With the release this week of the ACS report on Diabetes and Cancer risk, we return to the growing cancer burden caused by obesity and excess weight gain during adult years. We might approach this problem from several angles. First, which cancers are caused by obesity and second, by focusing on diabetes, we might ask does this disease give added insights to the pathway from weight gain to cancer?
Weight, weight gain, and risk of cancer
While evidence shows that adult overweight and obesity are related to risk of many cancers, the growing epidemic of obesity provides a challenge to clinical practice and the implementation of guidelines for 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 as the US 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). It is now estimated that the total health burden of overweight and obesity exceeds 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 is a cause of 11% of colon cancer; 9% of postmenopausal breast cancer; 39% of endometrial cancer; 25% of kidney cancer; and 37% of esophageal cancer (4). In addition, data from the American Cancer Society (ACS) suggested that overweight and obesity were related to mortality from liver cancer, pancreatic cancer, non-Hodgkin lymphoma, and myeloma (1). This effect on mortality reflects both excess incidence and excess mortality among those with cancer.
To conclude that a cause and effect relation exists between obesity and cancer at each cancer site scientists pursue studies of mechanism that confirm the underlying biology of this relation and provide insights to guide 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 (9-10). When the action of estrogens is interrupted by estrogen receptor modulators in randomized controlled trials, breast cancer incidence is reduced by approximately 50% (11-12).
Just as smoking cessation leads to a reduction in risk of lung cancer adding to the evidence of a cause and effect relation, so documenting a 50% reduction in risk of breast cancer among women who lost 10kg or more after menopause and kept it off (13) adds to both our understanding of this causal relation. In addition, focusing on weight loss after menopause, a time in life when obesity clearly increases risk of breast cancer, provides important evidence on the time frame for change in cause (weight) and subsequent change in cancer incidence. This reduction in incidence of postmenopausal breast cancer will follow the decline in circulating estrogen after weight loss.
For colon cancer, growing evidence points to insulin pathways mediating the effect of 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 vs. saline show significant increases in colon cancer among those injected with insulin (16). Finally, preclinical data provides additional support for the insulin-IGF hypothesis of cancer risk, as outlined in several excellently detailed recent reviews (17-18). The PI3K/Akt pathway likely compromises the downstream target of insulin and is one of the most commonly altered in epithelial tumors.(18-19) In sum, strong evidence points to hyperinsulinemia as the direct pathway from adiposity to colon cancer.
Returning to the ACS committee report the concensus committee convened by ACS and the American Diabetes Association concluded that Diabetes (primarily type 2) is associated with an increased risk of liver, pancreas, endometrium, colon/rectum, breast, and bladder cancers. Furthermore, the association between diabetes and some cancers may be due in part to shared risk factors between the 2 diseases such as aging, obesity, diet, and physical inactivity. Possible mechanisms for a causal pathway between diabetes and cancer include hyperinsulinemia, hyperglycemia, and inflammation.
Building on this summary and the extensive work by Dr Renehan and colleagues revieweing the evidence linking obesity to cancer, we present summary estimates of relative risk from the rigorous meta-analysis by Renehan (5) and the likely pathway or mechanism for a causal relation between obesity and cancer (see Table 1 and 2).
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Table 1. Relative Risk of Cancer per 5 kg/m2 Increase in BMI, Males, and most likely causal mechanism
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Cancer
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RR
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Causal mechanism
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Oesophageal adenocarcinoma
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1.52***
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Reflux esophagitis and chronic irritation
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Thyroid
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1.33*
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Unknown
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Colon
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1.24***
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Insulin
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Renal
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1.24***
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In part though hypertension
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Liver
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1.24
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Fatty liver cirrhosis
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Malignant melanoma
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1.17**
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?
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Multiple myeloma
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1.11***
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Inflammatory pathways – IL6
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Rectum
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1.09***
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?
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Gallbladder
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1.09
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Chronic secretion-gallstones and irritation
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Leukemia
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1.08**
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?
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Pancreas
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1.07
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Possible insulin pathway
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Non-Hodgkin lymphoma
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1.06***
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Inflammatory pathways – IL6
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Prostate¶
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1.03
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?
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Lung
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0.76***
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Smoking leads to leanness and causes lung cancer
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Esophageal squamous
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0.71***
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Smoking leads to leanness and causes squamous esophageal cancer
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Relative risk for a 5 point increase in BMI. For example, the relative risk linked to a BMI of 28 compared to a BMI of 23; or a BMI of 32 compared to 27.
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***p < .0001; **p < .01; *p < .05
¶ biased to null as this includes predominantly low grade lesions
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Adapted from Renehan et al, 2008; Fig 3 (5).
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Table 2. Relative Risk of Cancer with RR per 5kg/m2Increased BMI, Females, and most likely causal mechanism
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Cancer
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RR
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Causal mechanism
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Endometrium
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1.59***
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Endogenous Estrogen
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Gallbladder
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1.59*
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Chronic secretion-gallstones and irritation
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Oseophageal adenocarcinoma
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1.51***
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Reflux esophagitis and chronic irritation
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Renal
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1.34***
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In part through hypertension
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Leukemia
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1.17*
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Unknown
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Thyroid
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1.14**
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Unknown
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Breast (postmenopausal)
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1.12*
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Endogenous estrogen
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Pancreas
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1.12*
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Possible insulin pathway
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Multiple myeloma
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1.11***
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Inflammatory pathways – IL6
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Colon
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1.09***
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Insulin
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Non-Hodgkin lymphoma
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1.07
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Inflammatory pathways – IL6
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Liver
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1.07
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Fatty liver cirrhosis
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Breast (premenopausal)
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0.92**
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Irregular menstrual cycles- hormones
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Lung
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0.8*
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Smoking leads to leanness and causes lung cancer
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Esophageal squamous
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0.57***
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Smoking leads to leanness and causes squamous esophageal cancer
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Relative risk for a 5 point increase in BMI. For example, the relative risk linked to a BMI of 28 compared to a BMI of 23; or a BMI of 32 compared to 27.
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***p < .0001; **p < .01; *p < .05
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Adapted from Renehan et al, 2008; Fig 4 5.
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Impact of obesity among cancer patients
Obesity also impacts outcomes among cancer patients. Growing evidence also points to benefits of physical activity for breast and colon cancers. Dosing of chemotherapy and radiation therapy among obese patients may also be impacted and therapy related toxicity may vary with level of obesity. These issues will be addressed in a subsequent post.
References