1932

Abstract

There is growing appreciation that the current obesity epidemic is associated with increases in cancer incidence at a population level and may lead to poor cancer outcomes; concurrent decreases in cancer mortality at a population level may represent a paradox, i.e., they may also reflect improvements in the diagnosis and treatment of cancer that mask obesity effects. An association of obesity with cancer is biologically plausible because adipose tissue is biologically active, secreting estrogens, adipokines, and cytokines. In obesity, adipose tissue reprogramming may lead to insulin resistance, with or without diabetes, and it may contribute to cancer growth and progression locally or through systemic effects. Obesity-associated changes impact cancer in a complex fashion, potentially acting directly on cells through pathways, such as the phosphoinositide 3-kinase (PI3K) and Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathways, or indirectly via changes in the tumor microenvironment. Approaches to obesity management are discussed, and the potential for pharmacologic interventions that target the obesity–cancer link is addressed.

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2015-01-14
2024-04-12
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Literature Cited

  1. Flegal KM, Carroll MD, Kit BK. 1.  et al. 2012. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307:491–97 [Google Scholar]
  2. Wang Y, Baker JL, Hill JO. 2.  et al. 2012. Controversies regarding reported trends: Has the obesity epidemic leveled off in the United States?. Adv. Nutr. 3:751–52 [Google Scholar]
  3. Lam DW, LeRoith D. 3.  2012. The worldwide diabetes epidemic. Curr. Opin. Endocrinol. Diabetes Obes. 19:93–96 [Google Scholar]
  4. 4. Expert Panel on Identif., Eval., Treat. Overweight in Adults 1998. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Am. J. Clin. Nutr. 68:899–917 [Google Scholar]
  5. Ramachandran A, Chamukuttan S, Shetty SA. 5.  et al. 2012. Obesity in Asia—Is it different from rest of the world?. Diabetes Metab. Res. Rev. 28:Suppl. 247–51 [Google Scholar]
  6. 6.  Expert Panel on Detect., Eval., Treat. High Blood Cholest. in Adults. 2001. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–97 [Google Scholar]
  7. Alberti KG, Eckel RH, Grundy SM. 7.  et al. 2009. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–45 [Google Scholar]
  8. Tchernof A, Despres JP. 8.  2013. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93:359–404 [Google Scholar]
  9. Gilbert CA, Slingerland JM. 9.  2013. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu. Rev. Med. 64:45–57 [Google Scholar]
  10. Renehan AG, Tyson M, Egger M. 10.  et al. 2008. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371:569–78 [Google Scholar]
  11. Calle EE, Rodriguez C, Walker-Thurmond K. 11.  et al. 2003. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348:1625–38 [Google Scholar]
  12. Chan DS, Vieira AR, Aune D. 12.  et al. 2014. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies. Ann. Oncol. 25:1901–14 [Google Scholar]
  13. Protani M, Coory M, Martin JH. 13.  2010. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res. Treat. 123:627–35 [Google Scholar]
  14. Niraula S, Ocana A, Ennis M. 14.  et al. 2012. Body size and breast cancer prognosis in relation to hormone receptor and menopausal status: a meta-analysis. Breast Cancer Res. Treat. 134:769–81 [Google Scholar]
  15. Arem H, Chlebowski R, Stefanick ML. 15.  et al. 2013. Body mass index, physical activity, and survival after endometrial cancer diagnosis: results from the Women's Health Initiative. Gynecol. Oncol. 128:181–86 [Google Scholar]
  16. Parekh N, Chandran U, Bandera EV. 16.  2012. Obesity in cancer survival. Annu. Rev. Nutr. 32:311–42 [Google Scholar]
  17. Allott EH, Masko EM, Freedland SJ. 17.  2013. Obesity and prostate cancer: weighing the evidence. Eur. Urol. 63:800–9 [Google Scholar]
  18. 18. Am. Cancer Soc 2014. Cancer Facts & Figures 2014. Atlanta, GA: Am. Cancer Soc.
