ABSTRACT

IMPORTANCE Obesityisassociatedwithincreasedrisk ofcancer, including endometrial,
esophageal, gastric, kidney, colorectal, liver, gallbladder, pancreas, prostate, postmenopausal
breast, ovarian, and thyroid cancers. Overweight and obesity account for approximately 10% of newcancerdiagnosesannuallyintheUSandupto50%ofcertaincancerssuchas
endometrial andhepatobiliary cancer.
OBSERVATIONS Overweightisdefinedasbodymassindex(BMI)of25to29.9andobesityas
BMIof30orgreater.Obesityandoverweightarecharacterizedbyexcessaccumulationof
adipose tissue, which disrupts its primary function of energy storage. Excess energy, in the form
of free fatty acids, is transferred to developing cancer cells and stimulates cancer development
throughgenomicinstability caused byoxidative stress and DNAdamage.Otherdefining
features of adipose tissue dysfunction include inflammation and altered hormoneproduction
suchasincreasedestrogensandleptinanddecreasedadiponectin.Inflamedadiposetissueis
associated with systemic elevations in inflammatory mediators, such asprostaglandin E2, the
cytokines interleukin 1β and interleukin 6, and tumor necrosis factor α. These mediators
promotetumorgrowthdirectlyorindirectlybystimulatingestrogenbiosynthesis, whichcan
promoteproliferation of hormone-sensitive cancers such asbreast, ovarian, and endometrial
cancer, or bysuppressingimmune-mediatedeliminationofdevelopingcancercellsthrough
accumulation ofmyeloid-derived suppressorcells andreductions in theamountandfunctionof
cytotoxic T cells and natural killer cells. Inflammation and oxidative stress are also stimulated by
obesity-associated depletion of gut commensalbacteria species (eg, Akkermansiamuciniphila)
andovergrowthofbacterialpopulationsassociated withcancerdevelopmentinpreclinical
models(eg,Bilophila). In observational studies, patients who lost more than 10%ofbody
weightthroughbariatric procedures (n = 30318)orwithglucagon-likepeptide1receptor
agonists (n = 1651452)hadmodestreductionsinobesity-associatedcancerincidence
(absolute change, −0.02%to−0.5%).
CONCLUSIONSANDRELEVANCE Overweightandobesityareassociatedwithhigherratesof
cancer andaccountfor10%ofnewcancerdiagnosesannuallyintheUS.Weightlossmay
reduce cancerrisk by attenuating adverse effects of obesity, but greater than 10% weight loss
maybenecessarytoreducecancerrisk