SUBMISSIONTOSENATEINQUIRYFORFUNDINGRESEARCHINTOCANCERSWITH

LOWSURVIVALRATES

IntroductionDefinition‘Lesscommon’cancersasthosewithanincidenceofbetween6and12(inclusive)per100,000Australiansperannum.1‘Rare cancers’ are defined as thosewith an incidence of less than 6 per 100,000Australiansperannum–atotalof186cancertypeshavebeendefinedasrare.In2015RareCancersAustraliareleaseditssecond“Justalittlemoretime”.Thereportwas launched in ParliamentHouseCanberraby theAssistantHealthMinister, KenWyattMP.Thereportdemonstratedthatoverthepast20years,survivalratesinmanyrareandlesscommon(RLC)cancershaveonlyimprovedmarginally,ifatall,whileoutcomesfor common cancers have improved dramatically. It is no small coincidence thatgovernment research funding into rare cancers remains disappointingly anddisproportionatelylow,asdoesthemoneywespendontreatmentsforthesepatientsthroughthePharmaceuticalBenefitsScheme(PBS).2Thereareinherentchallengesintreatingverysmallpatientgroups.Thesechallengeshave conspired to create an environment whereby these patients are completelyexcludedfromtheprogressachievedforthosewithmorecommoncancervariations.Asaresultofpoorinvestmentinresearchandtreatment,patientswithrarecancersare,almostwithoutexception,thosemostlikelytohavethelowestsurvivalrates.Itisestimatedthatin2014:

• 42,000peoplewerediagnosedwithanRLCcancer;• 24,000 patients died from an RLC cancer, accounting for half of all cancer

deaths;and• RLCcancerscontributedtosevenpercentof thetotalburdenofdisease in

Australia.31Gattaetal.,RareCancersarenotsorare:Therarecancerburden inEurope.EuropeanJournalofCancer47,2493-2511(2011).2RareCancersAustralia2014,JustaLittleMoreTime:RareCancersBaselineReport3RareCancersAustralia,JustaLittleMoreTime:RareCancersBaselineReport2013

Thedifferencebetweencommon,RLCandrarecancersCommonCancers

Graph1:Incidenceandmortalityratesforcommoncancerscomparedtopopulationchangesince1992The successeswe’ve seenover thepast 20 years for common cancer patients aresignificant.Whileincidencerateshaveincreased,asaresultofincreasedsurveillanceand screening,mortality rates havedecreaseddue to investment in research, andtreatment.Asaresult,patientstodaydiagnosedwithacommoncancerhaveamuchhigherchanceofsurvivalthantheydidintheearly1990s.Despitetheactualnumberofdeathsforallcancersincreasing,themortalityrateforallcancersfellby20percentbetween1982and2014.4Whileitistruethatsignificantadvanceshavebeenmadeforcommoncancers,datashowsthatthisisnotthecaseforRLCcancers.RareandLessCommonCancers

Graph 2: Incidence andmortality rates for rare and less common cancers compared to populationchangesince1992Asdistinctfromcommoncancers,thepercentageincreaseinincidenceandmortalityfor RLC cancers occur at roughly the same rate, i.e. twice the rate of populationincrease.Whilewehaveseen increases in incidenceforcommoncancers,wehavealso seen dramatic reductions in mortality due to early diagnosis and improved

4AustralianInstituteofHealthandWelfare2014.CancerinAustralia:anoverview2014.Cancerseries90.Cat.No.CAN88.Canberra:AIHW.

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treatments,butthishasnotbeenthecaseforRLCcancerswhereresearchinvestmentispoorandtreatmentavailabilitylimited.Thesameeffectisevenmoredevastatinginrarecancerdiagnoses.RareCancers

Graph 3: Incidence andmortality rates for rare and less common cancers compared to populationchangesince1992Australianpatientsdiagnosedwithararecancerfacethegreatestchallengeofall;forrarecancerpatientsthe increase inmortalityratesfaroutstriptherising incidencerates.WeneedtorecognisethatararecancerdiagnosisisoftenaccompaniedbyaverypoorprognosisandasourpopulationagesGraph3providesastarkinsightintotheimpactoftheseveryneglectedandundertreatedcancers.Thefollowingsectionshowsthecomparisonbetweenthreecancers,andtheimpactthatfundingforresearchhashadonimprovementsinsurvival.

