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Alcoholic beverages, obesity, physical activity and other

nutritional factors, and cancer risk: A review of the

evidence

Paule Latino-Martel, Vanessa Cottet, Nathalie Druesne-Pecollo, Fabrice H.F.

Pierre, Marina Touillaud, Mathilde Touvier, Marie-Paule Vasson, Mélanie

Deschasaux, Julie Le Merdy, Emilie Barrandon, et al.

To cite this version:

Paule Latino-Martel, Vanessa Cottet, Nathalie Druesne-Pecollo, Fabrice H.F. Pierre, Marina

Touil-laud, et al.. Alcoholic beverages, obesity, physical activity and other nutritional factors, and cancer

risk: A review of the evidence. Critical Reviews in Oncology/Hematology, Elsevier, 2016, 99, pp.308

- 323. �10.1016/j.critrevonc.2016.01.002�. �hal-01440350�

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ContentslistsavailableatScienceDirect

Critical

Reviews

in

Oncology/Hematology

j ourna l h o m e pa g e : w w w . e l s e v i e r . c o m / l o c a t e / c r i t r e v o n c

Review

Alcoholic

beverages,

obesity,

physical

activity

and

other

nutritional

factors,

and

cancer

risk:

A

review

of

the

evidence

Paule

Latino-Martel

a,b,∗

,

Vanessa

Cottet

b,c

,

Nathalie

Druesne-Pecollo

a,b

,

Fabrice

H.F.

Pierre

b,d

,

Marina

Touillaud

b,e

,

Mathilde

Touvier

a,b

,

Marie-Paule

Vasson

b,f

,

Mélanie

Deschasaux

a,b

,

Julie

Le

Merdy

a,b

,

Emilie

Barrandon

a,b

,

Raphaëlle

Ancellin

g aSorbonneParisCitéEpidemiologyandStatisticsResearchCentre(CRESS),InsermU1153,InraU1125,Cnam,Paris13University,NutritionalEpidemiology

ResearchTeam(EREN),Bobigny,France

bFrenchNetworkonNutritionandCancerResearch(NACReNetwork),France1

cUniversityHospitalofDijon,InsermU866,DigestiveCancerRegistryofBurgundy,UniversityofBurgundy,Dijon,France dUMR1331Toxalim,Inra,INP,UPS,Team9“Prevention,PromotionofCarcinogenesisbyFood”,Toulouse,France eCancerandEnvironmentDepartment,Léon-BérardCancerCentre,Lyon,France

fClermontUniversité,Universitéd’Auvergne,UFRPharmacie;Inra,UMR1019,CRNHAuvergne;CentreJean-Perrin,CHUGabriel-Montpied,Unitéde

Nutrition,Clermont-Ferrand,France

gFrenchNationalCancerInstitute,DepartmentofPrevention,Boulogne-Billancourt,France

Contents

1. Introduction...309

2. Methods ... 309

2.1. Evaluationprocess...309

2.2. Searchstrategyandselectioncriteria...309

2.3. Dataextraction...310

2.4. Updatingtheevidence...310

3. Results...310

3.1. Alcoholicbeverages...310

3.2. Overweightandobesity ... 311

3.3. Redandprocessedmeat...312

3.4. Saltandsaltedfoods...313

3.5. Beta-carotenesupplements...313

3.6. Physicalactivity...314

3.7. Fruitsandvegetables...314

3.8. Dietaryfiber...315

3.9. Dairyproducts...315

3.10. Breastfeeding...316

3.11. Summaryoftheupdatedevidence...318

4. Discussion...318

5. Conclusions...319

Conflictofinterest...319

Funding...319

AppendixA. Supplementarydata...319

References...319

Biography...323

∗ Correspondingauthorat:NutritionalEpidemiologyResearchTeam(EREN),InraU1125,RéseauNACRe,InstitutNationaldelaRechercheAgronomique,F-78350Jouyen Josas,France.

E-mailaddress:paule.martel@jouy.inra.fr(P.Latino-Martel).

1 www.inra.fr/nacre.

http://dx.doi.org/10.1016/j.critrevonc.2016.01.002

1040-8428/©2016TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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a

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t

i

c

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i

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Articlehistory:

Received30October2015 Receivedinrevisedform 18December2015 Accepted7January2016 Keywords: Cancer Diet Beta-carotenesupplements Obesity Alcohol Physicalactivity Breastfeeding Prevention

a

b

s

t

r

a

c

t

Purpose:Preventionisapriorityinthefightagainstcancers,especiallynutritionalprevention.Toupdate thelevelsofevidenceofrelationshipsbetween10nutritionalfactorsandcancerrisk,thescientific literaturepublishedfrom2006to2014wasreviewedbyanexpertgroup.

Methods:Datafrom133meta-analyses,pooledanalysesorinterventiontrialswereexamined.Nearly150 relationshipsbetweennutritionalfactorsandcanceratvarioussiteswereevaluated.

Results:Accordingtotheevidencegradedasconvincingorprobable,thesefactorsweredividedintwo groups.Factorswhichincreasetheriskofcancerarealcoholicbeverages,overweightandobesity,redmeat andprocessedmeat,saltandsaltedfoodsandbeta-carotenesupplements.Factorswhichdecreasethe riskofcancerarephysicalactivity,fruitsandvegetables,dietaryfiber,dairyproductsandbreastfeeding. Conclusion:Threemainnutritionalobjectivesshouldbeattainedtoimprovecancerprevention:toreduce alcoholicbeveragesconsumption,tohaveabalancedanddiversifieddietandtobephysicallyactive.

©2016TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

The worldwide burden of cancer has been estimated to 14 millionnewcasesfortheyear2012,themostcommoncancers diagnosedgloballybeingthoseofthelung,breast,andlargebowel. Thisfigureisexpectedtoriseto22millionperyearwithinthenext twodecades(Ferlayetal.,2013).Thisalarmingsituation empha-sizestheneedforurgentpreventionmeasurestowinthebattle againstcancer(IARC,2014a).

Preventionstrategiesmustbebasedonabetterevidence-based knowledgeoffactorsabletoeitherincreaseordecreasecancerrisk. Cancerisamultifactorialdiseaseinvolvinggenetic, environmen-talandbehavioralfactors,thelatterincludingnutritionalfactors thatcomprisediet,alcoholconsumption,bodyfatnessand physi-calactivity.Formorethantwodecades,theWorldCancerResearch Fund(WCRF)andtheAmericanInstituteforCancerResearch(AICR) havejoinedtheireffortstosummarize,assessandjudgethe evi-denceonnutritionalfactorsandtheriskofvariouscancers.Since theirreportpublishedin2007(WCRF/AICR,2007),theWCRF/AICR expertpanelkeepupdatingtheevidenceforindividualcancersites, accordingtotheContinuousUpdate Project(CUP),in collabora-tionwithateamoftheImperialCollegeofLondon(ICL)incharge ofsystematicreviewsandmeta-analysesofepidemiologicaldata, independentlyoftheexpertpanel’sjudgementoftheevidence.

In 2013, within the framework of the third Cancer Plan (2014–2019), the French National Institute of Cancer (INCa) decidedtoreviewthemostrecentscientificliteratureandupdate thelevelsofevidencefortherelationshipsbetweenriskofcancers andnutritionalfactors.Tennutritionalfactorswereconsidered: alcoholicbeverages,overweight andobesity, redmeatand pro-cessedmeat, salt and salted foods, beta-carotenesupplements, physicalactivity,fruitsandvegetables,dietaryfiber,dairyproducts, breastfeeding. They were selected on the basis of the follow-ingcriteria:(i)relevantinterms ofmodifiableexposureforthe Frenchpopulationandmoregenerallyfordevelopedcountriesand (ii)levelof evidencequalified asconvincingor probableinthe 2007WCRF/AICRreport(WCRF/AICR,2007)foratleastonecancer site.Forthesefactors,thelevelsofevidencehavebeenevaluated byWCRF/AICRinthe2007mainreport(WCRF/AICR,2007),and 2010–2014CUPreportsonbreast,colorectal,pancreatic, endome-trialand ovarian cancers (WCRF/AICR,2010, 2011,2012,2013, 2014a).However,manyepidemiologicalstudieshavebeen pub-lishedsincethen,requiringareassessmentofthelevelsofevidence.

2. Methods

2.1. Evaluationprocess

FromApril2013toMarch2015,INCagatheredanexpertgroup bringingtogetherscientistsfromtheFrenchnetworkonNutrition AndCancerResearch(NACRenetwork),whohaveexpertiseinthe fieldofnutritionandcancer.Themodalitiesforthesystematic lit-eraturereviewandevaluationoftheevidencehavebeendiscussed andadoptedbytheexpertgroup.Notably,thenutritionalfactors andtypesofstudiestoconsider,thesearchstrategies,andthe selec-tioncriteriaforpublicationshavebeendefined.Thebibliographic reviewwasdividedamongexpertsaccordingtotheirrespective competences.Themethodofbibliographyanalysis,thenatureof datatoextractfromarticlesandthecriteriaforevaluatingthe lev-elsofevidencefortherelationshipsbetweennutritionalfactors andriskofcancershavebeendefinedbytheexpertgroup.Theyare summarizedinthenextsection.

