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Obesity and cancer: “Dangerous friendship”
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Review
Obesity and cancer: “Dangerous friendship”夽 Carlos A. González Svatetz a,∗ , Alberto Goday Arnó b,c a
Unidad de Nutrición, Ambiente y Cáncer, Instituto Catalán de Oncología (ICO), L’Hospitalet de Llobregat, Barcelona, Spain Servicio de Endocrinología y Nutrición, Hospital del Mar, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain c Centros de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain b
a r t i c l e
i n f o
Article history: Received 3 March 2014 Accepted 8 May 2014 Available online xxx Keywords: Obesity Cancer Overweight Obesity prevalence Abdominal obesity
a b s t r a c t Obesity and cancer are one of the most important health problems is Spain. Between 23 and 28% of the adult population in Spain are obese, 39% are overweight and 36% have abdominal obesity. The association between obesity and type 2 diabetes mellitus, hypertension, dyslipidemia and sleep obstructive apnea is well known. On the contrary, the association between obesity and cancer is less known, because the recent evidence on it. Several prospective studies have shown during the last years the strong relationship between obesity and cancer of colon, breast in post-menopausal women, endometrial, kidney and pancreas as well as esophageal adenocarcinoma. Furthermore there is recent evidence showing that liver, gallbladder, thyroid and ovarian cancer as well as leukaemia, multiple myeloma and Hodgkin lymphomas are probably associated with obesity, yet more studies are needed. A better knowledge of the relation between cancer and obesity will allow improving the prevention strategies against cancer, a more efficient early detection, and a more suitable treatment of obesity and overweight. Although the mechanisms of carcinogenesis of obesity are not well established, avoiding overweight and obesity are considered one of the best approaches to reduce the risk of cancer. Therefore the general population must be aware that cancer is one of the most important hazards associated with the current obesity epidemic in our society. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Obesidad y cáncer: «las amistades peligrosas» r e s u m e n Palabras clave: Obesidad Cáncer Sobrepeso Prevalencia obesidad Obesidad abdominal
˜ La obesidad afecta al Obesidad y cáncer son 2 problemas sanitarios de primera magnitud en Espana. ˜ 23–28% de la población adulta espanola, y el sobrepeso y la obesidad abdominal al 39 y 36%, respectivamente. Es bien conocida la relación entre obesidad y diabetes mellitus tipo 2, hipertensión arterial, ˜ Menos conocida es en cambio la asociación con el cáncer, dislipidemia, y apnea obstructiva del sueno. porque la evidencia es más reciente. Numerosos estudios prospectivos han demostrado en los últimos ˜ anos, con un alto grado de evidencia científica, una asociación clara entre la obesidad y los cánceres ˜ de colon y recto, mama en mujeres pos-menopáusicas, endometrio, rinón, esófago y páncreas. Esta asociación es también probable con los tumores de hígado, vesícula biliar, cardias, tiroides, y hematológicos, para los que se requieren más estudios. Un mejor conocimiento de la relación entre obesidad y cáncer puede permitir mejorar las estrategias de prevención del cáncer, así como una más eficiente detección precoz, y un tratamiento más adecuado de la obesidad y el sobrepeso. Aunque los mecanismos por los cuales la obesidad induce los distintos tipos de cánceres no son suficientemente conocidos, evitar el
夽 Please cite this article as: González Svatetz CA, Goday Arnó A. Obesidad y cáncer: «las amistades peligrosas». Med Clin (Barc). 2016. http://dx.doi.org/ 10.1016/j.medcli.2014.05.026 ∗ Corresponding author. E-mail address: [email protected] (C.A. González Svatetz). ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
MEDCLE-3028; No. of Pages 7
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sobrepeso y la obesidad es hoy una de las medidas más efectivas para reducir el riesgo de cáncer, por ˜ la lo que es necesario concienciar a la población general sobre uno de los mayores peligros que entrana actual epidemia de obesidad. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
Obesity in Spain Obesity and cancer are 2 major health problems.1–3 While they may seem unrelated, scientific evidence shows a very strong relationship between obesity and cancer, which clearly establishes what we could call a “dangerous friendship”. When considering the comorbidities associated with excess weight, we generally include prevalent processes such as type 2 diabetes (DM2), hypertension and dyslipidaemia (classic cardiovascular risk factors4 ), arthropathy and obstructive sleep apnoea syndrome, among others. Cancer is rarely included in this association, if at all.5 Obesity is considered to be a 21st-century epidemic.1 Weight status analyses in the various population studies conducted in the last 35 years show a gradual increase in mean sample weight,6 and indicate that the Spanish population has not been immune to this global pandemic either.7,8 The evolution of the prevalence of obesity in Spain, according to data from the national health survey, is shown in Fig. 1. It shows a gradual, steady increase in levels, rising from 7.7% in 1987 to 13.6% in 2001, over all age groups and in both sexes.9 One of the most alarming facts comes from analysing trends in the prevalence of the various grades of obesity. During the period from 1993 to 2006, grade 1 obesity (body mass index [BMI] 30–34 kg/m2 ) increased by 50%, grade 2 (BMI 35–39 kg/m2 ) by 110%, and morbid obesity (BMI ≥ 40 kg/m2 ) by 240%.10 The number of obese individuals in Spain is therefore growing, as is the number and proportion of individuals with extreme levels of overweight. Information from health surveys, together with various regional and local studies in Spain had estimated the prevalence of obesity through direct anthropometry; pooling data from some of these studies enabled this prevalence to be analysed (SEEDO).11,12 These data were the most widely used reference for many years, in the absence of specific national studies. Recent epidemiological studies have provided data with direct measurement of weight and height in broad samples representative of the entire Spanish population (Table 1). The ENRICA study analysed a population sample of 12,883 individuals over the age of 18 between 2008 and 2010.13 The estimated prevalence of obesity was 22.9% (24.4% in men and 21.4% in women), and abdominal obesity—defined as a waist circumference over
Prevalence %
18 15 12.9 12
13.6
11.3 9.9
9
7.7
6 3 0 1987
1993
1995
1997
2001
Fig. 1. Evolution of the prevalence of obesity in Spain according to national health survey data.