  19. Goodwin PJ, Ennis M, Pritchard KI. 19.  et al. 2002. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J. Clin. Oncol. 20:42–51 [Google Scholar]
  20. Goodwin PJ, Ennis M, Bahl M. 20.  et al. 2009. High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome. Breast Cancer Res. Treat. 114:517–25 [Google Scholar]
  21. Goodwin PJ, Ennis M, Pritchard KI. 21.  et al. 2012. Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations. J. Clin. Oncol. 30:164–71 [Google Scholar]
  22. Pritchard KI, Shepherd LE, Chapman JA. 22.  et al. 2011. Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC CTG MA.14. J. Clin. Oncol. 29:3869–76 [Google Scholar]
  23. Duggan C, Irwin ML, Xiao L. 23.  et al. 2011. Associations of insulin resistance and adiponectin with mortality in women with breast cancer. J. Clin. Oncol. 29:32–39 [Google Scholar]
  24. Yun SJ, Min BD, Kang HW. 24.  et al. 2012. Elevated insulin and insulin resistance are associated with the advanced pathological stage of prostate cancer in Korean population. J. Korean Med. Sci. 27:1079–84 [Google Scholar]
  25. Wolpin BM, Meyerhardt JA, Chan AT. 25.  et al. 2009. Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J. Clin. Oncol. 27:176–85 [Google Scholar]
  26. Dankner R, Shanik MH, Keinan-Boker L. 26.  et al. 2012. Effect of elevated basal insulin on cancer incidence and mortality in cancer incident patients: the Israel GOH 29-year follow-up study. Diabetes Care 35:1538–43 [Google Scholar]
  27. Pisani P.27.  2008. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch. Physiol. Biochem. 114:63–70 [Google Scholar]
  28. Autier P, Koechlin A, Boniol M. 28.  et al. 2013. Serum insulin and C-peptide concentration and breast cancer: a meta-analysis. Cancer Causes Control 24:873–83 [Google Scholar]
  29. Frasca F, Pandini G, Scalia P. 29.  et al. 1999. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol. Cell. Biol. 19:3278–88 [Google Scholar]
  30. De Meyts P, Whittaker J. 30.  2002. Structural biology of insulin and IGF1 receptors: implications for drug design. Nat. Rev. Drug Discov. 1:769–83 [Google Scholar]
  31. Mulligan AM, O'Malley FP, Ennis M. 31.  et al. 2007. Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res. Treat. 106:39–47 [Google Scholar]
  32. Law JH, Habibi G, Hu K. 32.  et al. 2008. Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res. 68:10238–46 [Google Scholar]
  33. Braun S, Bitton-Worms K, LeRoith D. 33.  2011. The link between the metabolic syndrome and cancer. Int. J. Biol. Sci. 7:1003–15 [Google Scholar]
  34. Furstenberger G, Senn HJ. 34.  2002. Insulin-like growth factors and cancer. Lancet Oncol. 3:298–302 [Google Scholar]
  35. Cohen DH, LeRoith D. 35.  2012. Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. Endocr. Relat. Cancer 19:F27–F45 [Google Scholar]
  36. Yee D.36.  2012. Insulin-like growth factor receptor inhibitors: baby or the bathwater?. J. Natl. Cancer Inst. 104:975–81 [Google Scholar]
  37. Warburg O.37.  1956. On respiratory impairment in cancer cells. Science 124:269–70 [Google Scholar]
  38. Vander Heiden MG, Cantley LC, Thompson CB. 38.  2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–33 [Google Scholar]
  39. Seshasai SR, Kaptoge S, Thompson A. 39.  et al. 2011. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364:829–41 [Google Scholar]
  40. Hirakawa Y, Ninomiya T, Mukai N. 40.  et al. 2012. Association between glucose tolerance level and cancer death in a general Japanese population: the Hisayama Study. Am. J. Epidemiol. 176:856–64 [Google Scholar]
  41. Muti P, Quattrin T, Grant BJ. 41.  et al. 2002. Fasting glucose is a risk factor for breast cancer: a prospective study. Cancer Epidemiol. Biomark. Prev. 11:1361–68 [Google Scholar]