2.2. Searchstrategyandselectioncriteria

Searches wereconducted in PubMed databasefrom January 2006toFebruary2014,restricted toEnglishlanguage,by com-biningmedicalsubjectheadings(MeSH)and/orentryterms.Study typeswerelimitedtometa-analyses,pooledanalysesand interven-tiontrials.Searchstrategiesforeachofthe10selectednutritional factorsaredetailedinAppendixA,Part1.Foreachnutritional fac-tor,thetitleandabstractofallreferencesprovidedbythesearch wereexaminedbyoneexperttoselectpotentialrelevantfull-text articles,anyuncertaintiesbeingresolvedbydiscussionwithinthe expertgroup.Studieswereselectediftheymetthefollowing inclu-sioncriteria:meta-analysis,pooledanalysisorinterventiontrial, associationbetweenoneofthe10selectednutritionalfactorsand cancerriskinadults,reportofhazardratio(HR),relativerisk(RR)or oddsratio(OR)andoftheir95%confidenceinterval(CI).Studieson aspecificcancersitewereselectediftheirpublicationdatewas sub-sequenttothemorerecentWCRF/AICRreport(2007mainreport orCUPreportonthiscancersite)(WCRF/AICR,2007,2010,2011, 2012,2013,2014a);publicationsfromtheICLteamwere consid-eredasnewmeta-analysesiftheyprovidedupdatedoradditional resultsascomparedtothosepresentedinthe“systematicliterature review”reportsassociatedtothemainWCRF/AICRorCUPreports (WCRF/AICR,2007,2010,2011,2012,2013,2014a).Theoutcome

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shouldbefirstprimarycancers,excludingpreneoplasticlesionsor biomarkers,andmortality.Populationsathighriskofcancer(e.g., withLynchsyndrome,polycysticovarysyndromeordiabetes)were excluded.

2.3. Dataextraction

Usingastandardizeddatacollectionform,eachexpertextracted thefollowinginformationfromthefull-textselectedarticles:for allstudies,firstauthor’slastname,publicationyear,typeofstudy, populations’characteristics(samplesize,meanage,gender), can-cersite, number ofcases,groups’ comparison ordose-response relationship and corresponding HRs, RRs or ORs, and 95% CIs, heterogeneity,adjustmentfactorsandbias;formeta-analysesor pooledanalyses:inclusion/exclusioncriteria,numberandtypeof studiesincluded,meanfollow-upforincludedcohortstudies, coun-triesin which the included studies were conducted,exposure, adjustmentfor covariates and stratification; for meta-analyses: sensitivityanalyses;forinterventiontrials:nameofthetrial, coun-tryin whichthetrialwasconducted,randomization,blindness, intervention(type,duration),follow-updurationandnumberof subjectslosttofollow-up. For each nutritionalfactor, a second expertindependentlydouble checkedtheextractionof primary datafromeverystudy.Discrepanciesweresolvedthrough discus-sion.AllextracteddataareavailableinFrenchlanguageontheINCa website(INCa,2015a).

2.4. Updatingtheevidence

Thesummaryofextracteddataandtheupdatedlevelof evi-denceproposedbyeachexpertwerereviewedindependentlyby asecondexpertanddiscussedbytheoverallexpertgroupuntila consensuswasfound.Finally,thelevelsofevidencewerequalified asconvincing,probable,suggestiveornotconclusive,accordingto thecriteriathatweredefined(Table1).

3. Results

Fig.1showstheflowchartofthestudyselectionprocess.From the1959abstractsprovidedbysearchesinMedlinedatabase,262 potentiallyfulltextarticleswereidentifiedandexamined.Finally, 133articlesmeetingtheinclusion criteriaand reportingusable informationwereanalyzedbytheexpertgroup.Theyinclude108 meta-analyses,20pooledanalyses,4interventiontrialsandone post-interventionstudywhichrelateto26cancersitesoverall. Gen-erally,inthestudiesincludedinmeta-analysesorpooledanalyses, age,genderandthemainknownconfoundingfactorsforthe stud-iedcancersitehavebeencontrolledfor.InTables1–10ofAppendix A,Part2,themainresultsfromthesestudiesandtheupdated lev-elsofevidencearereportedfortheassociationsbetweentheten nutritionalfactorsandcancersites.Inthefollowingsectionsthe definitionandindicatorsofeach nutritionalfactorandthenew studiesidentifiedarepresented.Then,theresultsandconclusions oftheevaluationprocessbytheexpertgrouparesummarized:for cancerssitesforwhichaconvincingorprobablelevelofevidence isestablished,followedbythoseforwhichitissuggestiveornot conclusive,andfinallyplausiblemechanismswhenavailable. 3.1. Alcoholicbeverages

Alcoholicbeveragesincludewines,beers,spirits,cidersand var-iousotheralcoholicdrinks thatmaybelocally important.They containethanolwhich resultsfromtheprocessoffermentation. In epidemiological studies,theexposureto alcoholic beverages isexaminedby differentmeasures: drinkingornot, number of drinks/glassesorunitsof10galcoholperdayorperweek.

Theassociationsbetweenalcoholdrinkingandtheriskof var-ious cancers have been evaluated by WCRF/AICR in 2007 and 2010–2014CUPreports(WCRF/AICR,2007,2010,2011,2012,2013, 2014a).Sincethepublicationofthesereports,25meta-analyses (Islamietal.,2010;Turatietal.,2010;Tramacereetal.,2010;Turati etal.,2013a;Pettietal.,2013;Islamietal.,2011;Tramacereetal., 2012a;Seitzetal.,2012;Songetal.,2012;Rotaetal.,2012;Mao etal.,2010;Pelucchietal.,2012;Tramacereetal.,2012b,c,d;Lietal., 2011a;Zhuoetal.,2012;Fangetal.,2011;Yangetal.,2010;Zhang etal.,2010;Liuetal.,2011a;Liuetal.,2012a;Chao,2007;Boccia etal.,2009;Guoetal.,2012)and12pooledanalyseswere identi-fied(Hashibeetal.,2007;Hashibeetal.,2009;Purdueetal.,2009; Freedmanetal.,2011;Lubinetal.,2012;Lucenteforteetal.,2012; Leeetal.,2007a;Kelemenetal.,2013;Boffettaetal.,2012;Kitahara etal.,2012;Langevinetal.,2009;Shimazuetal.,2012)(Appendix A,Part2:Table1).Theassociationbetweenalcoholdrinkingand theincidenceof19differentcancersiteswasinvestigated.Among the37newstudiesidentified,25providedresultsontotal alco-holdrinkingandcancerrisk(Islamietal.,2010;Turatietal.,2010; Tramacereetal.,2010;Turatietal.,2013a;Pettietal.,2013;Islami etal.,2011;Tramacereetal.,2012a;Seitzetal.,2012;Songetal., 2012;Rota etal.,2012; Maoet al.,2010; Pelucchiet al.,2012; Tramacereet al.,2012b,c,d;Hashibeet al.,2007;Hashibeetal., 2009;Purdueetal.,2009;Freedmanetal.,2011;Lubinetal.,2012; Lucenteforteetal.,2012;Leeetal.,2007a;Kelemenetal.,2013; Boffettaetal.,2012;Kitaharaetal.,2012)and12focusedon cer-taingeneticpolymorphisms(Zhuoetal.,2012;Fangetal.,2011; Yangetal.,2010;Zhangetal.,2010;Liuetal.,2011a;Liuetal., 2012a;Bocciaetal.,2009;Guoetal.,2012;Langevinetal.,2009), Asianpopulations(Lietal.,2011a;Shimazuetal.,2012)orspecific alcoholicbeverages(Chao,2007).

Overall, the associations between alcohol drinking and increasedriskofseveralcancers,previouslyevaluatedand con-sideredas “convincing”intheWCRF/AICR previousreports,are strengthenedbytheresultsofrecentpublications.Forthecancers ofthemouth,pharynxandlarynxcombined,theresultsof6recent meta-analyses(Islamietal.,2010;Turatietal.,2010;Tramacere etal.,2010;Turatietal.,2013a;Lietal.,2011a;Zhuoetal.,2012)and 3pooledanalyses(Hashibeetal.,2007;Hashibeetal.,2009;Purdue etal., 2009)of observationalstudiesconfirmed theassociation. Theincreasedriskofoesophagealcancerwasobservedin2recent pooledanalysesofobservationalstudies(Freedman etal.,2011; Lubinetal.,2012)and2meta-analyses,oneincludingobservational studies(Lietal.,2011a)andoneexclusivelycohorts(Islamietal., 2010).Forbreastcancer,theWCRF/AICRconclusion(WCRF/AICR, 2010)wasreinforced bya newmeta-analysisof cohortstudies (Seitzetal.,2012).Concerningcolorectalcancerassociations con-sideredas“convincing”inmenand“probable”inwomen,thelevel ofevidence wasnot changedsince theonlynewmeta-analysis includingexclusively10case-controlstudiesconductedonChinese menandwomencombinedshowednosignificantresults(Lietal., 2011a).Theassociationwithlivercancer,consideredas“probable” inthe2007WCRF/AICRreport(WCRF/AICR,2007),wasalso con-firmedby2meta-analyses(Lietal.,2011a;Liuetal.,2011a)and onepooledanalysis(Shimazuetal.,2012)ofobservationalstudies. Theincreasedrisk ofpancreaticcancerassociated with con-sumptionof3drinksperdayormoreisconfirmedbytheresults ofarecentpooledanalysisof10case-controlstudies(Lucenteforte etal.,2012)thoughanon-significantincreasedriskwasobserved inthemeta-analysisconductedonChinesepopulations(Lietal., 2011a). Thus, the corresponding level of evidence previously judgedas“suggestive”isunchanged.

Thenewresultsavailableforothercancersites—kidney(Song etal.,2012;Leeetal.,2007a),lung(Lietal.,2011a;Chao,2007), prostate(Rotaetal.,2012;Lietal.,2011a),bladder(Maoetal.,2010; Pelucchietal.,2012;Lietal.,2011a),stomach(Tramacereetal.,

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Table1

CriteriausedbytheINCaexpertgrouptoconfirmorupdatetheevidence.

