Personalized,Cancer,Treatment,2, Impact,of,Emerging,Science,on, Treatment,Paradigms! UICC,World,Cancer,Congress,, August,2012,

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1 Personalized,Cancer,Treatment,2, Impact,of,Emerging,Science,on, Treatment,Paradigms! UICC,World,Cancer,Congress,, August,2012,! Elizabeth*A.*Eisenhauer*MD*FRCPC* Department*of*Oncology,*Queen s*university* *Kingston,*Canada*

2 Outline! What!is!personalized!cancer!treatment?! Examples!of!successes! Challenges!to!be!addressed! And!poten<al!solu<ons!

3 One!Concept!!Many!Names! Personalized!Medicine!!!=!Stra<fied!Medicine!!!!!=!Precision!Medicine!!!!!!=!Tailored!Medicine!

4 Personalized!Medicine!!! One!concept,!a!mul<tude!of! meanings!and!perspec<ves! Pa$ent:! I!want!my!doctor!to!know!about! my!life,!to!understand!me!and!my! family!and!to!help!me!reach, decisions,that,are,best,for,me.,, I!did!not!want!to!lose!my!hair!on! treatment!so!we!found!an!op<on! for!me!that!would!spare!my!hair.! Clinician:! Which!pa<ent!or!disease! features!will!alter,my, approach,to!preven<on,! screening,!or!treatment?!!

5 Personalized!Medicine!!! Scien$st:! One!concept,!a!mul<tude!of! Each!pa<ent s!cancer!has!gene<c! changes!and!each!pa<ent!has! meanings!and!perspec<ves! genomic!varia<ons!that!make! them!unique.!we!are!looking!for! those!changes!that!will!allow!the! right!pa<ent!to!receive!the!right! treatments!matched!to!their! genedc,fingerprint.,

6 Today s!topic:!! Matching!specific!muta<ons!in!a!pa<ent s! cancer!with!targeted!therapy(ies)!

7 Personalized!Medicine!Examples!! Already*in*Use*in*Cancer*Medicine* Safe!chemotherapy!dosing! Carbopla<n!dosed!based!on!individual!GFR.! Breast!cancer!screening!in!BRCA!mut.!carriers:!! MRI!based;!prophylac<c!surgery! Prognos<c!gene!signatures! Guide!who!does!NOT!need!treatment! Individualized!planning!for!radia<on!treatment! Stra<fica<on!of!tumours!based!on!molecular! findings!that!predict!treatment!benefit!thus! allow!treatment!selec<on!

8 Examples!! Personalized!! New!Cancer!Therapies!

9 Example*1:! Breast!cancer:!! Inhibi<ng!HER2!

10 Newly!diagnosed! breast!cancer!pts! have!cancer! analysed!markers:! Estrogen!and! progesterone! receptors! HER2!protein! Pa<ents!with!HER2!+! cancer!treated!with! trastuzumab:! Breast!Cancer! 7%! improvement! at!4!years!

11 Example*2:! Malignant!Melanoma:!! Inhibi<ng!Mutated!BRAF!

12 Here we report BRAF somatic missense mutations in 66% of malignant melanomas June*2002:* BRAF!muta<ons!in! ~2/3!melanoma! >90%!are!V600E! Development!of! inhibitors!of! mutated!braf!next! logical!step!

13 Targe<ng!MUTANT!BRAF!protein! Agent!designed!to!inhibit!mutated!variant!of!target!!!select! for!pa<ents!having!tumours!with!mutated!target.! Vemurafenib! (PLX!4032)!!

14 Metasta<c!Melanoma:!! Drama<c!improvement! in!scans!within!2!weeks! of!targeted!braf! inhibitor!therapy!

15 Chapman!PB,!et!al!NEJM!2011!

16 Over!past!decade!!Several!other!examples!of! successful!molecular!targeted!therapy! Disease, GeneDc,abnormality/ Test, Drug,, (examples), Survival, impact, Breast!cancer! HER2!amplifica<on! trastuzumab!! years! Melanoma! BRAF!V600E!muta<on! vemurafenib! months! GI!Stromal! Tumour! Chronic!Myeloid! Leukemia! clkit!muta<on! ima<nib!! years! bcrlabl!transloca<on! ima<nib!! years! Colorectal!cancer!! Kras!wild!type! cetuximab! months! Lung!cancer!! EGFR!muta<on! gefi<nib! months! ALKlEML4! transloca<on! crizo<nib! months!

