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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�
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,NutritionalEpidemiologyResearchTeam(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/).
a
r
t
i
c
l
e
i
n
f
o
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
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.,
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:I2≥75%(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
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).
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
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
(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
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
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
NUTRITION AND CANCER RISK
PRIORITY OBJECTIVESREDUCE 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
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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