Grade Criteriarequired Lacksorlimits

Convincing Meta-analysisorpooledanalysisofprospectivestudieswith: —Statisticallysignificantassociation

—Dose-responseanalysis —Highnumberofstudiesorcases —Nohighandunexplainedheterogeneity*

—Robustnessofresultsinsensitivityanalyses —Interventiontrialifpossible

—Plausiblemechanisms

Probable Meta-analysisorpooledanalysiswith: —Statisticallysignificantassociation —Highnumberofstudiesorcases —Nohighandunexplainedheterogeneity*

—Plausiblemechanisms

—Neithermeta-analysisnorpooledanalysisofprospectivestudies OR

—Nodose-responseanalysis

Suggestive Meta-analysisorpooledanalysiswith: —Statisticallysignificantassociation —Plausiblemechanisms

—Neithermeta-analysisnorpooledanalysisofprospectivestudies ANDnodose-response

OR

—Highunexplainedorunspecifiedheterogeneity Notconclusive —Neithermeta-analysisnorpooledanalysis

OR

—Nostatisticallysignificantassociationfrommeta-analysisorpooled analysis

OR

—Inconsistencybetweenmeta-analysesorpooledanalyses OR

—Noplausiblemechanisms

Improbable Meta-analysisorpooledanalysisofprospectivestudieswith: —Nostatisticallysignificantassociation

—Dose-responsethatisnotstatisticallysignificant —Highnumberofstudiesorcases

—Nohighandunexplainedheterogeneity*

—Robustnessofresultsinsensitivityanalyses —Interventiontrialifpossible

—Noplausiblemechanisms

*Highheterogeneity:I275%(WCRF/AICR,2007).

2012b;Lietal.,2011a)andovary(Kelemenetal.,2013)—confirm the“notconclusive”levelofevidenceoftheWCRF/AICRreports (WCRF/AICR,2007,2014a).Recentpublicationsconcerningcancer siteswhichwerenotpreviouslyevaluatedbyWCRF/AICR—small intestine(Boffettaetal.,2012), Hodgkinandnon-Hodgkin lym-phoma(Tramacereetal.,2012c,2012d),AmpullaofVater(Lietal., 2011a)andthyroid(Kitaharaetal.,2012)—donotsuggestany asso-ciationbetweentheriskofthesecancersandalcoholdrinking.In theabsenceofnewdata,the“notconclusive”levelofevidencefor endometrialcancerremainsunchanged.

Themechanismsofalcoholicbeverages-mediated carcinogen-esismainlyinvolvethepro-carcinogeniceffectsofacetaldehyde, the main metabolite of ethanol. Several other molecular and physiopathologicaleffects have been identified:redox changes, formationofradicals,liverinjury,elevationofsexhormones lev-els,folatedeficiency,interactionwithtobaccosmokingetc(IARC, 2012).

3.2. Overweightandobesity

Bodyfatnesswhichincludesoverweightandobesityis gener-allyestimatedby thebody massindex (IMC)calculated bythe ratioweight(kg)/height2(m2).Abdominalfatness,estimatedbythe waistmeasurementorthewaist-to-hipsratio,isanotherindicator usedtocharacterizecorpulence.

Theassociationsbetweenoverweight/obesityand theriskof variouscancershavebeenevaluatedbyWCRF/AICRin2007and 2010–2014CUPreports(WCRF/AICR,2007,2010,2011,2012,2013, 2014a).Sincethepublicationof the2007report,24new meta-analyses(Turatietal.,2013b;Auneetal.,2012a;Maetal.,2013; Cheraghietal.,2012;Amadouetal.,2013;Ildaphonseetal.,2009;

1959 referencesidenfiedin Medline

262 full-text arcles assessed for eligibility

133 arcles meeng inclusion criteria, with usable informaon: 108 arcles correspondingto meta-analyses , 20 to pooled analyses and 5 to intervenon trials

1697 referencesexcludedby reviewof the tle and abstract

129 full-text arcles excluded for irrelevant design, outcome or exposure, for incomplete data, or publicaon before the more recent WCRF/AICR report

Fig.1.Flowchartofstudyselection.

Mathew etal.,2009;Chenet al.,2012a;Ruietal., 2012;Wang etal.,2012;Discacciatietal.,2012;Willettetal.,2008;Larssonand Wolk,2011,2008;Castilloetal.,2012;WallinandLarsson,2011; Yangetal.,2009;Chenetal.,2013;Zhaoetal.,2012;Lerroetal., 2010;Olsenetal.,2008;Sergentanisetal.,2013;Yangetal.,2013a; Gaudetetal.,2010)andonepooledanalysiswereidentified(Hoyo etal.,2012)(AppendixA,Part2:Table2).Theycoveratotalof17 differentcancersites.

Theassociationbetweenbody fatnessand theincreasedrisk of oesophagus adenocarcinoma, previously judged as “convinc-ing” (WCRF/AICR,2007).is confirmedbyrecent resultsof both apooledanalysis(Hoyoetal.,2012)andameta-analysis(Turati etal.,2013b)ofobservationalstudies.SincetheWCRF/AICR2012 report (WCRF/AICR, 2012), one recent meta-analysis of the ICL team (Aune et al., 2012a) confirms the increase of pancreas

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cancerriskassociatedwithbothbodyandabdominalfatness,and thecorrespondinglevelofevidencejudgedas“convincing”. Consis-tentwithpreviousevaluations(WCRF/AICR,2011),theassociations betweenbody/abdominalfatnessandcolorectal/colon/rectum can-cerwithalevelofevidencejudgedas“convincing”,areconfirmed byonenewmeta-analysisofprospectivestudies(Maetal.,2013). Forbreastcancer,2007and2010WCRF/AICRreports(WCRF/AICR, 2007,2010)emphasizedtheneedforstratificationaccordingto themenopausal status. The increase of postmenopausal breast cancerriskwithbodyfatnesswhichwasjudgedas“convincing”, isconfirmedbyonenewmeta-analysisofobservationalstudies (Cheraghietal.,2012).Inaddition,thedecreaseofpremenopausal breastcancerriskwithbodyfatnesswhichwasjudgedas “prob-able”consideringthespeculativemechanismsandthedivergent data, is confirmed by two new meta-analyses of observational (Cheraghietal.,2012)andprospective(Amadouetal.,2013) stud-ies.The “convincing” level of evidenceestablished in the2013 WCRF/AICRreport(WCRF/AICR,2013)fortheincreaseof endome-trialcancerriskassociatedwithbodyfatness,weightgaininthe adulthoodand abdominal fatness, is unchanged, since nonew studywasidentified.Forkidneycancer, thelevelofevidenceof theincreasedriskassociatedwithbodyfatnesswhichwasjudged as“convincing” (WCRF/AICR, 2007)is confirmed by two meta-analysesofobservationalstudies(Ildaphonseetal.,2009;Mathew etal.,2009).

Inthe absenceof newdata,thelevel of evidencejudged as “probable” for an increased risk of gallbladder and ovary can-cer associated with body fatness (WCRF/AICR, 2007) remains unchanged.Theevidenceoftheassociationbetweenbodyfatness andtheriskoflivercancerjudgedas“suggestive”(WCRF/AICR, 2007), in the light of three new meta-analyses of prospective studies(Chenetal.,2012a;Ruietal.,2012;Wangetal.,2012), is thereafter consideredas “probable”. For prostate cancer, the levelofevidenceoftheassociationbetweenbodyfatnessandthe increasedriskwasjudgedas“notconclusive”consideringthe het-erogeneity ofdata (WCRF/AICR,2007).In the light ofone new meta-analysisof13prospectivestudies(Discacciatietal.,2012), thelinkbetweenbody/abdominalfatnessandadvancedprostate cancerrisk isstrengthenedand thelevelofevidenceis defined as “probable”. For the localised prostate cancer, the “not con-clusive”levelof evidenceremainsunchanged intheabsenceof plausible mechanisms. Concerning lymphoid and haemopoietic systemwhichwerenotpreviouslyevaluatedbyWCRF/AICR,recent meta-analysesonnon-Hodgkin(Willettetal.,2008;Larssonand Wolk,2011)and Hodgkin(LarssonandWolk,2011)lymphoma, leukemia(LarssonandWolk,2008;Castilloetal.,2012),and multi-plemyeloma(WallinandLarsson,2011)suggestanincreasedrisk associatedwithbodyfatness(IMC)withalevelofevidencejudged as“probable”.

Forstomach,since theWCRF/AICR2007report(WCRF/AICR, 2007),threenewmeta-analyses(Turatietal.,2013b;Yangetal., 2009;Chenetal.,2013)areinfavorofanincreasedriskof proxi-mal(cardia)gastriccancerinrelationwithbodyfatness.Sothelevel ofevidenceisthereafterdefinedas“suggestive”.Fordistal(not car-dia)gastriccancerthe“notconclusive”levelofevidenceremains unchanged.Inthelightofresultsofonenewmeta-analysisof7 prospectivestudies(Zhaoetal.,2012),thelevelofevidenceofthe associationbetweenbodyfatnessandtheincreasedriskof thy-roidcancerisjudgedas“suggestive”.Thenewresultsavailablefor testis(Lerroetal.,2010)andskin(melanoma)(Olsenetal.,2008; Sergentanisetal.,2013)cancersdonotsuggestanyassociationwith bodyfatness.Thelevelsofevidenceofadecreasedriskoflung(Yang etal.,2013a)andmouth,pharynx,larynxcancers(Gaudetetal., 2010)associatedwithbodyfatness,arejudgedas“notconclusive”, consideringthelackofmechanisticjustificationandtheexistence ofconfoundingfactorsnottakenintoaccount.

