Prevention/Chemoprevention

YueshengZhang

February9,2016

DepartmentofCancerPreventionandControl

yuesheng.zhang@roswellpark.org

Topicstocover:1. Whycancerprevention?

2. Whatiscancerprevention?

3. Whatiscancerchemoprevention?

4. Thecurrentstatusofcancerchemoprevention

CancerRatesAreIncreasingGlobally

14.1millionnewcases;8.2millioncancerdeaths;32.6millionpeoplelivingwithcancer(within5yearsofdiagnosis).

Themostcommonlydiagnosed:lung(13.0%),breast(11.9%),colorectum(9.7%).Themostcommoncausetodeath:lung(19.4%),liver(9.1%),stomach(8.8%).

About30%ofcancerdeathsareduetofiveleadingbehavioralanddietaryrisks:highbodymassindex,lowfruitandvegetableintake,lackofphysicalactivity,tobaccouse,andalcoholuse.

Tobaccousecausesover20%ofglobalcancerdeathsandabout70%ofgloballungcancerdeaths

About65%ofallcancerdeathsoccurredinlow-andmiddle-incomecountries.

Projectionsfor2030:21.7millionnewcases,13.1milliondeaths.

WHOGLOBOCAN2012

CACancerJClin2015;65:5-29.

TrendsinCancerIncidenceandMortalityRatesinUS,1975-2011

CA Cancer J Clin 2015; 65: 5-29

Annul Age-Adjusted Cancer Incidence Rates in the United States

Rat

e pe

r 100

,000

Pop

ulat

ion

Annual Age-Adjusted Cancer Death Rates Among Males in the United States

CA Cancer J Clin 2015; 65: 5-29

CA Cancer J Clin 2015; 65: 5-29

Annul Age-Adjusted Cancer Death Rates Among Females in the United States

CancerisnowthenumberonekillerintheUSpopulationyoungerthan85years

CA Cancer J Clin 2011; 61: 212-236

Chest 1997; 111: 1414-1416

Trends in prevalence of cigarette smoking among US men aged 18 years or older and age-adjusted lung cancer mortality rate

Chest 1997; 111: 1414-1416

Trends in prevalence of cigarette smoking among US women aged 18 years or older and age-adjusted lung cancer mortality rate

• Forpatientswithmetastaticcancer,eventhemostadvancedtreatmentmethodsoftendonotsavetheirlives.

•Inpatientswithlessadvancedcancer,treatmentextractsahighmorbidityandcausestremendoussocialandeconomicdevastation.

Oncecancerisdiagnosed…

Cancercellsareextremelydifficulttoeliminate

•Unlimitedreplicativepotential

•Selfsufficiencyingrowthsignals

•Insensitivitytoanti-growthsignals

•Evadingapoptosis

•Sustainedangiogenesis

•Tissueinvasionandmetastasis

NormalCell

InitiatedCell

Pre-MalignantCell

MalignantCell

Dx:ClinicalCancer

Metastasis

Clonalselectionandexpansion(multiyear,multistageandmultipath)

GeneticChangesActivationofprotooncogenes

InactivationoftumorsuppressorgenesDisturbanceofproliferationandapoptosis

ChemicalsRadiationBiologicalagentsRandom

Carcinogenesis

ClinCancerRes2006;12:3661-3697

CancerCanBePrevented

Cancer-causingfactors:• Whatyoueat:carcinogen-contaminatedfoods.

• Whatyoudrink:alcohol,carcinogen-contaminatedwater.

• Whatyouinhale:tobaccosmoke,pollutedair.

• Sunshine:UVAandUVB.

• Medicine:certaindrugs,radiationtherapy.

• Infection:hepatitisBandCvirus,humanpapillomavirus,

Epstein-Barrvirus,Helicabecterpylori,Shistosoma

Haematobium.

• Germlinemutations.

• RandommutationsduringDNAreplicationinstemcells.

NicotineAddition

PAHandNNK Excretion(metabolicdetoxification)

DNAadducts

MetabolicActivation

Mutationsink-ras,p53,andothercriticalgenes

Lungcancer

Cigarettesmoking

Someonewhohassmokedalltheirlifehasalung-cancerrisk20-30timesgreaterthananon-smoker

PAH,polynucleararomatichydrocarbonsNNK,4-(methylnitrosamino-1-(3-pyridil)-1-butanone

Persistingmiscoding

EffectsofSmokingCessationonLungCancerRisk

Timesincestopping

Relativerisk

Men Women

Currentsmokers

2-9years

10-19years

20-29years

>30years

Non-smokers

1.00

0.66*

0.27*

0.17*

0.08*

0.04*

1.00

0.41*

0.19*

0.08*

0.13*

0.11*

* p<0.05

Tyczynskietal.,LancetOncology4,45-55,2003

Inadditiontoavoidingexposuretocarcinogens,cancerriskcanbereducedbyemployinginterventionmeasures.

