By Dr. Geoffrey Modest
The International Agency for Research on Cancer (IARC) working group just assessed the relationship between overweight/obesity and cancers, finding 8 more cancers associated with obesity (see Lauby-Secretan B. N Engl J Med 201; 375: 794). They relied on over 1000 epidemiological/observational studies to assess this association, since there really are no large randomized clinical intervention trials with long-term follow-up assessing the effects of weight-loss vs maintaining weight to see if there is a difference in cancer incidence.
- Background, worldwide estimates:
- In 2014: 640 million adults in 2014 (an increase by a factor of 6 since 1975) were obese
- In 2013: 110 million children and adolescents (an increase by a factor of 2 since 1980) were obese
- In 2014: prevalence of obesity was 10.8% among men, 14.9% among women, and 5.0% among children; and globally more people are overweight or obese than are underweight.
- In 2013: 4.5 million deaths worldwide were caused by overweight and obesity; the obesity-related cancer burden represents up to 9% of the cancer burden among women in North America, Europe, and the Middle East.
- In 2012: 1 million new cancer cases and 8.2 million cancer-related deaths
- The 8 new cancer associations:
- Colon or rectum, RR = 1.3, with positive dose response relationships (e., the more overweight, the higher the risk)
- Gastric cardia, RR = 1.8, with positive dose response relationships
- Liver, RR = 1.8, with positive dose response relationships
- Gallbladder, RR = 1.3, with positive dose response relationships (though in their analysis, comparing the top vs bottom decile of activity, this achieved a P=0.06 only)
- Pancreas, RR = 1.5, with positive dose response relationships
- Kidney, RR = 1.8, with positive dose response relationships
- Esophageal adenocarcinoma, RR=8, with positive dose response relationships
- In general the relative risks increased from 1.2 to 1.5 for overweight and from 1.5 to 1.8 for obesity for cancers of the colon, gastric cardia, liver, gallbladder, pancreas and kidney
- These results were consistent in different geographic regions, and were similar for men and women
- The previously known cancers with associations:
- Breast cancer in postmenopausal women, RR of 1.1 per 5 BMI units, esp in estrogen-receptor positive tumors
- Endometrial cancer: RR=1.5 for overweight,5 for BMI 30-35, 4.5 for BMI 35-40, and 7.1 for BMI>40
- Ovarian cancer (epithelial): RR=1.1
- Multiple myeloma, RR=1.2 for overweight, 1.2 for BMI 30-35, 1.5 for BMI 35-40, and 1.5 for BMI>40
- Meningioma, RR = 1.5
- Thyroid, RR=1.1
- And there is some limited evidence of an obesity association with male breast cancer, fatal prostate cancer, and diffuse large B-cell lymphoma
- For breast cancer, there was an association between increased BMI at the time of diagnosis and reduced survival
- In terms of weight loss: the quality of the data are not great, but there are some suggestions that weight loss (including by bariatric surgery) may reduce the breast and endometrial cancer risks.
- As supporting evidence:
- Animal data (different animals) confirm an association between obesity and cancer at many different sites
- Animal data also supports the effect of limiting weight gain vs food ad libitum for some cancers (mammary gland, colon, liver, pancreas, skin, pituitary) but inverse relationship with others (prostate, lymphoma, leukemia)
Commentary:
- As with all of these observational studies, association does not imply causality. For example, is it the obesity itself which is associated with cancer? Or, are there specific things that obese people do differently than normal weight ones (e.g., eating certain oncogenic foods? not exercising enough? living in more toxic environments?)
- The above results were similar for BMI and waist circumference when that data was available (waist circumference has a higher correlation with visceral obesity, which is the metabolically more active obesity associated with metabolic syndrome, increased inflammatory markers, )
- In many of the above associations, the associations persisted in studies using mendelian randomization (see https://stg-blogs.bmj.com/bmjebmspotlight/2016/04/28/primary-care-corner-with-geoffrey-modest-md-bmi-height-and-socioeconomic-status/ , which describes mendelian randomization and some of its limitations, but overall it is a process that assesses known genetic markers for a disease to help assess causality (to differentiate in this case whether the causality is if those genetically predisposed to obesity are more likely to get the cancer, not vice-versa or as independent phenomena)
- Possible mechanisms: increased body fat is associated with multiple metabolic and endocrine changes (sex hormones, insulin and insulin-like growth factor, inflammation), which could promote tumor initiation and/or growth
- It is important to keep in mind the strength of the associations above. Typically, in observational studies, a relative risk of under 1.5-2 often does not pan out as being really significant, despite the fact that it can be really significant in randomized controlled trials. So, a bit of a caution in over interpreting the above results for many of the cancers. The dose-response relationship does add some support the associations, however.