17 Over!same!decade.! Powerful!next!genera<on!genomic!sequencing! technologies!have!become!available! QUESTION:! Could!we!simply!sequence!an!individual! pa<ent s!tumour!to!discover!all!abnormali<es!to! design! cocktail!of!therapeu<cs?!

18 The!proposed!new!! personalized!paradigm! New,cancer,diagnosis, Malignant,Dssue, sent,for,genedc,tests, Specific,therapies,as,dictated,by,test,results,added,, to,standard,of,care,(surgery,,radiadon,,chemo), Disease,relapses, Malignant,Dssue, sent,for,genedc,tests, Specific,therapies,as,dictated,by,test,results,

19 High!expecta<ons!within!scien<fic!community! and!public!of!transforma<on!in!cancer!care!and! beper!outcomes!coming!soon!

20 How!realis<c!is!this?! What!challenges!must!be!overcome! before!this!is!a!reality!for!all!cancer! pa<ents?!! Technology!and!tes<ng! Complex!muta<onal!nature!of!cancers! Drugs! Costs!

21 Challenges!!! Muta<on/Gene<c!Tes<ng! How!will!SYSTEM!address!issues:! When,to!test! Access!to!tests/technology! Quality!controlled!tes<ng! Standard!test!interpretaDon,

22 When!to!test?! At!diagnosis?!At!relapse?!In!all!pa<ents?! Paradigms!will!need!to!be!disease!specific!as! new!treatments!are!relevant!in!different! diseases!at!different!<mes.! Evidence!base!upon!which!to!build! recommenda<ons!

23 Which!Tests?! Oneltestlatlal<me! * versus*! Mul<plex!tes<ng! * versus*! Genome!sequencing!

24 Which!Tests?! One2test2at2a2Dme, * versus*! Mul<plex!tes<ng! * Most!similar!to!tes<ng!done!in!pathology!labs!now.!! versus* Quality!control!(QC)!easily!achievable!! Cost!per!test!high! Genome!sequencing! Limited!to!exact!muta<on!in!test!

25 Which!Tests?! Oneltestlatlal<me! * versus*! MulDplex,tesDng, * More!efficient!l!!cost!per!muta<on!lower;!<ssue!per! versus* muta<on!lower!! QC!more!challenging!but!achievable!!regional!network!of! Genome!sequencing! labs?! Results!limited!to!muta<ons!in!panel!

26 Which!Tests!and!When?! Many!muta<ons!will!be!found!!!interpreta<on!becomes! more!of!an!issue! QC!/<meliness!issues?! Oneltestlatlal<me! Will!need!specialized!network!of!labs! * Data!storage!and!analysis!major!issues!esp.!for!clinical! applica<ons! versus* EXPENSIVE!!though!costs!falling!! Mul<plex!tes<ng! * versus*! Genome,sequencing,

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28 Addressing!Challenges! Whole!exome!sequencing,!although!important! for!discovery!research,!is!not!going!to!be!a! rou<ne!test!for!treatment!decisions!any<me! soon.! More!likely!scenario:!tes<ng!for!specific! muta<ons!in!mul<plex!panel!l!perhaps! bundled!by!disease!type!in!designated! networks!of!laboratories!! Several!countries!are!undertaking!ini<a<ves! aimed!at!implemen<ng!

29 Ini<a<ves!to!Enable!Laboratory! Implementa<on!!Cancer!Research!UK! Stra<fied!Medicine!Programme! Aims!to!establish!the!founda<ons!of!a!na$onal! service!of!gene$c!tes$ng! Phase!I!l!!July!2011l2013:! Pilot!study!!in!7!exis<ng!Experimental!Medicine!Centres! Will!recruit!7,!000!pa<ents!with!breast,!bowel,!lung,! prostate,!ovary,!melanoma! Tissue!samples!sent!to! technology!hubs!to!extract! DNA,!test!for!a!panel!of!specific!gene<c!abnormali<es!!

