NEWS & VIEWS EPIDEMIOLOGY

Obesity and cancer—the evidence is fattening up A large-scale study with 5.24 million participants has found statistically significant associations between increased BMI and 17 of 22 frequent cancers. The strongest associations were observed for cancers of the endometrium, kidney, gallbladder and uterus. Questions remain as to whether several of the weaker associations reported in this study reflect genuinely causal relationships. Kaaks, R. & Kühn, T. Nat. Rev. Endocrinol. 10, 644–645 (2014); published online 30 September 2014; doi:10.1038/nrendo.2014.168

Epidemiologic evidence that obesity increases the risk of several major cancers has been steadily accumulating. In 2001, an expert panel convened by the International Agency for Research on Cancer (IARC) concluded that excess adiposity is related to an increased risk of endometrial cancer, renal cell tumours, oesophageal adenocarcinomas, colon cancer and breast cancer (only in postmenopausal women).1,2 The evidence at that time was predominantly from case– control studies; however, many reports from large prospective cohorts have subsequently been published. A meta-analysis summarizing the evidence from prospective studies, covering >282,000 incident cases of cancer in ~4.8 million participants, confirmed the conclusions of the IARC panel and also showed that high BMI was associated with an increased risk of liver cancer, rectal cancer and malignant melanoma (only in men), as well as leukaemias, multiple myeloma and non-Hodgkin lymphomas (for men and women).3 A recent report in The Lancet adds to these findings.4 Bhaskaran and co-workers conducted a large prospective study in the UK, using a primary care database containing the records of 5.24 million individuals.4 After a median follow-up of 5.8 years, 166,955 participants developed one of the 22 most common cancers. Increases in BMI were associated with strong increases in the risks of cancers of the endometrium (for each 5 kg/m 2 increase in BMI, HR 1.62; 99% CI 1.56–1.69), gallbladder (HR 1.31; 99% CI 1.12–1.52) and kidney (HR 1.25; 99% CI 1.17–1.33).

Distinct increases were also seen in cancers of the liver (HR 1.19; 99% CI 1.12–1.27) and, among never smokers, the oesophagus (HR 1.16; 99% CI 1.09–1.24). Weaker associations were found for cancers of the breast in postmenopausal women, cervix, colon and ovaries, whereas a statistically significant inverse association was seen for the risk of breast cancer in premenopausal women (HR 0.89; 99% CI 0.86–0.92).

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…the large sample size enabled even weak associations to become statistically significant

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As a result of the large number of patients with each cancer, Bhaskaran and colleagues could model the relationship between BMI and cancer risk with greater precision than any previous study. Interestingly, the risk of cancers of the endometrium, gall­bladder, kidney and breast (postmenopausal women) were found to increase with increasing BMI even within the range of 18.5–25.0 kg/m2 (which is considered normal weight) and not only at the high BMI levels corresponding to overweight (BMI of 25.1–30.0 kg/m2) and obesity (BMI ≥30 kg/m2). As in previous studies,3 Bhaskaran and colleagues found that the association between increased BMI and large bowel cancer was stronger for men than for women. The overall association between BMI and risk of breast cancer in postmenopausal women was weak. How­ ever, supplementary analyses confirmed previous findings5 that the risk is increased

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Rudolf Kaaks and Tilman Kühn

more markedly for women >65 years, whose tumours are diagnosed many years after the women have gone through menopause, and among postmenopausal women not using hormone replacement ther­apy. Unfor­ tunately, analyses that restricted followup to women not using hormone replacement therapy were not reported for cancers of the endometrium and colon, which are two other cancers that have previously been found to be more strongly related to BMI among women who did not use this therapy compared with those who did.6,7 A limitation of the study by Bhaskaran et al. was the undifferentiated coding of some of the cases of cancer, which resulted in insufficient detail being available on the histologic subtype and/or tumour grade for some cancers. Thus, it was not possible, using the database at hand, to distinguish between risk associations that were probably hetero­geneous depending on specific cancer subtypes. For example, the association between increased BMI and ovarian cancer might differ depending on the histologic subtype, and the association is known to be different for oesophageal adenocarcinomas and squamous cell carcinomas, as well as for high-grade and low-grade prostate cancer. The study also lacked information on some major confounders, such as the intensity of past and current smoking habits. In fact, the finding that the total population, but not nonsmokers, had inverse or J‑shaped associations between BMI and the risk of lung, oral cavity, stomach, pancreatic, or liver cancer exemplifies that residual VOLUME 10  |  NOVEMBER 2014