Somemechanismsseemcommontoallcancersites:theexcess ofintra-abdominaladiposetissuefavorstissueinsulinoresistance, chronichyperinsulinemia,increasedproductionandactivityofthe mitogenicfactorinsulingrowthfactor1(IGF-1),estrogen produc-tionviathearomataseactivity,chroniclow-gradeinflammation resulting from the production of pro-inflammatory factors i.e., tumor-necrosisfactor-␣(TNF␣),interleukin(IL-6),andadipokins, andoxidative stressduetolipidperoxidationproduction (Calle andKaaks,2004).Othermechanismsarespecifictocertaincancer sites:foroesophagus,gastro-oesophagealrefluxfavoringlesionsof theoesophagealepitheliumandcardia;forpostmenopausalbreast andendometrialcancer,increasedproliferation-effectofestrogens viatheirestrogenreceptorexpression;for kidney,development ofahighbloodpressureleadingtoanincreaseofthe glomeru-larfiltrationandthustheriskofrenaldamage,andalterationsof thecholesterolmetabolism;forgallbladder,increasedformation ofgallstones,probablybyanover-saturationofthebilein choles-terol;forliver:developmentofasteatosiswithalocalinflammation throughanoxidativestressandagreaterriskoffibrosisand car-cinogenesis;forprostate,areducedproductionoftestosterone,an importantfactorinthedifferentiationoftheprostaticepithelium; forhaemopoieticsystem,localinflammationofthebonemarrow microenvironmentactivating Tcells and macrophages (Askmyr etal.,2011;Meijeretal.,2011).

3.3. Redandprocessedmeat

Redmeatcomprisesallfleshfromdomesticatedanimalsthat havemoreredthanwhitemusclefibers.Inepidemiologicalstudies, itreferstobeef,pork,lambandgoat.Processedmeatreferstomeats preservedbysmoking,curingorsalting oradditionofchemical preservatives.

Theassociationsbetweentheintakesofredandprocessedmeat andtheriskofvariouscancershavebeenevaluatedbyWCRF/AICR in2007and2010–2014CUPreports(WCRF/AICR,2007,2010,2011, 2012,2013,2014a).Sincethepublicationofthesereports,15new meta-analyses(Chanetal.,2011;Alexanderetal.,2011;Larsson andWolk,2012;Paluszkiewiczetal.,2012;D’Eliaetal.,2012;Yang etal.,2012;Choietal.,2013;Huangetal.,2013;Salehietal.,2013; WangandJiang,2012;Tayloretal.,2009;Alexanderetal.,2010a; Alexanderand Cushing,2009;Faramawiet al.,2007;Alexander etal.,2010b)andonepooledanalysis(Leeetal.,2008)were iden-tified(AppendixA,Part2:Table3).Theycoveratotalof9different cancersites.Twelvestudiesconcernbothredandprocessedmeat (Chanetal.,2011;Alexanderetal.,2011;LarssonandWolk,2012; Yangetal.,2012;Choietal.,2013;Huangetal.,2013;Salehietal., 2013;WangandJiang,2012;Alexanderetal.,2010a;Faramawi etal.,2007;Alexanderetal.,2010b;Leeetal.,2008),threefocuson redmeat(Alexanderetal.,2011;Paluszkiewiczetal.,2012;Taylor etal.,2009)andoneonprocessedmeat(D’Eliaetal.,2012).

The“convincing”levelofevidenceoftheassociationbetween redandprocessedmeatandtheincreaseofcolorectalcancerrisk establishedinthe2011WCRF/AICRreport(WCRF/AICR,2011),is confirmedby results of recent meta-analysesof cohort studies (Chanetal.,2011;Alexanderetal.,2011).

Basedonresultsoftworecentmeta-analyses(LarssonandWolk, 2012;Paluszkiewiczetal.,2012),thelevelofevidencepreviously judged as“suggestive” (WCRF/AICR, 2007)for increasedrisk of pancreascancerassociatedwithredandprocessedmeatremains unchanged.Thelevelofevidencealsopreviouslyjudgedas “sug-gestive”fortheincreasedriskofstomachcancerwithprocessed meatandfortheincreasedriskoflungcancerwithredmeatis confirmedbytherecentresultsofrespectivelyonemeta-analysis includingsevencohorts(D’Eliaetal.,2012)andonemeta-analysis of18observationalstudies(Yangetal.,2012).

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Inthelightofresultsofthreenewmeta-analyses(Choietal., 2013;Huangetal.,2013;Salehietal.,2013),thelevelofevidence oftheassociationbetweentheriskofoesophaguscancerandred andprocessedmeatpreviouslyjudgedas“suggestive”(WCRF/AICR, 2007)isthereafterconsideredas“notconclusive”.Theassociation betweentheincreaseoflungandprostatecancerswithprocessed meatpreviouslyjudgedas“suggestive”(WCRF/AICR,2007)isnot confirmed respectively by a new meta-analysis of 10 observa-tionalstudies(Yangetal.,2012)andbyanewmeta-analysisof15 prospectivestudies(Alexanderetal.,2010b).Therefore,thelevel ofevidenceisjudgedas“notconclusive”.

Recentpublicationsinvestigatedtheassociationsbetweenred andprocessedmeatandbladder,breastandkidneycancersand betweenredmeatandprostatecancer,whichwerenotpreviously evaluatedby WCRF/AICR.Thenewresultsavailable forbladder (WangandJiang,2012)andbreast(Tayloretal.,2009;Alexander etal.,2010a)suggestanassociationbetweentheincreasedriskof thesecancersandtheconsumptionofredmeat,andthelevelof evidenceisjudgedas“suggestive”.Consideringtheheterogeneity ofresultsbetweenmeta-analysesorthelimitednumberof stud-ies,thelevelofevidenceisconsidered“notconclusive”forkidney cancerandredandprocessedmeat(AlexanderandCushing,2009; Faramawietal.,2007;Leeetal.,2008),andforbladder(Wangand Jiang,2012)andbreast(Alexanderetal.,2010a)cancersand pro-cessedmeat,andforprostatecancerandredmeat(Alexanderetal., 2010b).In addition,the evidence for endometrial (WCRF/AICR, 2013)andovarian(WCRF/AICR,2014a)cancersforwhichnonew studywasidentified,remains“notconclusive”.

Themechanismsexplainingtheassociationofredandprocessed meatconsumptionwithanincreasedriskofcancerinseveralsites arenotclearlydefined.Theeffectoncancersmaybelinkedto muta-geniccompoundssuchasneoformedproductsgenerated inred meatsandprocessedmeat:heterocyclicamines(HCA),polycyclic aromatichydrocarbons(PAHs)andN-nitrosocompounds(NOC) (Abidetal.,2014).Forcoloncancer,inadditiontothose assump-tions, excessof hemeiron hasbeenproposedtoplaya central role.Forprocessedmeats,nitratesandnitritesusedduring pro-cessmayrepresentanimportantpartofthecarcinogeniceffectvia facilitationofNOCformation(Bastideetal.,2011).

3.4. Saltandsaltedfoods

Accordingtoepidemiologicalstudies,thegeneralterm“salt” comprises total salt consumption, including salt added during cookingandattablebutalsosaltfromprocessedfoods,including saltyandsaltedfoods.

Sincetheevaluationoftheassociationbetweentheintakeofsalt andtheriskofstomachcancerbyWCRF/AICRin2007(WCRF/AICR, 2007),onlyonenewmeta-analysisof7cohortstudieswas identi-fied(D’Eliaetal.,2012)(AppendixA,Part2:Table4).The“probable” levelofevidenceoftheincreasedriskofstomachcancerproposed isthusconfirmed.

Severalmechanismsinvolvedinthetumorpromotingeffectof saltonstomachcancerriskhavebeenproposed.Highdietarysalt intakemay(i)facilitatethecolonizationofH.pylori,ariskfactorfor stomachcancer,(ii)changethemucousviscosityandthus aggra-vateexposuretoN-nitrosocompounds,knownascarcinogens,and (iii)causeinflammatoryresponsesofthegastricepithelium,with anincreasedepithelialcellproliferationandsoanincreasedriskof endogenousmutations(WangandJiang,2012).

3.5. Beta-carotenesupplements

Beta-caroteneisapigmentfromthecarotenoidfamily anda precursortovitaminA.Itentersinthecompositionofmanyfood supplements,asdefinedbytheEuropeanDirective2002/46/CE.

Theassociationsbetweentheintakeofbeta-carotene supple-ments and the risk of various cancers have been evaluatedby WCRF/AICRin2007and2010–2014CUPreports(WCRF/AICR,2007, 2010,2011,2012,2014a).Sincethepublicationofthesereports,17 newstudieswereidentified:11meta-analyses(Auneetal.,2012e; Jeonetal.,2011;Papaioannouetal.,2011;StrattonandGodwin, 2011;Cooperetal.,2010;Druesne-Pecolloetal.,2010;Jiangetal., 2010;Bardiaetal.,2008;Gallicchioetal.,2008;Tanvetyanonand Bepler,2008;Bjelakovicetal.,2008),onepooledanalysis(Lietal., 2012),4interventiontrials(Linetal.,2009;Neuhouseretal.,2009; Hercbergetal.,2007;Wrightetal.,2007)andonepost-intervention study(Ezzedineetal.,2010)(AppendixA,Part2,Table5).They coveratotalof15differentcancersites.

Theevidence oftheassociation betweentheintakeof beta-carotenesupplements(highdoses:≥20mg/d)andincreasedlung cancerriskinsmokersandsubjectsexposedtoasbestoswas pre-viouslyevaluatedinthe2007WCRF/AICRreportas“convincing” (WCRF/AICR,2007).Thisdirectassociationisconfirmedbythree recentmeta-analysesofinterventiontrials,especiallyinsmokers and subjectsexposed toasbestos(Druesne-Pecolloet al.,2010; Bardia et al., 2008; Tanvetyanon and Bepler, 2008).Two other meta-analysesofinterventiontrialsinthegeneralpopulation(Jeon etal.,2011; Gallicchioetal.,2008)observednoassociation.No level of evidence was provided in the 2007 WCRF/AICR report (WCRF/AICR,2007)regardingtheassociationbetweentheintake ofbeta-carotenesupplementsandstomachcancerrisk.Basedona meta-analysisof7interventiontrialsobservinganincreasedrisk in allsubjectsfordoses ≥20mg/dand in smokersand subjects exposedtoasbestos(Druesne-Pecolloetal.,2010),theincreased riskathighdoses(≥20mg/d),especiallyforsmokersandsubjects exposedtoasbestos,isthusconsideredas“probable”.