30 Ini<a<ves!to!Enable!Implementa<on!!! Ins<tut!Na<onal!du!Cancer!!(France)!! 28lcenter!personalized!medicine!tes<ng! network! INCa!funds!emerging!tests!while!they!progress! towards!standard!of!care,!thereby!facilita<ng! early!access.!! Network!focusses!on!single!tests:!currently! offers!egfr,!klras,!blraf,!eml4lalk,!and! HERl2!tes<ng.!

31 Challenges!!! Genome!sequencing:! Which!muta<ons!are!important?! Cancers!are!complex!and!heterogeneous!with! mul<ple!muta<ons,!copy!number!changes!

32 Nature,!June!2012! 100!primary!breast!cancers! 21,416!protein!coding!genes!and!1,664!microRNAs!sequenced! 7,!241!soma<c!point!muta<ons!l!!4,737!missense,!422!nonsense! Driver,mutaDons,in,at,least,40,cancer,genes, 73,different,combinaDons,of,mutated,cancer,genes,

33 Challenges!!!! Furthermore! Tumours!are!constantly!evolving!! Within!an!individual s!cancer,!molecular! changes!are!not!sta<c!geographically!or!over! <me.!

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36 RESISTANCE!to!treatment!can!develop:! BRAF!inhibitor!response!at!2!weeks!l!!and! progression!at!6!months!!

37 Challenges!!! Complexity!and!Malignant! Evolu<on! Some!argue!that!this!makes!the!no<on!of! undertaking!personalized!medicine!an! unobtainable!dream!!l!!constant!race!against! <me!where!the!more!we!run!the!more!we!will! stand!s<ll.!

38 Addressing!the!Challenges?! Not!all!muta<ons!are!relevant!or!important!!! need!more!research!into!the!biological! importance!of!(commonly)!iden<fied!muta<ons! that!are!discovery!in!sequencing!to!know!which! are!really! driving!cancer.!! Target,the,mutaDons,in,the, trunk,of,the, phylogenedc,tree,

39 Challenge!!Too!Few!Good!Drugs! Many!targeted!agents!have!only!modest!an<l cancer!ac<vity!!and! Most!have!toxici<es!related!to!effects!on! normal!<ssue!

40 Modest!effect!of!targeted!drugs?!! Most!new!drugs!tested!first!in!advanced!/! metasta<c!cancer.! While!many!can!induce!tumour!shrinkage!this! may!be!short!lived!and!effect!on!survival!is! limited!(with!some!notable!excep<ons)!! The!more!important!test!of!their!impact!is!in! the!adjuvant!sevng!!where!truly!ac<ve!drugs! should!increase!long!term!survival/cure!rates!

41 What,are,the,Adjuvant,Results,of, FDA,Approved,Targeted,Agents,

42 Target!Agent! Approved!advanced! Adjuvant!?!status?! disease!indica$on!! mtor! everolimus! Renal! 1!trial!ongoing! Panc.!Neuroend.!?! temsirolimus! Renal!?! VEGF/! bevacizumab! Colorectal! 2,trials,negaDve,(CO28,,AVANT)! VEGFR! Lung! 1!trial!not!reported!(E1505)!! Renal! l! Brain! 2!trials!in!GBMl!not!reported! Breast! Several!trials!not!reported! suni<nib! Renal! 3!trials!l!ongoing! Panc.!Neuroend.!?! GIST!?! sorafenib! Renal! 3!trials!l!ongoing! Hepatocellular! 1!trial!not!reported! pazopanib! Renal! 1!Trial!l!ongoing! vandetanib! Thyroid!?! axi<nib! Renal!?!

43 Target! Agent! Approved!advanced! Adjuvant!?!status?! disease!indica$on!! HER2! trastuzumab! Breast! Trials,posiDve,for,RFS/OS! Gastric!?! lapa<nib! Breast! 1!trial!(ALTTO)!not!reported! EGFR!! panitumumab! Colorectal! 1!trial!in!rectal!ongoing! cetuximab! Colorectal!!! 1,trial,,negaDve,in,RAS,WT;, worse!outcome!in!ras!mut* Head!and!Neck! 1!trial!(RTOG!0920)!ongoing! erlo<nib! NSCLC!!! 1!trial!!(RADIANT)!not!reported! 2!trials!ongoing! Pancreas! 2!trials!ongoing! gefi<nib!! NSCLC! 2,trials,negaDve,(BR19,,S0023), (gefi$nib!arm!?!worse!outcome)! 1!trial!recrui<ng!in!EGFR!mut! Kit! ima<nib! GIST!! Trials,posiDve,for,RFS,&,OS! BRAF! vemurafenib! Melanoma! ongoing! EML4l ALK! crizo<nib! NSCLC!?!