102 cm or 88 cm—was 36% (32% in men and 39% in women). A gradual increase was observed in the prevalence of general and abdominal obesity with age, affecting 35% and 62% of persons aged over 65 years. The [email protected] study,14 a population study of 5072 individuals over the age of 18 carried out in Spain between 2009 and 2010, found a prevalence of obesity of 28.25% (28.9% in men and 27.5% in women) by directly measuring weight and height. Both the ENRICA13 study and the [email protected] study showed a higher prevalence of obesity in men in the under-60 age groups only, while it was more common in women after that age. More recently, investigators in the DARIOS study, consisting of pooled analysis of data from 11 Spanish studies on cardiovascular risk factors conducted between 2000 and 2010 with a sample of 28,743 people aged between 35 and 74 years, also determined a prevalence of obesity of 28% in men and 28.3% in women.15 Both local/regional and national studies13–15 show significant heterogeneity in the prevalence of obesity in Spain, in that it is clearly higher in the south, specifically in Andalusia16 and the Canary Islands,17,18 than in the north.19 The prevalence of overweight for men and women in the 3 national studies was as follows: 46.4% and 32.5%, respectively, in the ENRICA study; 47.5% and 34% in the [email protected] study; and 50.7% and 35.6% in the DARIOS study. The prevalence of abdominal obesity (defined as previously) for both sexes combined in the 3 studies was 36%, 35.7% and 36%, respectively. Specific studies in the active working population, including younger, healthy individuals, have detected lower levels of obesity (17% in men and 7.7% in women), but alarmingly similar levels of overweight, especially in men (44.8% in men and 21.3% in women).20 A gradual increase in the prevalence of obesity was also observed over the 4 years studied. The prevalence of obesity is clearly associated with DM2, hypertension and dyslipidaemia.15 Obesity is also associated with low levels of physical activity,21 low socioeconomic status and education level, and unhealthier eating habits.22 Obesity and cancer Various international committees of experts have conducted a systematic review of the epidemiological evidence. In 2002, the International Agency for Research on Cancer (IARC)23 concluded that colon, breast, renal and endometrial cancer and oesophageal adenocarcinoma could be prevented by avoiding weight gain. A more recent report from an international committee of experts evaluating the evidence up to 200624 confirmed these associations and added to the list. They concluded that there is sufficient convincing evidence (Table 2) of a positive causal association between general obesity and colon and rectal cancer, breast cancer in postmenopausal women, renal, endometrial and pancreatic cancer and oesophageal adenocarcinoma, and between abdominal obesity and colorectal cancer (CRC). General obesity is probably positively associated with gallbladder cancer and negatively associated with breast cancer in premenopausal women, while abdominal obesity is probably positively associated with pancreatic, endometrial and breast cancer in postmenopausal women. Finally, in another systematic review and large meta-analysis of prospective studies,25 a strong positive association was found
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Table 1 Prevalence (%) of overweight and obesity in Spain, in individuals over the age of 18, according to sex and population study. Study
ENRICA13 [email protected] DARIOS15 (35 to 74 years)
Overweight
Obesity
Abdominal obesity
Men
Women
Total
Men
Women
Total
Men
Women
Total
46.4 47.5 50.7
32.5 34 35.6
39.4 39.5 51
24.4 28.9 28
21.4 27.5 28.3
22.9 28.25 28
32 23.1 35.8
39 54 54.6
36 35.7 36
BMI: body mass index. Overweight defined as BMI between 25 and 29.9 kg/m2 . Obesity defined as BMI equal to or greater than 30 kg/m2 . Abdominal obesity defined as waist circumference greater than 102 cm in men and 88 cm in women.
Table 2 Relative risk associated with overweight and obesity, and risk attributable to obesity with different cancers for which there is considered to be sufficient evidence of causality. Source: World Cancer Research Fund/American Institute for Cancer Research.24 Type of cancer
Relative risk for BMI 25–29.9 kg/m2 26
Relative risk for BMI ≥ 30 kg/m2 26
Attributable risk in the EU population26
Colorectal (men) Colorectal (women) Breast (postmenopausal women) Endometrial Kidney (renal cells) Oesophageal (adenocarcinoma) Pancreatic
1.5 1.2 1.3 2 1.5 2 1.3
2 1.5 1.5 3.5 2.5 3 1.7
27.5 14.2 16.7 45.2 31.1 42.7 19.3
BMI: body mass index; EU: European Union.
in men with increased BMI and oesophageal adenocarcinoma and thyroid, colon and kidney cancer, and a weaker association with rectal cancer and malignant melanoma. In women with increased BMI, a strong positive association was found with endometrial and gallbladder cancer, oesophageal adenocarcinoma and kidney cancer, and a weaker association with breast cancer in postmenopausal women, pancreatic, colon and thyroid cancer. A positive association between obesity and leukaemia, multiple myeloma and non-Hodgkin lymphoma (NHL) was observed in both sexes. Overall, overweight and obesity are estimated to be associated with 14% of cancer-related deaths in men and 20% in women in the US population.26 The mechanisms26 (Fig. 2) can vary depending on the type of cancer, but are related to insulin resistance and the resulting chronic hyperinsulinaemia, as well as the increase in the bioavailability of steroid hormones and chronic inflammation. Adipose tissue is the main site of peripheral oestrogen synthesis. Obesity (and the subsequent increase in adiposity) causes an increase in the production and circulation of active free oestrogens (mainly oestradiol), androgens and testosterone, and a reduction in sex hormone-binding globulin levels. Oestradiol enhances sensitivity to insulin and insulin-like growth factor (IGF) receptors. Meanwhile, obesity increases the concentrations of insulin, IGF1 and IGF2, which in turn reduce apoptosis and promote cell growth. Adiposity also has a significant inflammatory component, with an increase in cytokines, such as interleukins 6 and 8, tumour necrosis factor-␣ and C-reactive protein. Finally, visceral fat adipocytes form an active endocrine organ that secretes adiponectin, the most abundant adipokine. It is inversely correlated with BMI, with higher plasma values in women compared to men. Adiponectin increases insulin sensitivity and may have an anti-inflammatory and anticancer effect.25 Leptin, on the other hand, has an effect on satiety and is positively associated with insulin resistance and obesity. Finally, ghrelin, a hormone produced by the fundic glands of the stomach, also plays a role in the regulation of appetite and fattyacid metabolism and promotes fat storage. It has been found to be inversely associated with the risk of gastric cancer and oesophageal adenocarcinoma.27 It has recently been noted that gut microbiota could have an effect on obesity through the immune response and inflammation.28
There is a very close relationship between DM2, obesity and cancer; obesity is a major risk factor common to certain tumours and DM2. DM2 is associated with an increased risk of pancreatic, liver, colorectal, endometrial and breast cancer, which are also associated with obesity.29 Diabetes is considered to have an effect on neoplastic processes through various mechanisms common to obesity, including hyperinsulinaemia, hyperglycaemia and chronic inflammation. Physical activity, which is an important factor in preventing weight gain, is also a protective factor against DM2, CRC, breast cancer in postmenopausal women and endometrial cancer, and potentially against other cancers.29
Obesity and breast cancer The association between obesity and breast cancer varies depending on the menopausal status. There is consistent evidence in premenopausal women of a modest risk reduction in women with BMI ≥ 28 kg/m2 . This reduction is due to the fact that young obese women have a higher number of anovulatory cycles and lower levels of circulating steroid hormones, mainly progesterone and oestradiol.30 In contrast, in postmenopausal women, BMI 25–30 kg/m2 increases the risk of breast cancer by 30%, while BMI ≥ 30 kg/m2 increases the risk by 50%.26 It is estimated that 16.7% of breast cancers in postmenopausal women in the European population are associated with obesity.26 Some studies have suggested that indicators of abdominal obesity could be independent predictors of risk with respect to BMI, but a large systematic review31 has shown that, when adjusted for BMI, the association with markers of abdominal obesity disappears. The effect of increased BMI is greater in women who have never used hormone replacement therapy (HRT), which supports the hypothesis that obesity increases risk through the effect of the increased circulating sex hormone levels.32 Moreover, there is evidence that postmenopausal women with breast cancer and a high grade of obesity (BMI > 40 kg/m2 ) have higher mortality than normalweight women, probably due to lower participation in screening programmes and lower self-detection of tumours.26 Furthermore, overweight and obesity increase the likelihood of breast cancer recurrence, independent of menopausal status.33
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Metabolic effect. Increased resistance to insulin and C-peptide, hyperinsulinaemia, increased production of insulin-like growth factors [IGF-I, IGF-II], increased cell growth and reduced apoptosis. Gastrointestinal and appetite-regulating hormones. Decreased adiponectin production by adipocytes (increased insulin resistance). Increased production of leptin and ghrelin. Increased production of steroid hormones (peripheral oestrogen production, reduced production of hormone-binding globulins) Inflammatory effect (increased production of cytokines [IL-6, IL-8 and TNF-α] and C-reactive protein).