Thenewresults(meta-analysesandinterventiontrials) avail-ableforothercancersites(detailedinAppendixA,Part2:Table 5)—breast (Aune et al., 2012e; Druesne-Pecollo et al., 2010), prostate(StrattonandGodwin,2011;Druesne-Pecolloetal.,2010; Jiangetal.,2010;Neuhouseretal.,2009),skin(melanomaand non-melanoma) (Druesne-Pecolloetal.,2010;Hercberg etal.,2007; Ezzedine et al., 2010), pancreas (Druesne-Pecollo et al., 2010; Bjelakovicetal.,2008),colonandrectum(Papaioannouetal.,2011; Cooperetal.,2010;Druesne-Pecolloetal.,2010;Bjelakovicetal., 2008),bladder(Bardiaetal.,2008),oesophagus(Bjelakovicetal., 2008;Wrightetal.,2007),ovary(Linetal.,2009),mouth/pharynx (Wrightetal.,2007),larynx(Wrightetal.,2007),uterus(Linetal., 2009),non-Hodgkinlymphoma(Linetal.,2009)andheadandneck (Lietal.,2012)—werenotsufficienttodrawconclusions regard-ingtheirassociationwithbeta-carotenesupplementuse,thus,the evidenceremains“notconclusive”.Similarly,theevidencefor kid-neycancer,forwhichnonewstudywasidentified,remains“not conclusive”.

Somemechanismsmay besuggestedtoexplain theadverse effectofbeta-carotenesupplementationoncancerrisk,especially ininteractionwithcigarettesmoking.Directcontactofcigarette smokewithtissuesofsomeorganssuchaslungorstomachmay explainwhythesetwocancersitesmaybemore susceptibleto beta-caroteneeffect.Forinstance,highdosesofbeta-carotenemay exertapro-oxidativeeffect:increasedactivationofcarcinogenic moleculesreleasedduringsmoking(activationofphaseIenzymes ofthexenobioticmetabolism,suchascytochromesP450) result-inginthereleaseoffreeradicals(Paolinietal.,2003)which,when combinedtotheonesproducedbycigarettesmoking,maylead totheircleavageintounstablecompoundsthatcouldintervenein theoxidativeprocess.Next,experimentalmodelsalsosuggestthat lowdosesofbeta-carotenemaybeprotectiveagainstthealteration of the tumor suppressive gene P53 caused by cigarette smok-ing,whereashighdosesmaypromotethesealterations.Besides, whencombinedtocigarettesmokecondensate,beta-carotenemay

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contributetoreducetheexpressionofaresponseproteinto cellu-larstress(hemeoxygenase1),therebydecreasingtheproduction ofanti-proliferationagents(Brambillaetal.,2008).

3.6. Physicalactivity

Physicalactivityisdefinedasanybodilymovementproduced byskeletalmusclecontractionresultinginincreasedenergy expen-ditureabovetherestingenergyexpenditure.Physicalactivityin thebroad senseincludesallmovementsperformedin dailylife andcannotbereducedonlytosport,whetherrecreationalor com-petitive(WHO,2010).Itisgenerallyexpressedbyitsintensityin metabolicequivalentoftask(MET),giventhatoneMETrefersby conventiontotheenergyexpenditureofanindividualatrest, sit-ting(estimatedataboutonekcalperkgofbodyweightperhour). Theintensityofaperson’sphysicalactivityexpressedinMET cor-respondstotheratiooftheirworkingmetabolicrate(i.e.,rateof energyconsumption)totheirrestingmetabolicrate.Thus, differ-entintensitiesofphysicalactivityaredefined(Nortonetal.,2010): verylightintensity(orsedentary):1–1.5METs;lightintensity:1.6 tolessthan3METs;moderateintensity:3tolessthan6METs; vigorousintensity: 6METs ormore. In epidemiologicalstudies, physicalactivityiscomputedbycombiningintensity,durationand frequency of differenttypes of physicalactivity. Corresponding totalenergyexpenditureisfrequentlyexpressedinMET.h/week. Accordingtotheirphysicalactivityprofile,subjectsareclassified intothreelevelsofphysicalactivity,“low”,“moderate”or“high”. Physicalactivityisconventionallydividedintofourtypes: occu-pational,transport,recreationaland householdsettings.Studies present“totalphysicalactivity,¨calculatedoverallasthesumofthe fourtypes,oranyofthefourtypesthatarepresentedasall-type physicalactivity.Thus,amajorbarriertoconductingmeta-analyses isthedisparitybetweenphysicalactivitymeasures.

Theassociationsbetweenphysicalactivityandtheriskof var-iouscancershavebeenevaluatedbyWCRF/AICRin2007andin 2010–2014CUPreports(WCRF/AICR,2007,2010,2011,2012,2013, 2014a).Sincetheirpublication,sevennewmeta-analyses(Boyle etal.,2012;Wuetal.,2013a;Sunetal.,2012;Liuetal.,2011b; BehrensandLeitzmann,2013;Schmidetal.,2013;Vermaeteetal., 2013)andonenewpooledanalysis(Nicolottietal.,2011)were identifiedthatcoveratotalofeightdifferentcancersites:headand neck,colon,lymphoma,lung,prostate,kidney,breastandthyroid (AppendixA,Part2:Table6).

Theassociationbetweenphysicalactivityandthedecreaseof coloncancerrisk,previouslyevaluatedintheCUPWCRF/AICR2011 reportwithalevelofevidencejudgedas‘convincing’(WCRF/AICR, 2011),isconfirmedbyresultsofarecentmeta-analysisof prospec-tivestudiesevaluatingall-typephysicalactivity(Boyleetal.,2012); theprotective effectwas similar for proximal and distal colon cancer,and wasstronger formenthan for women.The associ-ationwiththeriskof postmenopausalbreastcancer, previously evaluatedintheCUPWCRF/AICR2010reportwithalevelof evi-dencejudged as“probable” (WCRF/AICR,2010),isconfirmedby resultsofarecent meta-analysisof prospectivestudies evaluat-ingall-typephysicalactivity(Wuetal.,2013a).Thedecreasedrisk ofpremenopausalbreastcancerassociatedwithphysicalactivity, judgedas”suggested”bytheWRCF/AICR2007report(WCRF/AICR, 2007),isconfirmedbyarecentmeta-analysisofprospectivestudies (Wuetal.,2013a)andtheevidenceisnowconsideredas “proba-ble”.SincetheCUPWCRF/AICR2013reportwherethedecrease inendometrialcancerriskassociatedwithphysicalactivitywas judgedas“probable”(WCRF/AICR,2013),nonewstudywas iden-tified.Thedecreasedriskoflungcancerassociatedwithphysical activity,judgedas“suggested”bytheWCFR/AICR2007report,was confirmedbyarecentmeta-analysisofprospectivestudies(Sun etal.,2012).Theriskreductionwasevenstrongerforthehighest

thanformoderatephysicalactivitylevel,comparedtothelowest level,withalevelofevidencenowjudgedas“probable”.

New results available since the publication of WCRF/AICR reportsfortheriskofcancersoftheprostate(Liuetal.,2011b), kid-ney(BehrensandLeitzmann,2013),headandneck(Nicolottietal., 2011)andthyroid(Schmidetal.,2013)andtheriskoflymphoma (Vermaeteetal.,2013)suggestalevelofevidencequalifiedas“not conclusive”.No recentresultwasavailabletoreassessthelevel ofevidencejudgedas“notconclusive”intheWCRF/AICRreports fortheassociationbetweenphysicalactivityandtheriskofrectal, ovarianandpancreaticcancers(WCRF/AICR,2007,2013,2014a).

Themainmechanismsthatcouldexplainthebeneficialeffectof physicalactivityoncancerriskarerelatedtoitsdirecteffectson circulatinglevelsofvarioushormonesandgrowthfactors, includ-ingdecreasedplasmalevelsofestrogens,insulinandIGF-1that increasewithoverweightandobesityandpromotecell prolifer-ation(McTiernan,2008).Physicalactivitymayalsolowercancer riskbyimprovingsensitivitytoinsulin,bystimulatingimmunity andbydecreasingadipokinelevels,oxidativestressand inflam-matorymarkers(Wuetal.,2013a).Physicalactivityalsoindirectly contributestocancerriskreductionbydecreasingtheriskof over-weight or obesity, limiting fat and promoting lean body mass. Physicalactivitymayspecificallylower therisk ofcolon cancer throughtheaccelerationofguttransit,reducingtheexposuretime ofthedigestivemucosatofoodbornecarcinogens.Itmayalsolower lungcancerriskbyreducingtheconcentrationsandinteractions ofcarcinogenswithlungtissuethroughimprovedlungfunction (Tardonetal.,2005;Buffartetal.,2014).

3.7. Fruitsandvegetables

Fruitsandvegetablescomprisefresh,frozen,canned,rawand cookedfruitsandvegetables,excludingnuts,seeds, driedfruits, potatoesandpulses(WCRF/AICR,2007).Accordingto epidemio-logicalstudies,thegeneralterm“vegetables”maycoverdifferent categories:total vegetables(non-starchyvegetablesandstarchy vegetables),non-starchyvegetables,freshvegetables(asopposed topreservedvegetables) and rawvegetables(excludingcooked vegetables).

