Although evidence shows that adult overweight and obesity are related to risk for many cancers, the growing epidemic of obesity provides a challenge to clinical practice and the implementation of guidelines for the management of weight. Historical data from the past 25 years point to obesity as a cause of approximately 14% of cancer deaths in men and up to 20% of cancer deaths in women [1
]. These may be conservative estimates because the population has gained substantial weight over this time period and the prevalence of overweight and obesity has increased from 15% in 1980 to 35% in 2005 [2
] (). Some now estimate that the total health burden of overweight and obesity may exceed that for cigarette smoking [3
A major review of weight, physical activity, and cancer incidence by the International Agency for Research on Cancer (IARC) used obesity prevalence data from Europe and relative risks from a meta-analysis of published studies and concluded, in 2002, that obesity was a cause of 11% of colon cancer cases, 9% of postmenopausal breast cancer cases, 39% of endometrial cancer cases, 25% of kidney cancer cases, and 37% of esophageal cancer cases [4
]. In addition, data from the American Cancer Society suggested that overweight and obesity were related to mortality from liver cancer, pancreatic cancer, non-Hodgkin's lymphoma, and myeloma [1
]. This effect on mortality reflects both the excess incidence and excess mortality among those with cancer. Since the 2002 IARC report, substantial new evidence has supported a cause-and-effect relation between overweight and obesity and the onset of these cancers, further increasing the burden of cancer resulting from obesity [5
]. The American Institute for Cancer Research and World Cancer Research Fund reported that there is convincing evidence for a relation between obesity and esophageal, pancreatic, colorectal, postmenopausal breast, endometrial, and kidney cancers, with probable evidence for gallbladder cancer. In addition, they found probable evidence that abdominal fatness, in particular, increases the risk for pancreatic, endometrial, and postmenopausal breast cancer. Finally, emerging evidence suggests that obesity increases risk for aggressive prostate cancer [6
]. Overall, we estimate that overweight and obesity cause approximately 20% of all cancer cases. Previously Doll and Peto [7
] included overnutrition (overweight) with diet causing a combined 35% of all cancer cases. In , we break out overweight and obesity from diet and provide updated estimates for the causes of cancer.
Estimated proportion of cancer in the U.S. that could have been avoided by changes in each category of nongenetic cancer causes.
To conclude that a cause-and-effect relation exists between obesity and cancer at each site, one often pursues studies of mechanisms that confirm the underlying biology of this relation and provide insights into prevention strategies. Take, for example, postmenopausal breast cancer. Among postmenopausal women, obesity is directly related to circulating estradiol levels [8
], which themselves are directly related to breast cancer risk [9
]. When the action of estrogens is interrupted by estrogen receptor modulators in randomized controlled trials, breast cancer incidence is approximately 50% lower [11
Just as smoking cessation leads to a reduction in the risk for lung cancer, adding to the evidence of a cause-and-effect relation, a documented 50% reduction in the risk for breast cancer among women who lost ≥10 kg after menopause and kept it off [13
] adds to our understanding of this causal relation. In addition, focusing on weight loss after menopause, a time in life when obesity clearly increases the risk for breast cancer, provides important evidence on the time frame for change in cause (weight) and subsequent change in cancer incidence. This lower incidence of postmenopausal breast cancer follows the decline in circulating estrogen after weight loss.
For colon cancer, growing evidence points to insulin pathways mediating the effect of body mass index BMI and risk [14
]. Studies of blood glucose levels and colon cancer show a direct relation between higher glucose and subsequent risk [14
]. Providing further biologic rationale, c-peptide [15
], a marker of insulin production, also shows this positive relation, and animal models using insulin injection versus saline show a significantly higher incidence of colon cancer among those injected with insulin [16
]. Finally, preclinical data provide additional support for the insulin–insulin-like growth factor (IGF) hypothesis of cancer risk, as outlined in several excellently detailed recent reviews [17
]. The phosphoinositide 3-kinase/Akt pathway likely compromises the downstream target of insulin, and is one of the pathways most commonly altered in epithelial tumors [18
]. In sum, strong evidence points to hyperinsulinemia as the direct pathway from adiposity to colon cancer. For each cancer site, we present summary estimates of relative risk from the rigorous meta-analysis by Renehan et al. [5
] and the likely pathway or mechanism for a causal relation between obesity and cancer ( and ).
RR for cancer per 5 kg/m2 higher BMI and most likely causal mechanism: Males
RR for cancer per 5 kg/m2 higher BMI and most likely causal mechanism: Females
Of particular importance is the rapid rise in adenocarcinoma of the esophagus over the past 20 years. In parallel with the global epidemic of obesity, the morphology of esophageal cancer has shifted from squamous to adenocarcinoma, and a growing body of research points to the role of obesity in esophageal reflux, a pathway for this malignancy [20
]. Increasing BMI in the Nurses' Health Study was associated with a significantly higher risk for reflux esophagitis [21
]. Weight gain was associated with a higher risk for developing frequent reflux, and a weight loss of 3.5 kg was associated with a significantly lower risk for frequent symptoms of gastroesophageal reflux disease [21
]. The role of weight loss and the time course of the lower risk for esophageal cancer remain to be documented.
One concern raised by some is that obesity cannot cause cancer through so many different mechanisms. This opinion seems misplaced because the etiology of cancers is known to differ for different organ sites. Female hormones cause breast and endometrial cancer but have much less impact on other cancers, for example. Insulin may drive colon and prostate cancer [22
] (), whereas inflammation may drive other malignancies. All these mechanisms can have a role in mediating the relation between obesity and cancer risk. As noted by Roberts et al. [17
], in their review of the biologic mechanisms linking obesity and cancer risk, the pathophysiology of obesity is complex and multisystemic, and thus, it is unlikely that “one size fits all.”
Serum insulin and risk for prostate cancer. p (trend) = .02.