Obesity
Fig. 2. Cancer and obesity. Potential mechanisms.
Obesity and colorectal cancer Obesity has a greater effect on CRC in men than in women. Overweight increases the risk of CRC by 20% in men and 50% in women, while obesity increases the risk by 50% in women and 100% in men, compared to individuals with normal BMI. The prevalence of overweight and obesity in the European population is responsible for 14.2% of CRCs in men and 27.5% in women.26 Obesity generally increases the risk of colon cancer to a larger extent than rectal cancer. A large meta-analysis of 30 prospective studies34 has shown a higher risk in men than in women for BMI and abdominal obesity indicators, which is independent of the BMI and could be a more important predictor than this parameter. Another extensive metaanalysis35 has shown a positive association between increased BMI and the risk of colon, but not rectal, adenomas, which is independent of sex. The European EPIC cohort has shown that the use of HRT in women reduces the effect of obesity and overweight,36 which could partly explain the lower risk in women. The increased incidence of CRC is thought to be related to growing obesity rates, DM2, hyperinsulinaemia and increased insulin resistance, which form part of metabolic syndrome.26,37 The extensive European prospective EPIC study has observed a significant association between increased C-peptide in blood38 and the risk of CRC, which supports the insulin-effect hypothesis. Obesity and endometrial cancer There is also extensive, consistent epidemiological evidence on the positive association between obesity and the risk of endometrial cancer. The risk is twice as high in overweight individuals and 3.5-fold higher in obese individuals, compared to those of normal weight. Almost half (45.2%) of endometrial cancers in European women are attributed to obesity and overweight.26 A large prospective study in the US39 found no differences in risk as regards general or abdominal obesity, and that the use of HRT reduces the risk associated with obesity. The risk of endometrial cancer associated with obesity occurs in both pre- and postmenopausal women, and chronically high insulin, androstenedione and testosterone levels are important in its mechanism.40 Obesity and pancreatic cancer The risk of pancreatic cancer is 1.3-fold higher in overweight individuals and 1.7-fold higher in obese individuals compared to those with normal BMI. In the European population, 19.3% of pancreatic cancer cases are attributed to obesity and overweight.26
In an extensive analysis of 14 cohort studies,41 a 47% increase in risk was observed when BMI ≥ 30 kg/m2 was compared to BMI 21–22.9 kg/m2 . An independent association was also observed for both BMI and abdominal obesity indicators, with no differences according to sex. Obesity and renal cell carcinoma Overweight increases the risk of renal cell carcinoma 1.5-fold and obesity 2.5-fold compared to people with normal BMI. Almost one third (31.1%) of these tumours could be attributed to obesity and overweight in the European population.26 An extensive review of epidemiological studies42 has shown no differences according to sex. There is insufficient data to differentiate between the effect of BMI and abdominal obesity markers. The effect of obesity is considered to be independent of that caused by the increase in blood pressure, which would suggest that they act through different mechanisms.26 Obesity and oesophageal and cardia adenocarcinoma Overweight individuals have twice the risk of oesophageal adenocarcinoma and obese individuals have triple the risk compared to normal-weight individuals. It is thought that 42.7% of these tumours are due to overweight and obesity in the European population.26 However, there is no association with squamouscell carcinoma of the oesophagus. The significant increase in oesophageal adenocarcinomas in western countries, where it has become more common than squamous-cell carcinoma, is considered to be due to the increase in obesity in these populations. Large prospective studies,43 as well as joint analysis of an international consortium of studies,44 have shown that the increased risk is associated with both BMI and abdominal obesity indicators. The mechanism of this association is not yet clear. Obesity, especially abdominal obesity, contributes to an increase in gastrooesophageal reflux, which causes the metaplastic changes observed in Barrett’s oesophagus, although the effect of obesity could be independent of gastro-oesophageal reflux.45 In addition to the tumours previously described, for which there is considered to be enough evidence on their causal association with obesity,24 there are other neoplasms for which clear evidence is being gathered on their potential association with obesity (Table 3). Various epidemiological studies have found a positive association between obesity and gastric cardia cancer (which accounts for 20–30% of stomach tumours in the western population). In a recent meta-analysis of 24 prospective studies,46 it was observed
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Table 3 Relative risk associated with overweight and obesity, and risk attributable to obesity for different cancers probably associated with obesity. Type of cancer 26
Liver Gallbladder26 Gastric cardia (adenocarcinoma)46 Thyroid57 Multiple myeloma55 Non-Hodgkin lymphoma53 Hodgkin lymphoma53 Leukaemia29
Relative risk for BMI 25–29.9 kg/m2
Relative risk for BMI ≥ 30 kg/m2
Attributable risk in the EU population
N/A 1.5 1.5 1.20 1.12 N/A 0.97 1.14
1.5–4 2 2 1.53 1.21 1.07a 1.41 1.39
N/A 27.1 27.1 N/A N/A N/A N/A N/A
BMI: body mass index; EU: European Union; N/A: figure not available. a For every 5 kg/m2 increase in BMI.