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Another recent article came out on the relationship between physical activity and cancer (see doi:10.1001/jamainternmed.2016), finding that leisure-time physical activity was associated with lower risk of many cancers. Details:
- 12 prospective US and European cohorts with self-reported physical activity from 1987-2004, including 1.44 million participants, looking at 26 different cancers
- Mean age 59 (19-98), 57% female, mean follow-up 11 years (7-21), mean BMI 26, 54% ever-smokers
- 186,932 cancers diagnosed
- Leisure-time activity, defined as high if 6 or more METs. Median activity was 8 MET-h/week (equivalent to 150 minutes of moderate-intensity exercise, e.g. walking)
- Results:
- High vs low leisure-time activity was associated with lower risk of:
- Esophageal adenocarcinoma (HR 0.58, i.e., 42% decreased risk)
- Liver cancer (HR 0.73)
- Lung cancer (HR 0.74)
- Gastric cardia (HR 0.78)
- Endometrial (HR 0.79)
- Myeloid leukemia (HR 0.80)
- Myeloma (HR 0.83)
- Colon (HR 0.84)
- Head and neck (HR 0.85)
- Rectal (HR 0.87)
- Bladder (HR 0.87)
- Breast (HR 0.90)
- In aggregate, there was a 7% lower risk of total cancer in those performing higher levels of physical activity [HR 0.93 (0.90-0.95)]
- Adjusting for BMI (nullied the relationship above for liver, gastric cardia and endometrium) but otherwise only a small attenuation of the risk, on the order of 5-11% of the HR’s. Smoking status affected lung cancer but not the others
- Some cancers were associated with more activity
- Melanoma (HR 1.27)
- Prostate cancer (HR 1.05)
- High vs low leisure-time activity was associated with lower risk of:
Commentary:
- One striking finding is the overlap of cancers which seem to be affected by both BMI and exercise, reinforcing that these lifestyle/environmental issues seem to be particularly important.
- But, one needs to be particularly careful in meta-analyses in general and huge ones in particular: it is very hard to get granular data over time (what is “ever-smokers”? a few cigarettes at the beginning of the study? stopping smoking 2 packs/day near the end of the study?); how often did they track information, such as changes in BMI or physical activity over time? Was it just a one-shot assessment at the beginning of the study? And how did they then quantitate these typically changing variables over such a long follow-up? This data acquisition is done differently in different studies, so how is this all put together mathematically? It is pretty striking the range of ages (19-98) and years of follow-up (7-21) in the individual studies, suggesting they were pretty heterogeneous. And, in general, the people in this large meta-analysis were reasonably lean (BMI=26), so it may be difficult to really control for BMI in their data (they divided the patients into BMI <25 vs >25, but did not have the BMI spread of the IARC study). This limits the interpretation of their finding in this exercise study that 3 of the highest risk cancers in the AIRC study for BMI had no relationship to exercise when controlling for BMI.
- They only looked at leisure-time physical activity. It seems pretty intuitive that people with very physical jobs do have more exercise at work than those with office jobs (i.e., many of my patients are on their feet all day, walking around cleaning office buildings, etc. And it seems they should get some “exercise” credit for that.) There are not great studies which have looked at occupationally-related exercise, probably because it is hard to measure on an individual basis: even those with the same job category may have very different amounts of exercise if they clean a small office vs a large automated office building)
- One concern is that the burden of obesity and lack of exercise is increasing, especially with migration to larger cities and with increasing Westernization around the world
- But one potentially positive finding is that exercise is associated with lower cancer risk independent of BMI for many cancers (with above caveat): it is much easier to help people do exercise than to achieve sustained weight loss (see https://stg-blogs.bmj.com/bmjebmspotlight/2016/08/17/primary-care-corner-with-geoffrey-modest-md-weight-loss-and-resting-metabolic-rate/ ). And there are reasonable postulated mechanisms by which exercise could decrease cancer: hormonal changes (sex steroids, insulin and insulin-like growth factos, adipokines; similar to the BMI mechanisms postulated above) as well as nonhormonal (decrease inflammation, improve immune function/surveillance, decrease oxidative stress, and increase GI transit time, the latter of which could decrease colon cancer incidence)
- There are still many questions, even if one accepts the conclusions of these studies
- Does instituting a more aggressive exercise program lead to decreased cancer (i.e., an intervention study would provide stronger conclusions than an observational study)
- And how much exercise works? Is there a threshold? Is it different for different cancers? (this might be important in different parts of the world where different cancers predominate)
- But, the real bottom line is that there have been many studies over the years showing that lifestyle/environment are associated with pretty much all of the chronic diseases in the world. The above studies simply reinforce the association with cancer. And it offers us as clinicians yet another way to talk with patients about the importance of a healthy lifestyle. The association with cancer may be a particularly useful tool in motivating patients to avoid progressing to a less healthy lifestyle over time or instituting changes to improve their lifestyle (for better or worse, patients given equal mortality scenarios from cancer or heart disease, for example, are more afraid of the cancer one…it just sounds scarier)
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