HumanPapillomavirus(HPV)VaccinePreventsCervicalCancer

BackgroundandStudyDesign:HPVtypes16and18causeapproximately70%ofcervicalcancers.Inarandomized,double-blindedtrialinvolvingwomenof15-26yearsofage(withoutpriorHPVinfection),aquadrivalentvaccineagainstHPVtypes6,11,16and18,wasadministeredatday1,month2,month6,andsubjectswerethenfollowedfor3years.

CervicalIntraepithelialNeoplasiaorAdenocarcinomaInSituAssociatedwithHPV-16orHPV-18

VaccineGroup PlaceboGroup

TotalSubjects

No.ofCases

TotalSubjects

No.ofCases

5305 1 5260 42

NEnglJMed2007;356:1915-1927.

TheProstateCancerPreventionTrial(PCPT)TheFinasteridePreventsProstateCancerTrial

Background:Androgensareinvolvedinprostatecancerdevelopment.Finasteride,aninhibitorof5α-reductase,inhibitstheconversionoftestosteronetodihydrotestosterone,themainandrogenintheprostate.

Design:Finasteride(5mg/day)wasgiventomen≥55yearsfor7years.

FinasterideGroup PlaceboGroup

TotalSubjects

No.ofCases

TotalSubjects

No.ofCases

9423 989 9457 1412

NEnglJMed2013;369:603-610

ProstateCancer

Finasteridereducesprostatecancerincidenceby30%(P<0.01),buthigh-gradecancer(Gleasonscore,7-10)ismorecommoninthefinasteridegroup(relativerisk,1.17;P=0.05).Thisstudycostover$70m.

CelecoxibReducesColonCancerRiskBackground:Cox-2isinvolvedincoloncancerdevelopment.CelecoxibisaselectiveCox-2inhibitor.

Design:Celecoxibwasgivenat16mg/kgdailyfor3monthstochildrenofages10-14yearswithAPCgenemutationsand/orcolorectaladenomaswithafamilyhistoryoffamilialadenomatouspolyposis(FAP).

No.ofpolypsmedian(range) Placebo

AmJGastroenterol2010;105:1437-1443

Celecoxib

Baseline

Endofstudy

Changeinpolypnumber

Percentchangeinpolypnumber

40(21-68)

65(26-122)

17.5(-5to63)

39.1(-16.1to300)

43(8to68)

16.5(6to38)

-17.5(-2to-48)

-44.2*(-70.6to-25.0)

6-4patients/group.Celecoxibwaswelltolerated.*P=0.01.

Severalotherstudiesshowcelecoxiborasperinpreventscoloncancer,.e.g.,CancerPrevenRes2009;2:310-321.JNatlCancerInst2009;101:256-266.

ParadigmofCancerPreventionResearch

ExposureBiomarkers

ofExposure

EarlyDetectionofDiseaseBiomarkers

AdvancedClinical

DetectionofDisease

Cancer

PreventiveInterventions

GeneticandEnvironmentalFactors,CancerHealthDisparity

GeneticandEnvironmentalfactorsvs.cancerrisk/prognosis

1.GeneticChanges:AnalysisofSNP,haplotypeorwholegenome.

2.EnvironmentalFactors:carcinogens,anticarcinogens,nutritionalfactors.

3.GeneandEnvironmentInteraction.

CancerHealthDisparityResearchToidentifyandunderstandthefactorsthatcontributetothedisparitiesincancerincidence,mortalityorsurvivalinrelationtorace/ethnicity.

UnitedStatesCancerStatistic:2004IncidenceandMortality

FactorsthatContributetoHealthDisparitiesinCancer

1.Socioeconomicstatus(education,income,employment).

2.Accesstoandutilizationofhealthcareservices(e.g.,cancerscreening,timelycancerdiagnosisandtreatment).

3.Behaviors(physicalactivity,diet,tobaccouse).

4.Socialenvironment(educationalandeconomicopportunities,racialdiscrimination,neighborhood,andworkingconditions).

5.Exposuretocarcinogens.

DetectionExposureBiomarkers:endogenousorexogenousagentsandtheirmetabolitesoradductsintissuesorbodyproducts(e.g.,carcinogen-DNAadducts).

SusceptibilityBiomarkers:anindicatorofaheritableabilityofanindividualtorespondtothechallengeofcarcinogenicagent(s)orevent(s)(e.g.,GST-nullandAPCmutation).