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CancerSpecificExampleBreast,CervicalandOvarianCancers

Graph4:Incidenceandmortalityratesforbreastcancercomparedtopopulationchangesince1992TheAIHWestimatesthatin2016therewillbe16,080patientsdiagnosedwithbreastcancer;five-yearrelativesurvivalatdiagnosisforbreastcancerpatientsis89.6%.Theage-standardisedincidencerateforbreastcanceris116per100,000.5BreastcanceristhemostcommoncancerinAustralianwomen.Between1992and1994,theincidenceofbreastcancerincreasedsharplyfrom98newcasesofbreastcancerper100,000femalesto114per100,000.Thisobservedincreasecorrespondedwiththeintroductionofthenationalbreastcancerscreeningprogram,knowntodayasBreastScreenAustralia,in1991.6Duetosignificantinvestmentsinresearch,diagnostics,andtreatmentswehavebeenabletosignificantlyreducebreastcancermortalityoverthepast20years.

5AustralianInstituteofHealthandWelfare2014.CancerinAustralia:anoverview2014.Cancerseries90.Cat.No.CAN88.Canberra:AIHW.6AustralianInstituteofHealthandWelfare.InterpretingCancerData,accessedon12thJanuary2016http://www.aihw.gov.au/cancer/data/interpreting/

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Graph5:Incidenceandmortalityratesforovariancancercomparedtopopulationchangesince1992TheAIHWestimatesthatin2016therewillbe1480patientsdiagnosedwithovariancancer;five-yearrelativesurvivalatdiagnosisforovariancancerpatientsis43%.Theage-standardisedincidencerateforovariancanceris5.4per100,000.7Bycomparison,despitebeingthesixthmostcommoncauseofcancer-relateddeathinwomen inAustralia,noscreeningprogramsareavailable forovariancancerandincidencecontinuestoincreaseatthesamerateaspopulationincrease.TheAIHWestimatesthatin2016therewillbe1,480patientsdiagnosedwithovariancancer;itisalsoestimatedthattherewillbe1,040ovariancancerdeathsinthesameyear.8When ovarian cancer is detected at an early ‘localised’ stage, when the cancer isconfinedtotheovary,upto93%ofwomenarelikelytosurvivemorethanfiveyears.However,onlyabout15%ofallcasesarediagnosedatthisstage,9andasaresulttheaveragefive-yearsurvivalremainslowat43%.10Afurtherexampleoftheimpactofscreening,andtheintroductionofpreventativemeasuressuchasvaccination,isseenwhencomparingtheoutcomesincidenceandmortalityofcervicalandovariancancers.

7AustralianInstituteofHealthandWelfare2014.CancerinAustralia:anoverview2014.Cancerseries90.Cat.No.CAN88.Canberra:AIHW.8AustralianInstituteofHealthandWelfare2014.CancerinAustralia:anoverview2014.Cancerseries90.Cat.No.CAN88.Canberra:AIHW.9WorldOvarianCancerDay.5FactsEveryoneShouldKnowaboutOvarianCancer,accessedon12thJanuary 2016 http://ovariancancerday.org/about-ovarian/5-facts-everyone-should-know-about-ovarian-cancer/10AustralianInstituteofHealthandWelfare2014.CancerinAustralia:anoverview2014.Cancerseries90.Cat.No.CAN88.Canberra:AIHW.