Theassociationsbetweentheintakesoffruitsand(non-starchy) vegetablesand theriskof variouscancers havebeenevaluated byWCRF/AICRin2007and2010–2014CUPreports(WCRF/AICR, 2007, 2010, 2011, 2012, 2013, 2014a). Since the publication of these reports, 17 studies were identified: 14 meta-analyses (Soerjomatarametal.,2010;Liuetal.,2013a;Kimetal.,2010;Zhou etal.,2011;Auneetal.,2012b;Wuetal.,2013c,2013b;LiuandLv, 2013;Liuetal.,2013c;Chenetal.,2012b;Liuetal.,2012b;Liuetal., 2013b;Wuetal.,2013d;Yangetal.,2013b)and3pooledanalyses (Jungetal.,2013;Koushiketal.,2012;Leeetal.,2009)(Appendix A,Part2:Table7).Theycoveratotalof10differentcancersites. Sevenmeta-analysesfocusonfruitsandvegetablesaloneorin com-bination(Soerjomatarametal.,2010;Liuetal.,2013a;Kimetal., 2010;Auneetal.,2012b;Jungetal.,2013;Koushiketal.,2012;Lee etal.,2009)andothersstudymorespecificallycertainsubgroupsof vegetables:cruciferousvegetables(Wuetal.,2013c,b;LiuandLv, 2013;Liuetal.,2013c,2012b,2013b;Wuetal.,2013d),tomatoes (Chenetal.,2012b;Yangetal.,2013b),andalliumvegetables(Zhou etal.,2011).

Theassociationsbetweenfruitsand(non-starchy) vegetables andthedecreaseoftheriskofcancersofthemouth,pharynxand larynx combined, previously evaluatedin the 2007WCRF/AICR report(WCRF/AICR,2007), areconfirmedby resultsofa recent meta-analysis of observational studies (Soerjomataram et al., 2010).Consistentwithpreviousevaluations(WCRF/AICR,2007), theassociationbetweenfruitsandvegetablesandoesophagus can-cerisconfirmedbytwonewmeta-analysesofobservationalstudies

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(Soerjomataram et al., 2010; Liu et al., 2013a). Theassociation withstomachcancerisconfirmedforfruitsbyonemeta-analysis (Soerjomatarametal.,2010),forvegetablesbytwometa-analyses (Soerjomatarametal.,2010;Kimetal.,2010)andforallium vegeta-blesbyonemeta-analysis(Zhouetal.,2011).Thedecreaseoflung cancerassociated withfruitsisconfirmedbyonemeta-analysis (Soerjomataram etal.,2010).Sincethe2011WCRF/AICRreport (WCRF/AICR,2011),wherethedecreaseofcolorectalcancerrisk associated withgarlicwasjudged as “probable”, nonewstudy wasidentified.Forbreastcancer,whereasarecentmeta-analysis showednosignificantassociationbetweentotalbreastcancerrisk and vegetables (Aune et al., 2012b), consistent with the 2010 WCRF/AICRreportevaluation(WCRF/AICR,2010),arecentpooled analysisincluding20cohortstudiesshowedareductionoftherisk ofestrogenreceptor-negative(ER-)breastcancerassociatedwith non-starchyvegetables(Jungetal.,2013).Overall,withalevelof evidencejudgedas“probable”,theseresultsconfirmthedecrease ofrisksofcancersofthemouth,pharynx,larynx,oesophagus,and stomachassociatedwiththeconsumptionoffruitsandvegetables, thedecreaseinlungcancerriskassociatedwiththeconsumption offruitsandthedecreaseincolorectalcancerriskassociatedwith theconsumptionofgarlic;theyindicateadecreasedriskof(ER-) breastcancerassociatedwiththeconsumptionofvegetables.

With a level of evidence judged as “suggestive”, othernew studiesconfirmadecreaseinlungcancerriskassociatedwith con-sumptionofvegetables(Soerjomatarametal.,2010);theyindicate adecreasedriskoflung(Wuetal.,2013c),colorectal(Wuetal., 2013b)andbreast(LiuandLv,2013)cancerassociatedwiththe consumptionofcruciferousvegetables.Intheabsenceofnewdata, the“suggestive”levelofevidencefordecreasedriskofcolorectal andnasopharynxcancerassociatedwiththeconsumptionoffruits andvegetablesremainsunchanged.

The new results available for other cancer sites—pancreas (Koushiketal.,2012),kidney(Liuetal.,2013c;Leeetal.,2009), prostate(Chenetal.,2012b;Liuetal.,2012b),bladder(Liuetal., 2013b)and ER+breast for non-starchy vegetables(Auneet al., 2012b;Jungetal.,2013)—donotsuggestanyassociationbetween theriskofthesecancersandtheconsumptionoffruitsand vegeta-bles.Inaddition,theevidenceforcervical,endometrial,ovarian, andtotalbreastcancers,forwhichnonewstudieswereidentified, remains“notconclusive”.

Fruitsandvegetablescontainagreatdiversityofcomponents whichcanexertprotectivepropertiesagainstvariouscancers.Their microconstituentslikepolyphenols,carotenoidsandsulfur com-poundshaveantioxidantandantiproliferativeactivities,andthey modulate xenobiotic and hormonal metabolism, and immunity (Liu, 2013a;Liu,2013b).Fruitsand vegetablesareanimportant sourceofmicronutrients,notablyfolates(vitaminB9)whichplay animportantroleinDNAsynthesis andmethylationandinthe expressionofgenesinvolvedincarcinogenesis(Crideretal.,2012). Theyalsocontainfibersthatmayexertvariousprotectiveeffects (see next paragraph). More specifically, concerning ER- breast cancer,oestrogen-independentmechanismshavebeenproposed: reductionof proliferativefactorslikeIGF-1and cyclinE,and of nucleartranscriptionfactor NF-kappaBinvolvedin theimmune response(Jungetal.,2013).

3.8. Dietaryfiber

Dietaryfiberreferstocarbohydratepolymers(degreeof poly-merization:DP≥3)ofplantoriginthatmayormaynotbeassociated in the plant to lignin or other non-carbohydrate compounds (polyphenols,waxes, saponins,cutin,phytates, phytosterols...), andtomodified(physically,enzymaticallyorchemically)or syn-theticcarbohydratepolymers.

Theassociationsbetweendietaryfiberintakeandtheriskof variouscancershavebeenevaluatedbyWCRF/AICRin2007and 2010–2014CUPreports(WCRF/AICR,2007,2010,2011,2012,2013, 2014a).Sincethepublicationofthesereports,3newmeta-analyses wereidentified(Auneetal.,2012c;Colemanetal.,2013;Zhang et al.,2013)(AppendixA, Part2:Table8).Theycover 3 differ-entcancersites.Two meta-analyses(Aune etal., 2012c;Zhang etal.,2013)considereddifferenttypes(solubleandinsoluble)and sources(fruits,vegetablesandcereals)ofdietaryfiber.

Sincethe2011WCRF/AICRreport(WCRF/AICR,2011),where thedecreaseofcolorectalcancerriskassociatedwithdietaryfiber intakewasjudgedas“convincing”,nonewstudywasidentified. Theassociationbetweenbreastcancerriskanddietaryfiberintake previously judged as “not conclusive” in the 2010 WCRF/AICR report(WCRF/AICR,2010)wasstrengthened byonenew meta-analysisof16prospectivestudies(Auneetal.,2012c)showinga decreasedrisk,especiallyobservedforsolublefiberintake,andfor totaldietaryfiberintake≥25g/d.Thesenewresultswere consid-eredassufficienttoincreasethelevelofevidencetoa“probable” decreasedriskofbreastcancerassociatedwithdietaryfiberintake. One new meta-analysis (8 case-control studies) confirms a decreaseinoesophaguscancerriskassociatedwithdietaryfiber intake(Colemanetal.,2013),withalevelofevidencejudgedas “suggestive”.Anewmeta-analysis(2cohortsand19case-control studies)(Zhangetal.,2013)suggestedadecreasedstomach can-cerriskassociatedwithdietaryfiberintake(insolubleandsoluble andfromfruits,vegetablesorcereals).However,sincetheresults fromthetwoincludedprospectivestudieswerenon-significant, thelevelofevidenceremains“notconclusive”.Inaddition,the evi-denceforendometrium,ovary,pancreas,mouth,larynx,pharynx, lungandprostatecancers,forwhichnonewstudywasidentified, remains“notconclusive”.

Dietaryfibersarenotdigestedorabsorbedinthesmallintestine. Theyshowatleastoneofthefollowingphysiologicalproperties: increased stool bulk, increased fermentation by colonic micro-biota, reduced fasting blood cholesterol, reduced post-prandial bloodglucoseand/orinsulin.Dietaryfibersmayexertaprotective effectinthedevelopmentofseveralcancersthroughprevention ofinsulin-resistance,decreaseinIGF-1activity,decreasein sys-temicinflammationviatheproductionofshort-chainfattyacids (SCFA)bygutmicrobiota,andoptimizationofthecolonic micro-biotareinforcingtheintestinalbarrier(Probst-Henschetal.,2003; Cananietal.,2011;Kaczmarczyketal.,2012).Dietaryfibermayalso haveaspecificprotectiveroleagainsthormone-dependentcancer (i.e.,breastcancer)throughthereductionofcirculatingsteroid hor-monesconcentration(Mooreetal.,1998;Longcopeetal.,2000). Finally,thedecreasedcolorectalcancerriskissupportedbyalocal actionofdietaryfibersinthecolon:increasedstoolbulkand dilu-tionof carcinogensthrough waterbinding, decreasedintestinal transittime,bindingtocarcinogensand secondarybiliaryacids andproductionofSCFAwithanti-proliferativeandpro-apoptosis properties(Mooreetal.,1998).

3.9. Dairyproducts

Dairyproductsgenerallycomprisemilk(wholeorskimmilk), cheese(fresh,cottageandhardcheese),andyoghurt.Somerare studiesalsoincludebutteroricecream(Hunchareketal.,2008).