that overweight increases the risk 1.21-fold and obesity increases it 1.82-fold compared to normal BMI. Tumours of the gastric body and antrum, on the other hand, are not associated with obesity. There is no known mechanism to explain the association between obesity and cardia cancer. There is a growing trend in this type of cancer in many countries, which may be due in part to the increased prevalence of obesity in the population. Obesity and gallbladder and liver cancer The risk of gallbladder cancer is thought to be 1.5-fold higher in overweight individuals and twice as high in obese individuals, compared to those with normal BMI, while almost one third (27.1%) of these cases in the European population could be attributable to obesity.26 The EPIC prospective study47 showed that the effect is both for BMI and abdominal obesity markers. Obesity may increase the formation of gallstones, and could lead to tumour formation through the chronic inflammation it generates.26 This is also evidence on the association between obesity and primary liver cancer. A large meta-analysis of 26 prospective studies48 found a high risk associated with both overweight and obesity in both sexes, although it appears to be higher in men. The EPIC prospective study47 showed that both BMI and markers of abdominal obesity have an effect.
lymphocytic leukaemia in women, but not in men. The mechanism by which obesity increases the risk of leukaemia is unknown. A meta-analysis of 16 cohort studies53 showed a 7% increase in the incidence of NHL for each 5-point increase in BMI, and an increased risk of Hodgkin lymphoma (HL) with increasing BMI. More recently, an extensive cohort study in the US54 confirmed this association between obesity and NHL in the American population. Finally, a meta-analysis of 15 cohort studies55 found a 12% increase in the incidence of multiple myeloma in overweight individuals, and a 21% increase in obese individuals, compared to those with normal BMI. Another extensive American cohort study56 confirmed these results more recently.
Obesity and thyroid cancer A pooled analysis of 5 prospective studies in the US has also shown a positive association between thyroid cancer and obesity57 in both men and women. The risk was increased by 20% in the case of overweight and 53% in the case of obesity in both sexes, compared to normal BMI. These results have been confirmed in a recent meta-analysis of 7 cohort studies.58 The effect was shown to be greater in papillary carcinoma, and no association was observed in the Asian population.
Obesity and ovarian cancer
Conclusions
Despite the fact that adiposity has a clear effect on sex hormone production, that these substances are involved in the aetiopathogenesis of ovarian tumours, and that obesity is a known risk factor for other hormone-dependent tumours such as breast and endometrial cancer, evidence on the association between obesity and ovarian cancer is inconsistent.26 A pooled analysis of 12 cohort studies49 showed a positive association of BMI in premenopausal women, but not in postmenopausal women. In contrast, the EPIC study in the European population50 found a higher risk in postmenopausal women than in premenopausal women.
Between 23% and 28% of the Spanish population over the age of 18 are obese, 39% are overweight and 36% have abdominal obesity. There is sufficient convincing evidence of a positive association between obesity/overweight and colorectal cancer, breast cancer in postmenopausal women, endometrial, renal, oesophageal and pancreatic cancer. It is likely that obesity also increases the risk of tumours in the liver, gallbladder, gastric cardia, thyroids, leukaemia, multiple myeloma and Hodgkin and Non-Hodgkin lymphoma, although more studies are needed to confirm these associations. Although the mechanisms by which obesity acts in carcinogenesis are not yet sufficiently understood, it is widely accepted that one of the most effective methods for reducing the risk of cancer in the population is by avoiding overweight and obesity. It is important to highlight that the interrelationship between obesity and cancer has significant health implications. Thus, in the field of cancer epidemiology, taking this association into account could be useful when planning preventive or early-detection measures in the obese or overweight population, investigating the pathophysiological mechanisms involved in carcinogenesis, adapting treatment or establishing good recovery from the disease. In the public health field, campaigns informing of the dangers of excess weight on health must also include its association with cancer.
Obesity and haematopoietic tumours Several studies have been published in recent years that show increasing evidence of a relationship between obesity and haematopoietic tumours. The mechanisms are unknown, and it is believed that they may act through an alteration in immune functions. A meta-analysis of 9 cohort studies51 found a 14% increase in the incidence of leukaemias in overweight individuals and a 39% increase in obese individuals, compared to those with normal BMI. The increased risk was associated with all leukaemia subtypes, although it was greater in acute lymphocytic leukaemias. The European EPIC cohort52 found a significantly increased risk of
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26. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91. 27. Murphy G1, Kamangar F, Dawsey SM, Stanczyk FZ, Weinstein SJ, Taylor PR, et al. The relationship between serum ghrelin and the risk of gastric and esophagogastric junctional adenocarcinomas. J Natl Cancer Inst. 2011;103:1123–9. 28. Russell WR1, Duncan SH, Flint HJ. The gut microbial metabolome: modulation of cancer risk in obese individuals. Proc Nutr Soc. 2013;7:178–88. 29. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–85. 30. Potischman N, Swanson CA, Siiteri P, Hoover RN. Reversal of relation between body mass and endogenous estrogen concentrations with menopausal status. J Natl Cancer Inst. 1996;88:756–8. 31. Harvie M, Hooper L, Howell AH. Central obesity and breast cancer risk: a systematic review. Obes Rev. 2003;4:157–73. 32. Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, et al., Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218–26. 33. Rock CL, Demark-Wahnefried W. Nutrition and survival after the diagnosis of breast cancer: a review of the evidence. J Clin Oncol. 2002;20:3302–16. 34. Larsson SC, Wolk A. Obesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am J Clin Nutr. 2007;86:556–65. 35. Ben Q, An W, Jiang Y, Zhan X, Du Y, Cai QC, et al. Body mass index increases risk for colorectal adenomas based on meta-analysis. Gastroenterology. 2012;142:762–72. 36. Pischon T, Lahmann PH, Boeing H, Friedenreich C, Norat T, Tjønneland A, 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. 2006;98:920–31. 37. Chang CK, Ulrich CM. Hyperinsulinaemia and hyperglycaemia: possible risk factors of colorectal cancer among diabetic patients. Diabetologia. 2003;46:595–607. 38. Jenab M, Riboli E, Cleveland RJ, Norat T, Rinaldi S, Nieters A, et al. Serum C-peptide. IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2007;121:368–76. 39. McCullough ML, Patel AV, Patel R, Rodriguez C, Feigelson HS, Bandera EV, et al. Body mass and endometrial cancer risk by hormone replacement therapy and cancer subtype. Cancer Epidemiol Biomark Prev. 2008;17:73–9. 40. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomark Prev. 2002;11:1531–43. 41. Genkinger JM, Spiegelman D, Anderson KE, Bernstein L, van den Brandt PA, Calle EE, et al. A pooled analysis of 14 cohort studies of anthropometric factors and pancreatic cancer risk. Int J Cancer. 2011;129:1708–17. 42. Bergström A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer – a quantitative review. Br J Cancer. 2001;85:984–90. 43. Steffen A, Schulze MB, Pischon T, Dietrich T, Molina E, Chirlaque MD, et al. Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomark Prev. 2009;18:2079–89. 44. Hoyo C, Cook MB, Kamangar F, Freedman ND, Whiteman DC, Bernstein L, et al. Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON Consortium. Int J Epidemiol. 2012;41:1706–18. 45. Lagergren J, Bergström R, Adami HO, Nyrén O. Association between medications that relax the lower esophageal sphincter and risk for esophageal adenocarcinoma. Ann Intern Med. 2000;133:165–75. 46. Chen Y, Liu L, Wang X, Wang J, Yan Z, Cheng J, et al. Body mass index and risk of gastric cancer: a meta-analysis of a population with more than ten million from 24 prospective studies. Cancer Epidemiol Biomark Prev. 2013;22: 1395–408. 47. Schlesinger S, Aleksandrova K, Pischon T, Fedirko V, Jenab M, Trepo E, et al. Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer. 2013;132:645–57. 48. Chen Y, Wang X, Wang J, Yan Z, Luo J. Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur J Cancer. 2012;48:2137–45. 49. Schouten LJ, Rivera C, Hunter DJ, Spiegelman D, Adami HO, Arslan A, et al. Height, body mass index, and ovarian cancer: a pooled analysis of 12 cohort studies. Cancer Epidemiol Biomark Prev. 2008;17:902–12. 50. Lahmann PH, Cust AE, Friedenreich CM, Schulz M, Lukanova A, Kaaks R, et al. Anthropometric measures and epithelial ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2010;126:2404–15. 51. Larsson SC, Wolk A. Overweight and obesity and incidence of leukemia: a metaanalysis of cohort studies. Int J Cancer. 2008;122:1418–21. 52. Saberi Hosnijeh F, Romieu I, Gallo V, Riboli E, Tjønneland A, Halkjær J, et al. Anthropometric characteristics and risk of lymphoid and myeloid leukemia in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control. 2013;24:427–38. 53. Larsson SC, Wolk A. Body mass index and risk of non-Hodgkin’s and Hodgkin’s lymphoma: a meta-analysis of prospective studies. Eur J Cancer. 2011;47:2422–30. 54. Patel AV, Diver WR, Teras LR, Birmann BM, Gapstur SM. Body mass index, height and risk of lymphoid neoplasms in a large United States cohort. Leuk Lymphoma. 2013;54:1221–7.