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Graph6:ThedifferencebetweenscreeningandpreventionhasoncancerincidenceandmortalityforcervicalandovariancancersTheAIHWestimatesthatin2016therewillbe905patientsdiagnosedwithcervicalcancer; five year relative survival at diagnosis is 71.9%. The age-standardisedincidencerateforcervicalcanceris3.5per100,000.11Unlikeovariancancer,therehavebeenmajoradvancesincervicalcancerinthepast20years.ThecurrentNationalCervicalScreeningProgramwas introducedin1991,andin2007theGovernmentintroducedthefreeNationalHumanPapillomavirusVirus(HPV) Vaccination Program, using Gardasil, for school girls (boyswere included in2013).Asof1May2017theNationalCervicalScreeningProgram(Paptest)willbereplacedbyanimprovedprimaryHPVtest.Both breast cancer and cervical cancer offer great hope forwhat is achievable incancer prevention and treatment and, in differentways, can be seen as the ‘goldstandard’intermsofwhatispossibleforimprovingoutcomesforAustraliancancerpatients through investment in research. The demonstrable effect of preventativeinterventions, early diagnostic tests and improved access to treatment on theincidence and mortality of breast and cervical cancers is unfortunately not yetreplicableacrossallcancers.

11AustralianInstituteofHealthandWelfare2014.CancerinAustralia:anoverview2014.Cancerseries90.Cat.No.CAN88.Canberra:AIHW.

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FundingCancerResearchAustraliaisaleaderincancerresearch.The2015AuditofCancerResearchinAustraliareported that between 2006 and 2011, the Australian Government (including theNHMRC)provided$1.03bn(or58%of$1.77bntotalfunding)forcancerresearch.Ofthe$350mspentannuallyoncancerresearchonlyanegligible2%ofthatgoestosolidraretumours.12TheAudit reportnotedthatwhilebreastcancer,colorectalcancer,haematologicalcancersandgenitourinarycancersreceivedthehighestlevelsoffundinginAustralia,theproportionalfundingtoresearchinmanycancerswaslowcomparedtoincidence,mortalityandburdenofdiseaseontheAustralianpopulation.Thosecancersincludedlung, lymphoma, pancreas, oesophagus, kidney, stomach, bladder, myeloma andcancerofunknownprimary.13

Graph6:Percentagecancerresearchexpenditure(perannum)versuspercentageburdenofdiseaseanddeathsWhiletheAuditreportshowedaslightincreaseinresearchfundingforlesscommoncancers, itdemonstratedacontinuingstrong focusoncommoncancerswithin theAustralianResearchCommunity.Indeeditevenrecommendedthat‘Researchfundinginvestment in Australia could be prioritised for cancers which have a high impact

12CancerAustralia,2015.CancerResearchinAustralia:anoverviewoffundinginitiativestosupportcancerresearchcapacityinAustralia2006to2011.13CancerAustralia,2015.CancerResearchinAustralia:anoverviewoffundinginitiativestosupportcancerresearchcapacityinAustralia2006to2011.

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(incidence and mortality) and burden of disease – disability-adjusted life years(DALYs)’.14Theimpactofthisneglectofrarecancerresearchissignificantinanumberofways.Thefirstandmostobviousbeingthatif“youdon’tlookyoudon’tfind”meaningthatwithout focussed research we are unlikely to find and evaluate worthwhiletreatments.Equally importanthowever, is thatwithoutresearchwedonotbuildupcentresofknowledge and clinical excellence that are critical to providing the best possiblestandardofcareforpatientswithspecificrarecancers.Theestablishmentofproperlyfundedcentresforrarecancerresearchisnowanurgentpriority.In the 2014 Budget the Government announced that it would create a MedicalResearch Future Fund (MRFF), to deliver additional Commonwealth funding formedicalresearchandinnovationintothefuture.InAugust2015theBilltopasstheMRFFintolawwaspassed. ThisnewsourceofresearchfundingpresentsanidealopportunityforGovernmenttotake affirmative action and specifically target areas of neglect such as rare cancerresearch,whichremainswoefullylowcomparedtocombinedincidenceandmortality.

Graph7:Piechartrepresentingthedivisionofresearchfundingbycancertype

14CancerAustralia,2015.CancerResearchinAustralia:anoverviewoffundinginitiativestosupportcancerresearchcapacityinAustralia2006to2011.