CancerBiomarkers:predictfuturecancerdevelopmentorsuggestapotentialpresenceofcancer.

Phenotypicbiomarkers(e.g.,colorectaladenomasandactinic keratosis).

Molecularbiomarkers(e.g.,CA125,PSA).

Cell-freeDNAinbloodandotherspecimens:In2014,FDAapprovedCologuard,thefirststool-basedtestthatdetectsthepresenceofredbloodcellsandcertainDNAmutationsassociatedwithcolorectalcancer.

SomeoftheAmericanCancerSocietyGuidelinesfortheEarlyDetectionofCertainCancers

BreastCancer:Yearlymammogramatage≥40;clinicalbreastexamaboutevery3yearsatage≥20andeveryyearatage≥40.

ColonandRectalCancer:Atage≥50,flexiblesigmoidoscopyevery5years,colonoscopyevery10years,yearlyfecaloccultbloodtest.

CervicalCancer:Paptestevery3yearsatage21-29,Paptestevery5yearsatage30-65plusHPVtest.

ProstateCancer:UsedtobeyearlyPSAanddigitalrectalexaminationoftheprostateatage≥50,andmenathigherrisk(e.g.,African-American)shouldbegintestingatage≥45.Butnow,“ACSbelievesthatmenshouldnotbetestedwithoutlearningaboutwhatweknowanddon’tknowabouttherisksandpossiblebenefitsoftestingandtreatment.”

PreventiveInterventions

•Vaccination.

•WeightControl.

•Lifestylechange(physicalexcise,eatinghealthyandothers).

•Chemoprevention.

68.5%ofAmericanadultsand31.8%ofchildren/adolescentswereoverweightorobese(BMI≥25-29.9kg/m2)in2012-2012.

34.9%ofAmericanadultsand16.9%ofchildren/adolescentswereobese(BMI≥30kg/m2)2011-2012.

Overall,nosignificantchangesinobesityprevalenceinyouthoradultsbetween2003-2004and2011-2012.

In2001,expertsconcludedthatcancersofthecolon,breast,endometrium,esophagus,kidneyandthyroidareassociatedwithobesity.

Studieshavealsoshownlinksbetweenobesityandcancersofthegallbladder,ovaries,andpancreas.

Possiblemechanismsincludealterationsoflevelsofsexhormones,sex-hormonebindingglobulin,andinsulinandIGF-1.

WeightControl

JAMA2014;311:806-814

LifeStyleChange–TheSuccessStoryoftheNewYorkStateSmokers’Quitline(1-866-NY-Quits)

EstablishedinJanuary2000atRPCI

TheQuitlinereceiveditsmillionthcallin2008.

TheQuitlineprovidedsupporttomorethan75,000smokersin2013alone.

Thereareapproximately2.4millionadultsmokersinNewYork.

Interventionswithpharmaceuticals,vitamins,minerals,biologics,orotherchemicalstoretard,block,orreversethecarcinogenicprocess-ChemotherapyofCarcinogenesis,ortopreventcancerrecurrence.

CancerChemoprevention

‘PreemptiveStrikeagainstCancer’

Normal Cell

Initiated Cell

Pre- Malignant Cell

Malignant Cell

Dx: Clinical Cancer

Metastasis

(multiyear,multistageandmultipath)Clonalselectionandexpansion

GeneticChangesActivationofprotooncogenes

InactivationoftumorsuppressorgenesDisturbanceofproliferationandapoptosis

ChemicalsRadiationBiologicalagentsRandom

CarcinogenesisOffersManyOpportunitiesforIntervention

ExamplesofChemopreventiveTargets

• Carcinogen-activatingenzymes(CytochromeP450s)

•Carcinogen-detoxifyingenzymes(e.g.,GST)

•Estrogenreceptor

•Androgenreceptor

•5-αReductase

•Cyclooxygenase-2

•Retinoicacidreceptor(RAR)andretinoicXreceptor(RXR)

•Aromatase

•Thymidinesynthetase

•Viruses

SomeoftheAgentsThatHaveShownChemopreventiveActivityinClinicalTrials

Finasteride–ProstateCancer

Tamoxifen,Raloxifene–BreastCancer

Aspirin,Celecoxib,Sulindac–ColorectalCancer

13-cis-Retinoicacid–HeadandNeckCancer

VitaminA,Fluorouracil–SkinCancer

BacillusCalmette-Guérin(BCG)–BladderCancer

HPVVaccine–CervicalCancerandOtherCancers

Photodynamictherapy(PDT)withPhotofrin–BarrettEsophagus

FDA-ApprovedAgentsforTreatingPrecancerousLesionsorReducingCancerRisk

Tamoxifen,Raloxifene–BreastCancer

Celecoxib–AdenomatousColorectalPolyps

Fluorouracil–ActinicKeratosis

BCG–BladderCancer

HPVVaccine–CervicalCancerandOtherCancers

PDTwithPhotofrin–BarrettEsophagus

ClinChem2013;59:94-101

VitaminsandMinerals:Folicacid,vitaminA,vitaminC,vitaminE,vitaminD,selenium,calcium.

