforovarian cancer.October2014.  
9. NationalComprehensiveCancerNetwork.NCCNClinicalPracticeGuidelinesinOncology:
Genetic/FamilialHigh-riskAssessment:BreastandOvarian.V2(2019)
10. BerlinerJL,FayAM.Riskassessmentandgeneticcounselingforhereditarybreastandovarian cancer:recommendationsoftheNationalSocietyofGeneticCounselors. JGenet Couns. 2007;16(3):241–260.  
11. StatementoftheAmericanSocietyofClinicalOncology:Genetictestingforcancersusceptibility, AdoptedonFebruary20,1996.JCO1996;14)5):1730-6.  
12. American Society of Clinical Oncology policy statement update. Genetic testing for cancer susceptibility. J Clin Oncol. 2003;21:2397–2406.  
13. Robsonetal."AmericanSocietyofClinicalOncologyPolicyStatementUpdate:Geneticandgenomic testingforcancersusceptibility."JCO2010;28(6):893-901.  
14. Robsonetal."AmericanSocietyofClinicalOncologyPolicyStatementUpdate:GeneticandGenomic TestingforCancerSusceptibility."JCO2015;33(31):3660-7.  
15. LheureuxS,KarakasisK,HarterP,etal.GermlineBRCA1/2testingpracticesinovariancancer:
Currentstateandopportunitiesfornewdirections.GynecolOnc2016;140:90-94.  
16. FebbraroT,RobisonK,WilburJetal.AdherencepatternstoNationalComprehensiveCancer Network(NCCN)guidelinesforreferraltocancergeneticprofessionals.GynecolOnc2015;138: 109-114.  
17. Schwartzetal.Randomizednon-inferioritytrialoftelephoneversusin-persongeneticcounseling forhereditarybreastandovariancancer. J Clin Oncol.2014Mar1;32(7):618-26.  
18. TrepanierA,AllainD.Modelsofservicedeliveryforcancergeneticriskassessmentandcounseling.  
JGenetCounsel2014;23:239-253.  
19. Colomboetal.EvaluationofaStreamlinedOncologist-LedBRCAMutationTestingandCounseling ModelforPatientsWithOvarianCancer.JClinOncol2018May1;36(13):1300-1307.  
20. Kentwelletal.Mainstreamingcancergenetics:AmodelintegratinggermlineBRCAtestinginto routineovariancancerclinics.GynOnc.2017Apr;145(1):130-136.  
21. VanRoosmalenetal.ImpactofBRCA1/2testinganddisclosureofapositivetestresultonwomen affectedandunaffectedwithbreastorovariancancer.AmJMedGenetics2004;124A:346-344.  
22. Braithwaiteetal.Psychologicalimpactofgeneticcounselingforfamilialcancer:Asystematic reviewandmeta-analysis.JNatlCancerInst2004;96:122-33.  
23. Nordinetal.Isgeneticcounselingastressfulevent?ActaOncol2011;50(7):1089-1097.  
24. Zilliacusetal.Arevideoconferencedconsultationsaseffectiveasface-to-faceconsultationsfor hereditarybreastandovariancancergeneticcounseling?GenetMed201113(11):933-941.  
25. Cellaetal.Abriefassessmentofconcernsassociatedwithgeneticstestingforcancer:The multidimensionalimpactofcancerriskassessment(MICRA)questionnaire. HealthPsychology 2002;21(6):564-572.  
26. Weissetal.Quickassessmentofliteracyinprimarycare:Thenewestvitalsign.AnnFamMed.  
20053(6):514-522.  
27. Horowitzetal.Impactofeventsscale:Ameasureofsubjectivestress.PsychosomaticMed1979;3:
209-218.  
28. Bjornslettetal.PsychologicaldistressrelatedtoBRCAtestinginovariancancerpatients.Familial Cancer201514:495-504.