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Anecdotal information from researchers suggest that while there may have beensomechangesintheseratioswithmorefundinggoingtolesscommoncancerssuchas pancreatic and cancer of unknown primary, there is still a dearth of fundingprovidedtothevastmajorityofRLCcancers.TheimpactofresearchfundingWhenwe look across the spectrum of cancers it is clear that a correlation existsbetweenresearchspend,burdenofdiseaseandmortality.WhileAustralianresearchisonlyasmallpartofallglobalcancerresearch,withthepossibleexceptionofmelanoma,thereisnoreasontobelieveouroverallfocusoncommoncancerswouldnotbereplicatedthroughouttheglobalresearchcommunity.LackofresearchintoRLCcancershastwodirectimpacts;thefirstandmostobviousisthatwithoutresearch,thereisnolikelihoodofimprovedtreatmentsandpotentiallycures, the second and perhaps less obvious, is that without research we will notdeveloptheknowledgetodesignscreeningtestsorearlydiagnosismechanisms.Earlydiagnosisishighlysignificantinimprovingpatientsurvivalandourexperience,asseenwithmanyofourpatients,isthatmanyAustralianswithRLCcancershadtheiroutcomescompromisedbylatediagnosis.Giventheneglectofrareandlesscommoncancerresearchwhencomparedtoburdenofdiseaseandmortalitywemusttakeactiontoencouragetheresearchcommunitytoincreaseactivityrelatedtothesecancers.Research has shown that increasing the allocation of resources to research andfundingtreatmentsthroughthePBSpositivelyimpactssurvivalofcancerpatients.ThelackoffocusonRLCcancersmanifestsinpoorsurvivaloutcomesandconsequentlymuchhighermortality.AddressingthediscrepanciesforRLCcancerscomparedwithcommoncancersneedstooccuratthehighestlevel,andweneedtheAustralianGovernmenttotakeaction.Weneedtoimproveoutcomesforrareandlesscommoncancerpatientsandtodosowemustreviewexistingmechanismsandimproveresearch,diagnosticsandaccesstomedicinesforRLCcancers.Without similar mechanisms created for tackling common cancers, i.e. thosespecificallydesignedtoaddresstheprevention,diagnosis,andtreatment,wecannothope to have an impact on mortality or on improving patient outcomes for RLCpatientsinthefuture.

ImprovingResearchFundingforRareCancersDespite the Cancer Australia Audit of research funding demonstrating that totalfunding for rareand less commoncancershas increased in recent years, the totalfunding required toclose thegapbetween fundingand theburdenofdiseaseandmortalitycausedbyRLCcancerscomparedtocommoncancersremainssignificant.Clinical trials into effectiveness of novel, targeted therapies, in small patientpopulations, require collaborative trial development and research which crossestraditional boundaries of trials currently being undertaken in Australia, and theevidentiaryrequirementsforregulatorsmustalsobemadetobemoreflexibleforrareandsuperrarecancers.The Australian Government, through the NHMRC, and other Departments is thelargestfunderofcancerresearchinthiscountry,andthisfundingissettoincreasethroughtheMRFF.GiventhesignificantrolethattheGovernmenthastoplayinfundingthisimportantwork,RCA calls on theGovernment to take the lead throughaffirmativeaction todirectfundingtospecificallytargetareasofneglectsuchasrarecancerresearch.ExamplesofRareCancerResearchTheMolecularScreeningandTherapeutics(MoST)studyisAustralia’sfirstprecisionmedicine trial focused on the rare cancer population. It is a joint initiative of theGarvan Institute and theNHMRCClinical Trials Centre, and is funded by theNSWgovernment.ThegoaloftheMoSTistooffer1,000patientswithadvancedcancerastate-of-the-artgenomicprofile,andthenmatchtheoutputstomultipletherapeuticoptionsintheformof abasketof signal-seeking trials.Where cognate therapeutic optionsdon’texistwithinMoST,patientsandtheircliniciansarerefferedtoappropriateexternaltrials,orareprovidedsuggestionsforcompassionateaccessprograms.After5yearsinplanning,theMoSTopenedforrecruitmentattheKinghornCancerCentreatSVHinOctober2016,withthefirsttherapeuticmodulescomingonlineinNovember 2016. RCAwwas important in advocating for expediting the process ofopeningthetrialatSVH.Over 70 subjects have been recruited in the first 4 months of the study, theoverwhelming majority of which comprise subjects with advanced rare cancers.SubjectshavecomefromallpartsofAustralia,andevenfromNewZealand.Todate,approximately35subjectshavehadresultsreturned,andofthese8subjectshave been offered treatment on one of the two therapeutic modules currently