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NEWS & VIEWS confounding might have affected some of the presented risk estimates. Overall, Bhaskaran and colleagues found statistically significant associations between BMI and the risk of developing 17 of the 22 cancers studied; associations were absent only for multiple myeloma and non-Hodgkin lymphomas, as well as tumours of the central nervous system, bladder and stomach. Clearly, the large sample size enabled even weak associations to become statistically significant. In the absence of further clinical or experimental evidence indicating plausible biological mechanisms, it remains unclear whether all the recorded weaker associations reflected genuinely causal relationships or whether some were the result of confounding or other biases. Whilst several of the weaker associations reported by Bhaskaran and co-workers overlapped with findings of the large-scale meta-analysis by Renehan et al.,3 there were also noticeable discrepancies. For example, Bhaskaran et al. found a direct association between increased BMI and risk of ovarian cancer and multiple myeloma, whereas Renehan et al. found no statistically significant associations. For ovarian cancer, however, the findings of hetero­geneity by menopausal status and a stronger direct association in premenopausal women by Bhaskaran and colleagues are in line with recent results from another large meta-analysis.8 Assuming that all of the associations recorded were causal, Bhaskaran and collea­ gues estimated that in the UK, 41% of uterine cancers and >10% of gall­bladder, kidney, liver and colon cancers are attributable to

NOVEMBER 2014  |  VOLUME 10

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…weight control should clearly be ranked as a top priority for primary disease prevention

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany (R.K., T.K.). Correspondence to: R.K. [email protected]

individuals being overweight or obese (that is, having a BMI ≥25.0). These estimates are comparable to those from two independent analyses.9,10 Yet, BMI provides only an approximate measure of overall body fatness, generally explaining only about half of the interindividual variation in body fatness in a given study population, and it does not account for differences in the distribution of body fat. One could thus speculate that the effect of adiposity on the occurrence of many chronic diseases, including several cancers, will generally be underestimated when based on BMI. The additional use of waist circumference measurements, an independent proxy measure of abdominal fat, might somewhat improve estimates of the per­centage of cancer incidences that can be attributed to obesity. However, to further improve quantitative estimates of the occurrence of chronic disease as a result of body fatness, epidemiologic studies will need to use more advanced measurements of overall and regional body composition, such as advanced medical imaging methods. In the meantime, as excess body weight is a well-established risk factor for type 2 diabetes mellitus, cardiovascular disease, and certainly the cancers that showed the strongest associations in this study, as well as in other studies, weight control should clearly be ranked as a top p­riority for primary disease prevention.

Competing interests The authors declare no competing interests.

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1. IARC. Weight Control and Physical Activity, IARC Handbook of Cancer Prevention. Vol. 6 (WHO Press, 2002). 2. Bianchini, F., Kaaks, R. & Vainio, H. Overweight, obesity, and cancer risk. Lancet Oncol. 3, 565–574 (2002). 3. Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and metaanalysis of prospective observational studies. Lancet 371, 569–578 (2008). 4. Bhaskaran, K. et al. Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5.24 million UK adults. Lancet 384, 755–765 (2014). 5. Ritte, R. et al. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study. Breast Cancer Res. 14, R76 (2012). 6. Pischon, T. et al. Body size and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). J. Natl Cancer Inst. 98, 920–931 (2006). 7. Crosbie, E. J., Zwahlen, M., Kitchener, H. C., Egger, M. & Renehan, A. G. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 19, 3119–3130 (2010). 8. Olsen, C. M. et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr. Relat. Cancer 20, 251–262 (2013). 9. Bergström, A., Pisani, P., Tenet, V., Wolk, A. & Adami, H. O. Overweight as an avoidable cause of cancer in Europe. Int. J. Cancer 91, 421–430 (2001). 10. Parkin, D. M., Boyd, L. & Walker, L. C. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Br. J. Cancer 105 (Suppl. 2), S77–S81 (2011).

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Epidemiology: obesity and cancer--the evidence is fattening up.

A large-scale study with 5.24 million participants has found statistically significant associations between increased BMI and 17 of 22 frequent cancer...
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