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55. Wallin A, Larsson SC. Body mass index and risk of multiple myeloma: a metaanalysis of prospective studies. Eur J Cancer. 2011;47:1606–15. 56. Hofmann JN, Moore SC, Lim U, Park Y, Baris D, Hollenbeck AR, et al. Body mass index and physical activity at different ages and risk of multiple myeloma in the NIH-AARP diet and health study. Am J Epidemiol. 2013;177: 776–86.
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57. Kitahara CM, Platz EA, Freeman LE, Hsing AW, Linet MS, Park Y, et al. Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of five prospective studies. Cancer Epidemiol Biomark Prev. 2011;20:464–72. 58. Zhao ZG, Guo XG, Ba CX, Wang W, Yang YY, Wang YY, et al. Overweight, obesity and thyroid cancer risk: a meta-analysis of cohort studies. J Int Med Res. 2012;40:2041–50.
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www.elsevier.es/medicinaclinica
Review
Obesity and cancer: “Dangerous friendship”夽 Carlos A. González Svatetz a,∗ , Alberto Goday Arnó b,c a
Unidad de Nutrición, Ambiente y Cáncer, Instituto Catalán de Oncología (ICO), L’Hospitalet de Llobregat, Barcelona, Spain Servicio de Endocrinología y Nutrición, Hospital del Mar, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain c Centros de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain b
a r t i c l e
i n f o
Article history: Received 3 March 2014 Accepted 8 May 2014 Available online xxx Keywords: Obesity Cancer Overweight Obesity prevalence Abdominal obesity
a b s t r a c t Obesity and cancer are one of the most important health problems is Spain. Between 23 and 28% of the adult population in Spain are obese, 39% are overweight and 36% have abdominal obesity. The association between obesity and type 2 diabetes mellitus, hypertension, dyslipidemia and sleep obstructive apnea is well known. On the contrary, the association between obesity and cancer is less known, because the recent evidence on it. Several prospective studies have shown during the last years the strong relationship between obesity and cancer of colon, breast in post-menopausal women, endometrial, kidney and pancreas as well as esophageal adenocarcinoma. Furthermore there is recent evidence showing that liver, gallbladder, thyroid and ovarian cancer as well as leukaemia, multiple myeloma and Hodgkin lymphomas are probably associated with obesity, yet more studies are needed. A better knowledge of the relation between cancer and obesity will allow improving the prevention strategies against cancer, a more efficient early detection, and a more suitable treatment of obesity and overweight. Although the mechanisms of carcinogenesis of obesity are not well established, avoiding overweight and obesity are considered one of the best approaches to reduce the risk of cancer. Therefore the general population must be aware that cancer is one of the most important hazards associated with the current obesity epidemic in our society. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Obesidad y cáncer: «las amistades peligrosas» r e s u m e n Palabras clave: Obesidad Cáncer Sobrepeso Prevalencia obesidad Obesidad abdominal
˜ La obesidad afecta al Obesidad y cáncer son 2 problemas sanitarios de primera magnitud en Espana. ˜ 23–28% de la población adulta espanola, y el sobrepeso y la obesidad abdominal al 39 y 36%, respectivamente. Es bien conocida la relación entre obesidad y diabetes mellitus tipo 2, hipertensión arterial, ˜ Menos conocida es en cambio la asociación con el cáncer, dislipidemia, y apnea obstructiva del sueno. porque la evidencia es más reciente. Numerosos estudios prospectivos han demostrado en los últimos ˜ anos, con un alto grado de evidencia científica, una asociación clara entre la obesidad y los cánceres ˜ de colon y recto, mama en mujeres pos-menopáusicas, endometrio, rinón, esófago y páncreas. Esta asociación es también probable con los tumores de hígado, vesícula biliar, cardias, tiroides, y hematológicos, para los que se requieren más estudios. Un mejor conocimiento de la relación entre obesidad y cáncer puede permitir mejorar las estrategias de prevención del cáncer, así como una más eficiente detección precoz, y un tratamiento más adecuado de la obesidad y el sobrepeso. Aunque los mecanismos por los cuales la obesidad induce los distintos tipos de cánceres no son suficientemente conocidos, evitar el
夽 Please cite this article as: González Svatetz CA, Goday Arnó A. Obesidad y cáncer: «las amistades peligrosas». Med Clin (Barc). 2016. http://dx.doi.org/ 10.1016/j.medcli.2014.05.026 ∗ Corresponding author. E-mail address: [email protected] (C.A. González Svatetz). ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
MEDCLE-3028; No. of Pages 7
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sobrepeso y la obesidad es hoy una de las medidas más efectivas para reducir el riesgo de cáncer, por ˜ la lo que es necesario concienciar a la población general sobre uno de los mayores peligros que entrana actual epidemia de obesidad. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