Theassociationsbetweendairyproductsconsumptionandthe riskofvariouscancershavebeenevaluatedbyWCRF/AICRin2007 and2010–2014CUPreports(WCRF/AICR,2007,2010,2011,2012, 2013,2014a).Sincethepublicationofthesereports,7new meta-analyseswereidentified(Hunchareketal.,2008;Auneetal.,2012d; Qinetal.,2007;Lietal.,2011b;Maoetal.,2011;Dongetal.,2011; Leeetal.,2007b)(AppendixA,Part2:Table9).Theycover5 dif-ferent cancersites.Mostof thesestudiesconsideredtotal dairy

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Table2

Nutritionalfactorseitherincreasingorreducingtheriskofcancerwithaconvincingorprobablelevelofevidence,asupdatedbytheINCaexpertgroup.

Nutritionalfactorsincreasingcancerrisk Cancersites Nutritionalfactors reducingcancerrisk

Cancersites

Alcoholicbeverages Mouth

Pharynx Larynx Œsophagus Colonandrectum Liver

Breast

Physicalactivity Colon

Lung Breast Endometrium

Overweightandobesity Œsophagus

Pancreas Colonandrectum Breast(postmenopause) Kidney Gallblader Endometrium Ovary Liver

Prostate(advancedcancer) Hematologicalmalignancies

Fruitsandvegetables Mouth Pharynx Larynx Œsophagus Stomach Lung(fruits)

Redmeatandprocessedmeat Colonandrectum Dietaryfiber Colonandrectum

Breast

Saltandsaltedfoods Stomach Dairyproducts Colonandrectum

Beta-carotenesupplements* Lung

Stomach

Breastfeeding Breast

* Notablyforsmokersorasbestos-exposedsubjects,andadose>20mg/dofbeta-carotene.

products(includingmilk)and6studiesdetailedresultsformilk orcheeseseparately(Hunchareketal.,2008;Auneetal.,2012d; Qinetal.,2007;Lietal.,2011b;Maoetal.,2011;Leeetal.,2007b). Theassociationbetweencolorectalcancerriskandmilkintake previouslyjudgedas“probable”inthe2011WCRF/AICRCUPreport (WCRF/AICR,2011)wasconfirmedbyonenewmeta-analysisof9 prospectivestudies(Auneetal.,2012d)showingadecreasedrisk. Theassociationwithtotaldairyproducts,notevaluatedinthe2011 WCRF/AICRCUPreport(WCRF/AICR,2011),isalsoconsideredas “probable”sincethemeta-analysisbasedon10prospective stud-ies(Auneetal.,2012d)alsoshowedadecreasedriskofcolorectal cancer.Ontheopposite,themeta-analysisof7prospectivestudies foundnoassociationbetweencheeseintakeandriskofcolorectal cancer,justifyingtorequalifythelevelofevidencefrom “sugges-tive”to“notconclusive”.

The level of evidence previously judged as “suggestive” for increased risk of prostate cancer associated with total dairy products intake is confirmed by the new meta-analyses of 11 prospectivestudies(Hunchareketal.,2008)and13prospective studies(Qinetal.,2007),respectively.Thedecreasedriskof blad-dercancerwiththeconsumptionofmilkwaspreviouslyevaluated as“suggestive”.Theassociationisconfirmedbyonemeta-analysis (6prospectiveand13case-controlstudiescombinedoranalyzed separately)(Maoetal.,2011)butnotbytheothermeta-analysis(5 prospectiveand9case-controlstudies)(Lietal.,2011b).

Thedecreasedriskofbreastcancerassociatedwithtotaldairy productsintakeobservedinanewmeta-analysisof8prospective studies(Dongetal.,2011)wasconsideredassufficienttoincrease thelevelofevidencefrom“notconclusive”(WCRF/AICR,2010)to “suggestive”.Theevidencefortheassociationbetweenkidney can-cerandtotaldairyproductsintake,forwhichnonewstudywas identified,remains“notconclusive”.

Concerning cancer sites or subcategories of dairy products which were not previously evaluated by WCRF/AICR, the new resultsavailabledidnotallowtoconclude.Itconcerned associa-tionsbetweentheriskofbladdercancerandtotaldairyproducts intake(Liet al.,2011b)and betweenkidney (Lee etal.,2007b) orprostatecancers(Hunchareketal.,2008;Qinetal.,2007)and milk consumption. Finally, there was no new published study

concerningovary,endometrium,pancreas,oesophagus,mouth, lar-ynx,pharynx,lung,stomach,testis,lymphomaandskincancers. Thelevelofevidenceremains“notconclusive”.

Dairyproductshavethespecificitytocontainavarietyof bioac-tivecompoundsthatcouldberelatedtopositiveornegativeeffects oncarcinogenesisinthesametime.Themainhypothesis under-lyingapossibleprotectiveeffectofdairyproductsagainstcancer riskrelatestotheircalciumcontentandtoalesserextentvitamin D,lactoferrinandfermentationproducts(LamprechtandLipkin, 2001;NoratandRiboli,2003;Tsudaetal.,2010).Arecentreview oftheliteraturehighlightedtheabilityofdairyproductsto modu-lateinflammatoryprocesses(Bordonietal.,2015).Milkisasource ofcholesterolandsaturatedfattyacidsthatmightincrease can-cerrisk;butitalsocontainsconjugatedlinoleic,acid,sphingolipids and butyric acid, which mayhave hypolipidaemic and antioxi-dantproperties(HagueandParaskeva,1995;Parodi,1997;Kelley etal.,2007).Independentlyofitscompositionincarbohydratesand lipids,milkconsumedinhighquantitiesincreasesbloodlevelsof IGF-1whichhasbeenassociatedwithanincreasedriskofbreast

EHBCCollaborativeGroupetal.(2010)andprostatecancer(Chan etal.,1998).Althoughthelevelofevidenceofanincreasedrisk ofprostatecanceris“suggestive”fortotaldairyproductsand“not conclusive”formilk,suggestedhypothesesconcernaroleofhigh consumptionofmilk,viaincreasedlevelsofandrogensand oestro-gens(Fleshneretal.,2004),presenceofphytanicacid(Wrightetal., 2012)andhighintakeofproteins(Allenetal.,2008).

3.10. Breastfeeding

Epidemiological studies reporting on breastfeeding by the motherandherriskofcancereithersimplydistinguishbetween “ever”,exclusiveornot,and“never”,ortheymeasurelifetime dura-tionoflactation.

Theassociationsbetweenbreastfeedingandtheriskofvarious cancershavebeenevaluatedbyWCRF/AICRin2007and2010–2014 CUPreports(WCRF/AICR,2007,2010,2014a).Sincethepublication ofthesereports,twonewmeta-analyses(Anothaisintaweeetal., 2013;Luanetal.,2013)andonepooledanalysis(Cronin-Fenton etal.,2010)wereidentified(AppendixA,Part2:Table10).The

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Solid tumors Hematological malignancies N asoph ar y n x H ead and n ec k M ou th (or a l ca vity), ph ar yn x, l ar ynx O esoph agu s O esoph ag eal a nd g as tr ic j un c tion ad e n o ca rc in om a St o mac h Sma ll in tes tin e C olon and r ec tum Pancr ea s Am pull a o f Vater Live r Ga llbl add e r K idn ey Bla dd er Breast (pre me nop au s e ) Breast (po st meno paus e) E ndo metriu m Cervix Ova ry Prosta te T es tis Lun g Th yr oi d Skin Hodg k in ly m ph om a Non-H odg k in lymp ho ma Leuka em ia M ul tip le m y e lo ma Alcoholic beverages * Me n Wom e n * ** * * * Overweight, obesity *P ro xi ma l Di s tal ** ** A dv an c e d Lo ca lise d * ** * * * * * Red meat ** * * * * Processed meat ** * * * ** ** Salt, salted foods

Beta-carotene

supplements * * * * ‡ * * * * * ** ‡ * * Physical activity * Col o n Rec tum ** ** * * Fruits Vegetables (non starchy) Dietary fiber ** Dairy products * * ** Breastfeeding *

Convincing Probable Suggestive Non

conclusive Not studied Suggestive Probable Convincing

Increased cancer risk Decreased cancer risk

Fig.2. SummaryTableforlevelsofevidencebetweenalcoholicbeverages,obesity,physicalactivityandothernutritionalfactorsandcancerrisk. *Levelofevidencewasnewlystudiedsince2007or2010–2014CUPWCRF/AICRreports.

*Levelofevidencehasbeenchangedsince2007or2010–2014CUPWCRF/AICRreports.

Supplementscontaininghighdosesofbeta-carotene,notablyforsmokersandasbestos-exposedsubjects.

associationsbetweenbreastfeedingandcancerofthebreast,ovary, andadenocarcinomaoftheoesophagealandgastricjunctionwere investigated.

The“convincing”levelofevidenceoftheassociationbetween breastfeedinganddecreasedriskofbreastcancerintheWCRF/AICR previousreport(WCRF/AICR,2010),isstrengthenedbytheresults

of a recent meta-analysis including 69 observational studies (Anothaisintaweeetal.,2013).

