yuesheng zhang february 9, 2016 department of cancer … · 2019. 10. 25. · 2015;65:5-29. trends...
TRANSCRIPT
Prevention/Chemoprevention
YueshengZhang
February9,2016
DepartmentofCancerPreventionandControl
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