Phytochemicals:Phytoestrogens(e.g.,genistein,lignans),carotenoids (e.g.,b-carotene,lycopene),glucosinolates-derived(e.g.,sulforaphane),alliumorganosulfurcompounds(e.g.,diallylsulfide),flavonoids(e.g.,quercetin,catechins),phenolics(e.g.,curcumin),terpenoids(e.g.,d-limonene,perillylalcohol),dietary fiber(e.g.,chlorophyll,chlorophyllin).

Examples of over400AgentsThatAreatCertainStagesofEvaluationforCancerChemopreventiveActivities

SyntheticChemicals:Nonsteroidanti-inflammatorydrugs(NSAIDS, e.g.,aspirin,celecoxib),dithiolethiones(e.g.,oltipraz),modulatorsofestrogenreceptorsignaling(e.g.,tamoxifen, raloxifene).VitaminAandDanalogs(e.g.,13-cis-retinoicacid,calcitriol),5α-reductaseinhibitors(e.g.,finasteride),ornithinedecarboxylaseinhibitor(e.g.,difluoromethylornithine).

ParadigmforDevelopmentofChemopreventiveAgents

Leadsfromepidemiologicalandexperimentalresearch

Cell-based:targetsidentificationandvalidation,SARstudy

Animal-based:targetsvalidation,biomarkers,andtumors

Preclinicaltoxicologyandpharmacokinetics

PhaseI,II,andIIIclinicaltrials

FDAapproval

Becausechemopreventiveagentsareusedin“healthy”people(high-risksubjectsandeventhegeneralpopulation),andrequirechronicadministration,itiswidelysuggestedthatnoneorminimaldrugtoxicityisallowed.But,inreality,FDAhasapproveddrugsforcancerchemoprevention,whichhavesignificanttoxicities.

Tamoxifenwasdiscoveredasananti-estrogencompoundin1962byICIPharmaceuticals.

Tamoxifenhasbeenusedforover30yearsinpatientswithearlystagebreastcancerasadjuvanttherapytopreventbreastcancerrecurrence,andinthosewithmetastaticbreastcancertoslowthegrowthofcancer.

AnNCI-sponsoredbreastcancerchemopreventionstudyoftamoxifenwasinitiatedinearly1990sbasedonitsclinicalefficacyasanER-positivebreastcancertherapeuticagent.

TheCaseofTamoxifen

Jordon, Scientific American, October, 1998, 60-67

1. Estrogen binds to its receptor, which then binds to certain genes

2. A transcription complex forms and activates gene transcription

3. Cell behavior changes

Example1:TargetingEstrogenReceptor

SERMS, selective estrogen receptor modulators.

Tamoxifen

Raloxifene

Studydesign

Question: DoesTamoxifen(20mgdaily)reducetheriskof developingbreastcancerinahighriskpopulation ofwomen?

Protocol: Doubleblind;Placebocontrolled

13,388Women:enrolledApril1992toSept.1997 35yearsorolder 300CentersinU.S.andCanada

Exclusioncriteria: bloodclots;steroidreplacementororal contraceptives;pregnancyorcontemplated pregnancy;priorbreastcancer

Cost: $30-50million,NCI-sponsored

TheBreatCancerPreventionTrial(BCPT)

TheTamoxifenTrialResult

Reduced: InvasiveBreastCancer(45%) DuctalCarcinoma(48%) BoneFractures(34%),

Fisheretal.,TamoxifenforPreventionofBreastCancer:ReportoftheNationalSurgicalAdjuvantBreastandBowelProjectP-1Study.J.Natl.CancerInst.90:1371-1388,1998.

Increased: EndometrialCarcinoma(2.4-fold) PulmonaryEmbolism(2.8-fold) DeepVeinThrombosis(1.6-fold)

OtherAdverseEffects: Menopause-likesymptoms(hotflashes,vaginaldryness,jointpain,andlagcramps),cataracts,stroke,uterinesarcoma.