The level of evidence previously judged as “suggestive” for decreased risk of ovarian cancerassociated withbreastfeeding, isconfirmedbytherecentresultsofameta-analysisincluding3 cohorts(Luanetal.,2013).Arecentpooledanalysis(Cronin-Fenton

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NUTRITION AND CANCER RISK

PRIORITY OBJECTIVES

REDUCE ALCOHOLIC BEVERAGES COMSUMPTION

HAVE A BALANCED AND DIVERSIFIED DIET

BE PHYSICALLY ACTIVE PROMOTE BREASTFEEDING (PREGNANT WOMEN)

Fruits and vegetables

Dietary fiber

Dairyproducts

Physical activity

Breastfeeding Alcoholicbeverages

Red and processed meat

Salt and saltedfoods

Beta-carotenesupplements

Overweightand obesity

NUTRITIONAL FACTORS

INCREASING CANCER RISK

NUTRITIONAL FACTORS

DECREASING CANCER RISK

Fig.3.Fromnutritionalfactorstopriorityobjectives.

etal., 2010)investigating the associationsbetween breastfeed-ingandoesophagealandgastricjunctionadenocarcinomacancers, whichwerenotpreviouslyevaluatedbyWCRF/AICR(WCRF/AICR, 2007),observedsignificantdecreasedrisks.Consideringthe lim-itednumberofcasesincluded,thelevelofevidenceisconsidered “notconclusive”.

Several plausible mechanisms involved in lactation-induced protectiveeffectshavebeenidentified:increaseddifferentiation ofbreastcellsandlowerexposuretosexhormonesduring amen-orrhea, elimination of cells with DNA damage through strong exfoliationofbreasttissueandmassiveepithelialapoptosisduring orattheendoflactation(WCRF/AICR,2010).

3.11. Summaryoftheupdatedevidence

Fig.2givesanoverviewofallthelevelsofevidenceupdated through the evaluation process. Based on this state of knowl-edge,andtheevidencegradedasconvincingorprobable,theten nutritionalfactorscanbedividedintwogroups(Table2):factors thatincreasetheriskofcancer—alcoholicbeverages,overweight andobesity, redandprocessedmeat,salt andsaltedfoods, and beta-carotenesupplements—andfactorsthatdecreasetheriskof cancer—physicalactivity,fruitsandvegetables,dietaryfiber,dairy products,andbreastfeeding.Although,noquantitativerisk assess-menthasbeenconducted,thisinformationcanbetranslatedinto threeprioritynutritionalobjectivesforcancerpreventioninthe generalpopulation(Fig.3)(i)toreducealcoholicbeverages con-sumption,(ii)tohavea balancedanddiversifieddiet,(iii) tobe physicallyactive;andoneobjectivedirectedtopregnantwomen: topromotebreastfeeding.Indeed,allobjectivesrelatedtofood fac-torsthatincreasecancerrisk(redmeatandprocessedmeat,salt andsaltedfoods,andbeta-carotenesupplements)ortothosethat decreasecancerrisk(fruitsandvegetables,dietaryfiber,dairy prod-ucts)canbeaggregatedinonlyoneobjectivewhichis“tohavea balancedanddiversifieddiet”.Inaddition,thereductionof over-weightandobesitycanbedividedin twoobjectives“tohave a balancedanddiversifieddiet”and“tobephysicallyactive”.

4. Discussion

Overall,inthisevaluationnearly150relationshipsbetweenthe alcoholicbeverages,obesity,physicalactivityandtheother nutri-tionalfactorsconsideredandtheriskofcanceratvarioussiteswere examinedbytheexpertgroup.Thisworkreinforcesprevious evi-denceandalsoprovidesnewinformation.Firstly,itestablishesfor thefirsttime alevel ofevidencefor cancersites thatwerenot mentionedbefore, notablytheevidenceoftheincreasedriskof hematologicmalignanciesassociatedwithoverweightandobesity, gradedas“probable”.Secondly,itmodifiesthelevelofevidencefor severalassociations,forinstancetheevidenceofbreastcancerrisk associatedwithdietaryfiber,judgedas“probable”.Thisevaluation alsohighlights,forlevelsofevidencequalifiedassuggestiveornot conclusivewhichrepresenttwo thirdsofallassociations exam-ined,thatepidemiologicalandmechanisticresearchisstillneeded tostrengthenorrefutethem.

Thisupdatedstateofknowledgeenablestoclassifythe nutri-tionalfactorsconsideredaseitherriskfactorsorprotectivefactors andtoidentifythreepriorityobjectivesfornutritionalcancer pre-ventioninthegeneralpopulation:toreducealcoholicbeverages consumption,tohave abalanced anddiversified dietand tobe physicallyactive.ThesepriorityobjectivesarepertinentinFrance likeinotherdevelopedcountries(IARC,2014b;SteinandColditz, 2004).ThereportoftheINCaexpertgrouphasbeenpublishedin FrenchlanguageinJune2015(INCa,2015b)anditsmaincontentis nowdeliveredtothegeneralpublic,viatheInternetandaleaflet, intheframeworkoftheFrenchCancerplanandNationalnutrition andhealthprogram.

Since this evaluation, four WCRF/AICR CUP reports have beenpublished(WCRF/AICR,2014b,2015a,b,c).Theyfocusedon prostate,liver,gallbladderandkidneycancers.Overall,their con-clusionsareinagreementwiththoseoftheINCaexpertgroup,for theassociationsbetweenbodyfatnessandincreasedriskofcancer oftheprostate(advancedcanceronly),liver,gallbladderand kid-ney.Regardingalcoholicbeveragesandlivercancer,thejudgment oftheevidenceintheCUPreportis“convincing”whereasthatofthe INCaexpertgroupis“probable”.Thisdiscrepancycanbeexplained

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bysomedifferencesinthecriteriathatweremetineach evalua-tion.Inaddition,theCUPreportonkidneycancerconcludedthat lessthan30g/dalcoholconsumptionisassociatedwithadecreased riskofkidneycancerwithanevidencejudgedas“probable”,and thatbeyond30g/dthelevelofevidenceisinsufficient.However, themechanismsthatmightexplainadecreasedriskofkidney can-cerassociatedwithalcoholremainunclear.Thisisthereasonwhy theINCaexpertgroupconsideredtheevidenceas“notconclusive”. Furthermore,itmustberecalledtheimportanceofconsideringthat alcoholconsumptionisassociatedwithincreasedriskofseveral othercancersiteswithaconvincingorprobablelevelofevidence, suchasthecancersof themouth, pharynx,larynx, oesophagus, liver,colonandrectum,andbreast.

TheInternationalAgencyforResearchonCancer(IARC) eval-uatesthecarcinogenicity ofvarious factorsamong which some lifestylefactors.Inamonographypublishedin2012,alcoholic bev-erages,ethanolinalcoholicbeveragesandacetaldehydeassociated withconsumptionofalcoholicbeverageshavebeenclassifiedas carcinogenstohumans(Group1)(IARC,2012).InOctober2015, anotherIARCmonographworkinggroupconcludedthatprocessed meatiscarcinogenictohumans(Group1)and thatredmeatis probablycarcinogenictohumans(Group2A)(Bouvardetal.,2015). Theseconclusionsareconsistentwithourevaluations.

Recently,thefourtheditionoftheEuropeancodeagainst can-cerhasbeenpublished(Schuzetal.,2015).Thisinitiativeofthe EuropeanCommissionaimstoinformpeopleaboutactionsthat mayhelpthemtoreducetheirriskofcancer.Thisedition,which hasbeencoordinatedbytheIARC,consistsoftwelve recommen-dationsincludingnutritionalrecommendations.Recommendation 4is“Bephysicallyactiveineverydaylife.Limitthetimeyouspend sitting.”Recommendation5is“Haveahealthydiet:eatplentyof wholegrains,pulses,vegetablesandfruits.Limithigh-caloriefoods (foodshighinsugarorfat)andavoidsugarydrinks.Avoidprocessed meat;limitredmeatandfoodshighinsalt”.Recommendation6is “Ifyoudrinkalcoholofanytype,limityourintake.Notdrinking alcoholisbetterforcancerprevention.”Recommendation10afor womenis“Breastfeedingreducesthemother’scancerrisk.Ifyou can,breastfeedyourbaby”.Althoughthemethodstoevaluatethe literatureforalcohol drinking,diet,obesity/body fatness, physi-calactivityandbreastfeedinginassociationwithcancer,slightly differedaccordingtofactors(Scocciantietal.,2015a;Noratetal., 2015;Andersonetal.,2015;Leitzmannetal.,2015;Scocciantietal., 2015b)andwiththemethodoftheINCaexpertgroup,thegeneral nutritionalrecommendationsoftheEuropeancodeareconsistent withtheconclusionsandpriorityobjectivesthattheINCaexpert grouphasidentified.

Finally,theoverallimpactofmodificationsofexposuresto nutri-tionalfactorsoncancerincidencehasbeenestimated:addressing thesepriorityobjectivesbasedonnutritionalfactorsmighthelp populationsofdevelopedcountriestoreducetheburdenof can-cerandavoidabout30%ofthemostfrequentcancers(WCRF/AICR, 2009;WCRF,2015).

5. Conclusions

Thiscomprehensivereviewandevaluationofthecurrent evi-denceon10nutritionalfactorsandtheriskofmorethan25cancer sitesemphasizes threemain objectivesaddressing alcohol con-sumption,diet and physical activity that shouldbeattained to improvecancerpreventionatthepopulationandindividuallevels. Inthemeantime,researcheffortmustbemaintainedonnumerous associationswhoseevidenceisstillconsideredas“suggestive”or not“conclusive”.

Conflictofinterest

Theauthorshave noconflictofinterest associatedwiththis publication.

Funding

Vanessa Cottetwaspartiallysupportedby aFrench Govern-mentgrantmanagedbytheFrenchNationalResearchAgencyunder theprogram“Investissementsd’Avenir”,reference ANR-11-LABX-0021.

MélanieDeschasauxwasfundedbyaPhDgrantfromthe Can-céropôleIle-de-France(publicfundingfromtheParisregion).

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.critrevonc.2016. 01.002.

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Figure

Fig. 1. Flow chart of study selection.
Fig. 2. Summary Table for levels of evidence between alcoholic beverages, obesity, physical activity and other nutritional factors and cancer risk.
Fig. 3. From nutritional factors to priority objectives.

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