44 Toxicity!!may!limit!dosing!(and!efficacy?)! Many!targeted!drugs!are!designed!to!inhibit!normal! variant!of!the!molecule,!causing!normal!<ssue!toxicity! This!also!has!limited!our!ability!to!combine!targeted! agents.! Skin!rash!! EGFR!inhibitors! Hypertension!! angiogenesis! inhibitors!

45 This!is!the!most!important!challenge! No!maGer!how!good!we!are!at!defining!the! molecular!changes!in!a!pa$ents!tumours!! there!will!be!no!real!impact!on!cancer!control!if! the!drugs!available!to!treat!these!changes!have! limited!ac$vity.!

46 Solu<ons?! We!would!all!like!the!answer!to!this!one!! Some!sugges<ons?! Beper!choice!of!molecular!targets!!develop!drugs! that!target!abnormal!variants!of!key!proteins!! not!the!normal!ones! Set!bar!higher!for!performance!in!drugs!selected! for!tes<ng!test:!!! e.g.!those!that!inhibit!the! abnormal!target!by!>!95%! (even!>99%)!at!safe!doses!!instead!of!the!40l80%! inhibi<on!most!drugs!today!are!achieving!!

47 Effect!of!oral!PI3k!inhibitor!BKM120!on!pS6! levels!in!skin!biopsies,!by!dose!cohort.!! BKM120!>80!mg:! 40%,2,85%,decrease!in!pS6! levels!compared!to!baseline! 2012 by American Society of Clinical Oncology Bendell J C et al. JCO 2012;30:

48 AromaDzaDon,rate, inhibited,by,>,98.9%, at,2.5,mg,letrozole.,

49 Challenge!!Costs!vs.!Benefits! Is*vision*personalized*medicine*affordable*within* a*public*funded*system?* With!today s!technologies!and!drugs!!!no! New!cancer!drugs!are!very!expensive!and,!with! some!excep<ons,!have!not!had!drama<c!benefits! Tes<ng!is!expensive! May!!be!cost!savings!IF!(inexpensive)!test!to! restrict!popula<on!is!iden<fied!after!a!drug!is! already!being!used!in!prac<ce! BUT!for!drugs!marketed!with!test!developed!in! parallel!!costs!are!high!

50 Tipping!the!balance!in!favour!of!affordability?! Some!thoughts!of!a!nonleconomist! Gene<c!tes<ng!of!tumours:! Coordinated!lab!network;!Beper!(cheaper)!mul<plex!tests! Evidence!based!algorithms!of!when/who!to!test!! Drug!Treatments:! New!genera<on!of!treatment(s)!should!offer!gains!in! meaningful!outcomes!!that!are!sustained!(i.e.!survival)! Drug!pricing!! needs!discussion!across!borders price!should!reflect! meaningful!benefits!achieved.! But,we,are,a,long,way,from,global,access,to,, genome,based,personalized,cancer,treatment,

51 Summary:!Personalized!Medicine! Not!really!a!new!paradigm! New,breast,cancer,diagnosis, Malignant,Dssue, sent,for,her2,tests, Trastuzumab,treatment,HER2+,ajer, to,standard,of,care,(surgery,,radiadon,,chemo), Disease,relapses, Malignant,may,be, re2evaluated, Specific,therapies,as,dictated,by,test,results,

52 Many!Challenges!before!!Full! Vision!of! Personalized!Therapy!can!be!Realized! Cancer!genome!sequencing!of!all!pa<ents!to! determine!which!drugs!they!will!receive!is!far!in!future! but!progress!made!towards!this!in!past!decade.!! Several!important!challenges!remain:! Clear!algorithms!for!tes<ng!and!decision!points! Decisions!on!gene<c!tes<ng/plazorms/data!storage! Beper/more!affordable!drugs!targe<ng!mutated!variants! Encourage!real!world!evalua$on!!of!new! technologies/drugs!in!cancer!care!system!!fund! approaches!to!enhance!efficiencies!and!reduce!costs!

53 Thank!You!for!Your!Apen<on!!