Obesity in Spain Obesity and cancer are 2 major health problems.1–3 While they may seem unrelated, scientific evidence shows a very strong relationship between obesity and cancer, which clearly establishes what we could call a “dangerous friendship”. When considering the comorbidities associated with excess weight, we generally include prevalent processes such as type 2 diabetes (DM2), hypertension and dyslipidaemia (classic cardiovascular risk factors4 ), arthropathy and obstructive sleep apnoea syndrome, among others. Cancer is rarely included in this association, if at all.5 Obesity is considered to be a 21st-century epidemic.1 Weight status analyses in the various population studies conducted in the last 35 years show a gradual increase in mean sample weight,6 and indicate that the Spanish population has not been immune to this global pandemic either.7,8 The evolution of the prevalence of obesity in Spain, according to data from the national health survey, is shown in Fig. 1. It shows a gradual, steady increase in levels, rising from 7.7% in 1987 to 13.6% in 2001, over all age groups and in both sexes.9 One of the most alarming facts comes from analysing trends in the prevalence of the various grades of obesity. During the period from 1993 to 2006, grade 1 obesity (body mass index [BMI] 30–34 kg/m2 ) increased by 50%, grade 2 (BMI 35–39 kg/m2 ) by 110%, and morbid obesity (BMI ≥ 40 kg/m2 ) by 240%.10 The number of obese individuals in Spain is therefore growing, as is the number and proportion of individuals with extreme levels of overweight. Information from health surveys, together with various regional and local studies in Spain had estimated the prevalence of obesity through direct anthropometry; pooling data from some of these studies enabled this prevalence to be analysed (SEEDO).11,12 These data were the most widely used reference for many years, in the absence of specific national studies. Recent epidemiological studies have provided data with direct measurement of weight and height in broad samples representative of the entire Spanish population (Table 1). The ENRICA study analysed a population sample of 12,883 individuals over the age of 18 between 2008 and 2010.13 The estimated prevalence of obesity was 22.9% (24.4% in men and 21.4% in women), and abdominal obesity—defined as a waist circumference over
Prevalence %
18 15 12.9 12
13.6
11.3 9.9
9
7.7
6 3 0 1987
1993
1995
1997
2001
Fig. 1. Evolution of the prevalence of obesity in Spain according to national health survey data.
102 cm or 88 cm—was 36% (32% in men and 39% in women). A gradual increase was observed in the prevalence of general and abdominal obesity with age, affecting 35% and 62% of persons aged over 65 years. The [email protected] study,14 a population study of 5072 individuals over the age of 18 carried out in Spain between 2009 and 2010, found a prevalence of obesity of 28.25% (28.9% in men and 27.5% in women) by directly measuring weight and height. Both the ENRICA13 study and the [email protected] study showed a higher prevalence of obesity in men in the under-60 age groups only, while it was more common in women after that age. More recently, investigators in the DARIOS study, consisting of pooled analysis of data from 11 Spanish studies on cardiovascular risk factors conducted between 2000 and 2010 with a sample of 28,743 people aged between 35 and 74 years, also determined a prevalence of obesity of 28% in men and 28.3% in women.15 Both local/regional and national studies13–15 show significant heterogeneity in the prevalence of obesity in Spain, in that it is clearly higher in the south, specifically in Andalusia16 and the Canary Islands,17,18 than in the north.19 The prevalence of overweight for men and women in the 3 national studies was as follows: 46.4% and 32.5%, respectively, in the ENRICA study; 47.5% and 34% in the [email protected] study; and 50.7% and 35.6% in the DARIOS study. The prevalence of abdominal obesity (defined as previously) for both sexes combined in the 3 studies was 36%, 35.7% and 36%, respectively. Specific studies in the active working population, including younger, healthy individuals, have detected lower levels of obesity (17% in men and 7.7% in women), but alarmingly similar levels of overweight, especially in men (44.8% in men and 21.3% in women).20 A gradual increase in the prevalence of obesity was also observed over the 4 years studied. The prevalence of obesity is clearly associated with DM2, hypertension and dyslipidaemia.15 Obesity is also associated with low levels of physical activity,21 low socioeconomic status and education level, and unhealthier eating habits.22 Obesity and cancer Various international committees of experts have conducted a systematic review of the epidemiological evidence. In 2002, the International Agency for Research on Cancer (IARC)23 concluded that colon, breast, renal and endometrial cancer and oesophageal adenocarcinoma could be prevented by avoiding weight gain. A more recent report from an international committee of experts evaluating the evidence up to 200624 confirmed these associations and added to the list. They concluded that there is sufficient convincing evidence (Table 2) of a positive causal association between general obesity and colon and rectal cancer, breast cancer in postmenopausal women, renal, endometrial and pancreatic cancer and oesophageal adenocarcinoma, and between abdominal obesity and colorectal cancer (CRC). General obesity is probably positively associated with gallbladder cancer and negatively associated with breast cancer in premenopausal women, while abdominal obesity is probably positively associated with pancreatic, endometrial and breast cancer in postmenopausal women. Finally, in another systematic review and large meta-analysis of prospective studies,25 a strong positive association was found
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Table 1 Prevalence (%) of overweight and obesity in Spain, in individuals over the age of 18, according to sex and population study. Study
ENRICA13 [email protected] DARIOS15 (35 to 74 years)
Overweight
Obesity
Abdominal obesity
Men
Women
Total
Men
Women
Total
Men
Women
Total
46.4 47.5 50.7
32.5 34 35.6
39.4 39.5 51
24.4 28.9 28
21.4 27.5 28.3
22.9 28.25 28
32 23.1 35.8
39 54 54.6
36 35.7 36
BMI: body mass index. Overweight defined as BMI between 25 and 29.9 kg/m2 . Obesity defined as BMI equal to or greater than 30 kg/m2 . Abdominal obesity defined as waist circumference greater than 102 cm in men and 88 cm in women.