available (palbociclib, and durvalumab/tremelimumab immunotherapy). This is apleasingresult,andconfirmsthatthestudyisaddressingasubstantialpopulationwithunmetneed.Garvan Insitute and NHMRC Clinical Trials Centre have plans to open another 3modules(vismodegibfortumorswithmutationsinPTCH1;olaparibanddurvalumabimmunotherapy for patients with BRCA-type mutations; and eribulin for vascularcancers).TheyarealsoseeinganumberofmutationsingenessuchasHER2,forwhichtherearegoodtherapiesavailable.Theywoulddearlyliketoopenadditionalmodulesoverthenext24monthstoincreasetherangeofoptionsavailable.Excerpt from Professor David Thomas of the Garvan Insitute emphasising theimportanceofthisresearch

‘For example, at this week’s molecular tumor board, we had a patient withmetastaticsalivaryadenocarcinomawithHER2amplification,whocancurrentlyonlyaccessthedrugbypayingforit(partsubsidyfromRoche).Iestimatethatthecosttothisindividualforayear’streatmentwillbe~$50,000,mostofwhichwillbeeitherout-of-pocket,orsourcedfromphilanthropy(thanksfor[RCA’s]helpinthiscase).Rochearewillingtosupportnewmodules,includingHerceptin.

Animpendinglimitationinopeningmoretherapeuticoptionsisfunding.ThetrialhascorefundingfortheNHMRCCTCfor5years,withanintentiontoapplyforfurther core funding. We have funding for the correlative science at Garvan.Howeverthesitecostsofenrollingpatientsis$5000/case,meaningthateverynewmodulecostsabout$80,000.

Inaddition,wewanttofranchisetheMoSTtoVCCC,andthentoothernationalcentres who treat large populations with rare cancers. This is because it isundesirableforpatientswithadvanceddiseasetotraveltoNSWfromasfarasWAto get access to these treatments. In the next 12 months, as the programconsolidates its operations, itwill be ready to commenceopeningatnon-NSWcentres.’

ConclusionOnlyby improvingour investments in rarecancer researchwillweeverbeable todeliver improvements to patients and reduce mortality rates for these otherwiseneglectedpatients.ThesimplecostofdoingnothingtoimproveoutcomesforRLCcancersistoohighandthechallengetherefore,istofindamechanismwherebyresearch:

• FundingisincreasedandspecificallydirectedtoencourageanddriveresearchintoRLCcancersandraremolecularsub-types;

• That focuses on “re-purposing” existing drugs for rare cancers is activelyfunded–e.gMOSTTrial(asabove);

• Partnershipsarecreatedwiththepharmaceuticalindustrysothattheyprovidedrugsinreturnforclinicaltrialdata-that is,gettingresearcherstopartnerwithindustryinadvanceofrequestsforfunding;and

• Rarecancerspatientscanreceiveequitableandfairaccesstomedicinesthathavereasonableandprovensafetyandefficacyforthosediseases,specificallybydevelopingasimplifiedpathwayforrepurposeddrugstoachieveTGAandPBSlistingbasedontheresults.

Rarecancersrepresentamajordiagnosticaswellastherapeuticchallengeandtheyrepresent amajor sourceof discriminationamongpatients. It is timewe took theactionnecessarysothatwecangivetheseAustralianpatientstheresources,supportand treatment theyneedandmost importantlyprovide themallwith “justa littlemoretime”.