Tamoxifenalsoinhibitsthedevelopmentof7,12-dimethylbenz(a)-anthracene(DMBA)-

inducedratmammarycarcinoma

100

75

50

25

9 10 11 12 13 14

Mam

mar

y tu

mor

inci

denc

e (%

)

Time (weeks)

2 wk, pretreatment

A, placebo

B, subcutaneous leuprolide (chemical castration)

C, subcutaneous tamoxifen (10 mg/kg/wk)

D, oophorectomy (sugical castration)

4 wk, oral DMBA, 5 mg/wk 10 wk, experiment stopped

A

D

BC

0

Breast Cancer Research and Treatment 47, 63-70, 1998

Leuprolide and tamoxifen began two weeks prior to DMBA and ended one week after DMBA.

SomeoftheSignificantRiskFactorsofBreastCancer

Ahistoryofbreastcancer:3-4-foldincreasedriskofdevelopinganewbreastcancer,notarecurrence.

Havingonefirstdegreerelativewithbreastcancer,theriskdoubles;havingtwofirstdegreerelativeswithbreastcancer,theriskis5-foldhigher.

CarryinganinheritedalterationinBRCA1orBRCA2:Upto80%chanceofdevelopingbreastcancer.

Aprevioushistoryofatypicalhyperplasia:4-5foldhigherrisk.

TamoxifenwasapprovedbyFDAin1998forreducingtheincidenceofbreastcancerinwomenathighrisk

fordevelopingbreastcancer

Intervention:Tamoxifenat20mg/dorRaloxifeneat60mg/dover4years,beginning1999.

Design:Astudyoftamoxifenandraloxifeneforbreastcancerprevention(STAR)innearly20,000postmenopausalwomen

Background:Instudiestoevaluateitsabilitytoreducetheriskofbonefractureofolderwomenwithosteoporosis,raloxifenewasfoundtopreventbreastcancer

Result:raloxifeneisaseffectiveastamoxifen,bothreducingtheriskofinvasivebreastcancerbyabout50%.Buttheraloxifene-treatedwomenhad36%feweruterinecancersand29%fewerbloodclotsthanthetamoxifen-treatedwomen.

Outcome:FDAapprovalofraloxifenein2007inpostmenopausalwomenathighriskforinvasivebreastcancer.

JAMA2007;295:2727-2741

TheCaseofRaloxifene

Longer-termAnalysisofSTAR(about7years):Raloxifeneis76%aseffectiveastamoxifeninpreventinginvasivedisease.

CancerPrevRes2010;3:696-706

AlternativeStrategiesinBreastCancerPrevention

2.Aromataseinhibitors,e.g.,exemestane,letrozole.

Inpost-menopausalwomen,estrogenisnolongerproducedbytheovaries,butisconvertedfromandrogenbyaromatase.

1.Estrogenreceptordownregulators,e.g.,fulvestrant.

CancerControl4,217-221,2004.JClinOncol22,1605-1613,2004.NEnglJMed364,2381-2391,2011.

BreastCancerSubtypes

Type1(luminalA,40%):ERpositiveandPRpositive,likelytobenefitfromhormonetherapy.

Type2(luminalB,20%):ERpositive,PRnegativeandHER-2positive;maybenefitfromhormonetherapy.

Type3(HER-2positive,15-20%):ERnegativeandPRnegative,butHER-2positive,likelytohavenobenefitfromhormonetherapy.

Type4(basal-like,10-15%):ERnegative,PRnegativeandHER2negative,alsoknownastriple-negative,likelytohavenobenefit fromhormonetherapy.

EffectofSeleniumandVitaminEonRiskofProstateCancer

TheseleniumandvitaminEcancerpreventiontrial(SELECT)

JAMA2009;301:39-51

Design: Arandomized,placebo-controlledtrialof35,533menfrom427 participatingsites,double-blinded,≥50yearsofage,no prostatecancer(serumPSA≤4ng/ml).

Intervention:Oralselenium(200µg/dfromL-selenomethionine) and matchedvitaminEplacebo,vitaminE(400IU/dofallrac-α- tocopherylacetate)andmatchedseleniumplacebo,selenium+ vitaminE,orplacebo+placebo;7-12years.

Mainendpoint:Prostatecancer.

Supportedbyepidemiologicalandpreclinicaldata:JUrol1999,161:1651-1654;CancerRes2000,60:2882-2886;CancerRes2001,61:3061-3070;CEBP2000,9:1171-1182;CancerLett1998,125:103-110;JNCI1998,90:1184-1185;JNCI1998,90:1219-1224;CancerRes2001,61:7071-7078.

CumulativeIncidenceofProstateCancerDetectedEachYearbyInterventionGroup