Table 2 Relative risk associated with overweight and obesity, and risk attributable to obesity with different cancers for which there is considered to be sufficient evidence of causality. Source: World Cancer Research Fund/American Institute for Cancer Research.24 Type of cancer
Relative risk for BMI 25–29.9 kg/m2 26
Relative risk for BMI ≥ 30 kg/m2 26
Attributable risk in the EU population26
Colorectal (men) Colorectal (women) Breast (postmenopausal women) Endometrial Kidney (renal cells) Oesophageal (adenocarcinoma) Pancreatic
1.5 1.2 1.3 2 1.5 2 1.3
2 1.5 1.5 3.5 2.5 3 1.7
27.5 14.2 16.7 45.2 31.1 42.7 19.3
BMI: body mass index; EU: European Union.
in men with increased BMI and oesophageal adenocarcinoma and thyroid, colon and kidney cancer, and a weaker association with rectal cancer and malignant melanoma. In women with increased BMI, a strong positive association was found with endometrial and gallbladder cancer, oesophageal adenocarcinoma and kidney cancer, and a weaker association with breast cancer in postmenopausal women, pancreatic, colon and thyroid cancer. A positive association between obesity and leukaemia, multiple myeloma and non-Hodgkin lymphoma (NHL) was observed in both sexes. Overall, overweight and obesity are estimated to be associated with 14% of cancer-related deaths in men and 20% in women in the US population.26 The mechanisms26 (Fig. 2) can vary depending on the type of cancer, but are related to insulin resistance and the resulting chronic hyperinsulinaemia, as well as the increase in the bioavailability of steroid hormones and chronic inflammation. Adipose tissue is the main site of peripheral oestrogen synthesis. Obesity (and the subsequent increase in adiposity) causes an increase in the production and circulation of active free oestrogens (mainly oestradiol), androgens and testosterone, and a reduction in sex hormone-binding globulin levels. Oestradiol enhances sensitivity to insulin and insulin-like growth factor (IGF) receptors. Meanwhile, obesity increases the concentrations of insulin, IGF1 and IGF2, which in turn reduce apoptosis and promote cell growth. Adiposity also has a significant inflammatory component, with an increase in cytokines, such as interleukins 6 and 8, tumour necrosis factor-␣ and C-reactive protein. Finally, visceral fat adipocytes form an active endocrine organ that secretes adiponectin, the most abundant adipokine. It is inversely correlated with BMI, with higher plasma values in women compared to men. Adiponectin increases insulin sensitivity and may have an anti-inflammatory and anticancer effect.25 Leptin, on the other hand, has an effect on satiety and is positively associated with insulin resistance and obesity. Finally, ghrelin, a hormone produced by the fundic glands of the stomach, also plays a role in the regulation of appetite and fattyacid metabolism and promotes fat storage. It has been found to be inversely associated with the risk of gastric cancer and oesophageal adenocarcinoma.27 It has recently been noted that gut microbiota could have an effect on obesity through the immune response and inflammation.28
There is a very close relationship between DM2, obesity and cancer; obesity is a major risk factor common to certain tumours and DM2. DM2 is associated with an increased risk of pancreatic, liver, colorectal, endometrial and breast cancer, which are also associated with obesity.29 Diabetes is considered to have an effect on neoplastic processes through various mechanisms common to obesity, including hyperinsulinaemia, hyperglycaemia and chronic inflammation. Physical activity, which is an important factor in preventing weight gain, is also a protective factor against DM2, CRC, breast cancer in postmenopausal women and endometrial cancer, and potentially against other cancers.29
Obesity and breast cancer The association between obesity and breast cancer varies depending on the menopausal status. There is consistent evidence in premenopausal women of a modest risk reduction in women with BMI ≥ 28 kg/m2 . This reduction is due to the fact that young obese women have a higher number of anovulatory cycles and lower levels of circulating steroid hormones, mainly progesterone and oestradiol.30 In contrast, in postmenopausal women, BMI 25–30 kg/m2 increases the risk of breast cancer by 30%, while BMI ≥ 30 kg/m2 increases the risk by 50%.26 It is estimated that 16.7% of breast cancers in postmenopausal women in the European population are associated with obesity.26 Some studies have suggested that indicators of abdominal obesity could be independent predictors of risk with respect to BMI, but a large systematic review31 has shown that, when adjusted for BMI, the association with markers of abdominal obesity disappears. The effect of increased BMI is greater in women who have never used hormone replacement therapy (HRT), which supports the hypothesis that obesity increases risk through the effect of the increased circulating sex hormone levels.32 Moreover, there is evidence that postmenopausal women with breast cancer and a high grade of obesity (BMI > 40 kg/m2 ) have higher mortality than normalweight women, probably due to lower participation in screening programmes and lower self-detection of tumours.26 Furthermore, overweight and obesity increase the likelihood of breast cancer recurrence, independent of menopausal status.33
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Metabolic effect. Increased resistance to insulin and C-peptide, hyperinsulinaemia, increased production of insulin-like growth factors [IGF-I, IGF-II], increased cell growth and reduced apoptosis. Gastrointestinal and appetite-regulating hormones. Decreased adiponectin production by adipocytes (increased insulin resistance). Increased production of leptin and ghrelin. Increased production of steroid hormones (peripheral oestrogen production, reduced production of hormone-binding globulins) Inflammatory effect (increased production of cytokines [IL-6, IL-8 and TNF-α] and C-reactive protein).
Obesity
Fig. 2. Cancer and obesity. Potential mechanisms.
Obesity and colorectal cancer Obesity has a greater effect on CRC in men than in women. Overweight increases the risk of CRC by 20% in men and 50% in women, while obesity increases the risk by 50% in women and 100% in men, compared to individuals with normal BMI. The prevalence of overweight and obesity in the European population is responsible for 14.2% of CRCs in men and 27.5% in women.26 Obesity generally increases the risk of colon cancer to a larger extent than rectal cancer. A large meta-analysis of 30 prospective studies34 has shown a higher risk in men than in women for BMI and abdominal obesity indicators, which is independent of the BMI and could be a more important predictor than this parameter. Another extensive metaanalysis35 has shown a positive association between increased BMI and the risk of colon, but not rectal, adenomas, which is independent of sex. The European EPIC cohort has shown that the use of HRT in women reduces the effect of obesity and overweight,36 which could partly explain the lower risk in women. The increased incidence of CRC is thought to be related to growing obesity rates, DM2, hyperinsulinaemia and increased insulin resistance, which form part of metabolic syndrome.26,37 The extensive European prospective EPIC study has observed a significant association between increased C-peptide in blood38 and the risk of CRC, which supports the insulin-effect hypothesis. Obesity and endometrial cancer There is also extensive, consistent epidemiological evidence on the positive association between obesity and the risk of endometrial cancer. The risk is twice as high in overweight individuals and 3.5-fold higher in obese individuals, compared to those of normal weight. Almost half (45.2%) of endometrial cancers in European women are attributed to obesity and overweight.26 A large prospective study in the US39 found no differences in risk as regards general or abdominal obesity, and that the use of HRT reduces the risk associated with obesity. The risk of endometrial cancer associated with obesity occurs in both pre- and postmenopausal women, and chronically high insulin, androstenedione and testosterone levels are important in its mechanism.40 Obesity and pancreatic cancer The risk of pancreatic cancer is 1.3-fold higher in overweight individuals and 1.7-fold higher in obese individuals compared to those with normal BMI. In the European population, 19.3% of pancreatic cancer cases are attributed to obesity and overweight.26
In an extensive analysis of 14 cohort studies,41 a 47% increase in risk was observed when BMI ≥ 30 kg/m2 was compared to BMI 21–22.9 kg/m2 . An independent association was also observed for both BMI and abdominal obesity indicators, with no differences according to sex. Obesity and renal cell carcinoma Overweight increases the risk of renal cell carcinoma 1.5-fold and obesity 2.5-fold compared to people with normal BMI. Almost one third (31.1%) of these tumours could be attributed to obesity and overweight in the European population.26 An extensive review of epidemiological studies42 has shown no differences according to sex. There is insufficient data to differentiate between the effect of BMI and abdominal obesity markers. The effect of obesity is considered to be independent of that caused by the increase in blood pressure, which would suggest that they act through different mechanisms.26 Obesity and oesophageal and cardia adenocarcinoma Overweight individuals have twice the risk of oesophageal adenocarcinoma and obese individuals have triple the risk compared to normal-weight individuals. It is thought that 42.7% of these tumours are due to overweight and obesity in the European population.26 However, there is no association with squamouscell carcinoma of the oesophagus. The significant increase in oesophageal adenocarcinomas in western countries, where it has become more common than squamous-cell carcinoma, is considered to be due to the increase in obesity in these populations. Large prospective studies,43 as well as joint analysis of an international consortium of studies,44 have shown that the increased risk is associated with both BMI and abdominal obesity indicators. The mechanism of this association is not yet clear. Obesity, especially abdominal obesity, contributes to an increase in gastrooesophageal reflux, which causes the metaplastic changes observed in Barrett’s oesophagus, although the effect of obesity could be independent of gastro-oesophageal reflux.45 In addition to the tumours previously described, for which there is considered to be enough evidence on their causal association with obesity,24 there are other neoplasms for which clear evidence is being gathered on their potential association with obesity (Table 3). Various epidemiological studies have found a positive association between obesity and gastric cardia cancer (which accounts for 20–30% of stomach tumours in the western population). In a recent meta-analysis of 24 prospective studies,46 it was observed
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Table 3 Relative risk associated with overweight and obesity, and risk attributable to obesity for different cancers probably associated with obesity. Type of cancer 26
Liver Gallbladder26 Gastric cardia (adenocarcinoma)46 Thyroid57 Multiple myeloma55 Non-Hodgkin lymphoma53 Hodgkin lymphoma53 Leukaemia29
Relative risk for BMI 25–29.9 kg/m2
Relative risk for BMI ≥ 30 kg/m2
Attributable risk in the EU population
N/A 1.5 1.5 1.20 1.12 N/A 0.97 1.14
1.5–4 2 2 1.53 1.21 1.07a 1.41 1.39
N/A 27.1 27.1 N/A N/A N/A N/A N/A
BMI: body mass index; EU: European Union; N/A: figure not available. a For every 5 kg/m2 increase in BMI.
that overweight increases the risk 1.21-fold and obesity increases it 1.82-fold compared to normal BMI. Tumours of the gastric body and antrum, on the other hand, are not associated with obesity. There is no known mechanism to explain the association between obesity and cardia cancer. There is a growing trend in this type of cancer in many countries, which may be due in part to the increased prevalence of obesity in the population. Obesity and gallbladder and liver cancer The risk of gallbladder cancer is thought to be 1.5-fold higher in overweight individuals and twice as high in obese individuals, compared to those with normal BMI, while almost one third (27.1%) of these cases in the European population could be attributable to obesity.26 The EPIC prospective study47 showed that the effect is both for BMI and abdominal obesity markers. Obesity may increase the formation of gallstones, and could lead to tumour formation through the chronic inflammation it generates.26 This is also evidence on the association between obesity and primary liver cancer. A large meta-analysis of 26 prospective studies48 found a high risk associated with both overweight and obesity in both sexes, although it appears to be higher in men. The EPIC prospective study47 showed that both BMI and markers of abdominal obesity have an effect.
lymphocytic leukaemia in women, but not in men. The mechanism by which obesity increases the risk of leukaemia is unknown. A meta-analysis of 16 cohort studies53 showed a 7% increase in the incidence of NHL for each 5-point increase in BMI, and an increased risk of Hodgkin lymphoma (HL) with increasing BMI. More recently, an extensive cohort study in the US54 confirmed this association between obesity and NHL in the American population. Finally, a meta-analysis of 15 cohort studies55 found a 12% increase in the incidence of multiple myeloma in overweight individuals, and a 21% increase in obese individuals, compared to those with normal BMI. Another extensive American cohort study56 confirmed these results more recently.
Obesity and thyroid cancer A pooled analysis of 5 prospective studies in the US has also shown a positive association between thyroid cancer and obesity57 in both men and women. The risk was increased by 20% in the case of overweight and 53% in the case of obesity in both sexes, compared to normal BMI. These results have been confirmed in a recent meta-analysis of 7 cohort studies.58 The effect was shown to be greater in papillary carcinoma, and no association was observed in the Asian population.
Obesity and ovarian cancer
Conclusions
Despite the fact that adiposity has a clear effect on sex hormone production, that these substances are involved in the aetiopathogenesis of ovarian tumours, and that obesity is a known risk factor for other hormone-dependent tumours such as breast and endometrial cancer, evidence on the association between obesity and ovarian cancer is inconsistent.26 A pooled analysis of 12 cohort studies49 showed a positive association of BMI in premenopausal women, but not in postmenopausal women. In contrast, the EPIC study in the European population50 found a higher risk in postmenopausal women than in premenopausal women.
Between 23% and 28% of the Spanish population over the age of 18 are obese, 39% are overweight and 36% have abdominal obesity. There is sufficient convincing evidence of a positive association between obesity/overweight and colorectal cancer, breast cancer in postmenopausal women, endometrial, renal, oesophageal and pancreatic cancer. It is likely that obesity also increases the risk of tumours in the liver, gallbladder, gastric cardia, thyroids, leukaemia, multiple myeloma and Hodgkin and Non-Hodgkin lymphoma, although more studies are needed to confirm these associations. Although the mechanisms by which obesity acts in carcinogenesis are not yet sufficiently understood, it is widely accepted that one of the most effective methods for reducing the risk of cancer in the population is by avoiding overweight and obesity. It is important to highlight that the interrelationship between obesity and cancer has significant health implications. Thus, in the field of cancer epidemiology, taking this association into account could be useful when planning preventive or early-detection measures in the obese or overweight population, investigating the pathophysiological mechanisms involved in carcinogenesis, adapting treatment or establishing good recovery from the disease. In the public health field, campaigns informing of the dangers of excess weight on health must also include its association with cancer.
Obesity and haematopoietic tumours Several studies have been published in recent years that show increasing evidence of a relationship between obesity and haematopoietic tumours. The mechanisms are unknown, and it is believed that they may act through an alteration in immune functions. A meta-analysis of 9 cohort studies51 found a 14% increase in the incidence of leukaemias in overweight individuals and a 39% increase in obese individuals, compared to those with normal BMI. The increased risk was associated with all leukaemia subtypes, although it was greater in acute lymphocytic leukaemias. The European EPIC cohort52 found a significantly increased risk of
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