  42. Cust AE, Kaaks R, Friedenreich C. 42.  et al. 2007. Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr. Relat. Cancer 14:755–67 [Google Scholar]
  43. Luo J, Chen YJ, Chang LJ. 43.  2012. Fasting blood glucose level and prognosis in non-small cell lung cancer (NSCLC) patients. Lung Cancer 76:242–47 [Google Scholar]
  44. Vansaun MN.44.  2013. Molecular pathways: adiponectin and leptin signaling in cancer. Clin. Cancer Res. 19:1926–32 [Google Scholar]
  45. Goodwin PJ, Ennis M, Fantus IG. 45.  et al. 2005. Is leptin a mediator of adverse prognostic effects of obesity in breast cancer?. J. Clin. Oncol. 23:6037–42 [Google Scholar]
  46. Dallal CM, Brinton LA, Bauer DC. 46.  et al. 2013. Obesity-related hormones and endometrial cancer among postmenopausal women: a nested case-control study within the B∼FIT cohort. Endocr. Relat. Cancer 20:151–60 [Google Scholar]
  47. Luhn P, Dallal CM, Weiss JM. 47.  et al. 2013. Circulating adipokine levels and endometrial cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol. Biomark. Prev. 22:1304–12 [Google Scholar]
  48. Gross AL, Newschaffer CJ, Hoffman-Bolton J. 48.  et al. 2013. Adipocytokines, inflammation, and breast cancer risk in postmenopausal women: a prospective study. Cancer Epidemiol. Biomark. Prev. 22:1319–24 [Google Scholar]
  49. Cnop M, Havel PJ, Utzschneider KM. 49.  et al. 2003. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 46:459–69 [Google Scholar]
  50. Barb D, Williams CJ, Neuwirth AK. 50.  et al. 2007. Adiponectin in relation to malignancies: a review of existing basic research and clinical evidence. Am. J. Clin. Nutr. 86:s858–s866 [Google Scholar]
  51. Miyoshi Y, Funahashi T, Kihara S. 51.  et al. 2003. Association of serum adiponectin levels with breast cancer risk. Clin. Cancer Res. 9:5699–704 [Google Scholar]
  52. Mantzoros C, Petridou E, Dessypris N. 52.  et al. 2004. Adiponectin and breast cancer risk. J. Clin. Endocrinol. Metab. 89:1102–7 [Google Scholar]
  53. Dal Maso L, Augustin LS, Karalis A. 53.  et al. 2004. Circulating adiponectin and endometrial cancer risk. J. Clin. Endocrinol. Metab. 89:1160–63 [Google Scholar]
  54. Cust AE, Kaaks R, Friedenreich C. 54.  et al. 2007. Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. J. Clin. Endocrinol. Metab. 92:255–63 [Google Scholar]
  55. Song M, Zhang X, Wu K. 55.  et al. 2013. Plasma adiponectin and soluble leptin receptor and risk of colorectal cancer: a prospective study. Cancer Prev. Res. 6:875–85 [Google Scholar]
  56. Hofmann JN, Liao LM, Pollak MN. 56.  et al. 2012. A prospective study of circulating adipokine levels and risk of multiple myeloma. Blood 120:4418–20 [Google Scholar]
  57. Li H, Stampfer MJ, Mucci L. 57.  et al. 2010. A 25-year prospective study of plasma adiponectin and leptin concentrations and prostate cancer risk and survival. Clin. Chem. 56:34–43 [Google Scholar]
  58. Simpson ER, Mendelson CR. 58.  1987. Effect of aging and obesity on aromatase activity of human adipose cells. Am. J. Clin. Nutr. 45:290–95 [Google Scholar]
  59. Geisler J, Haynes B, Ekse D. 59.  et al. 2007. Total body aromatization in postmenopausal breast cancer patients is strongly correlated to plasma leptin levels. J. Steroid Biochem. Mol. Biol. 104:27–34 [Google Scholar]
  60. Cauley JA, Gutai JP, Kuller LH. 60.  et al. 1989. The epidemiology of serum sex hormones in postmenopausal women. Am. J. Epidemiol. 129:1120–31 [Google Scholar]
  61. Eliassen AH, Hankinson SE. 61.  2008. Endogenous hormone levels and risk of breast, endometrial and ovarian cancers: prospective studies. Adv. Exp. Med. Biol. 630:148–65 [Google Scholar]
  62. Eliassen AH, Missmer SA, Tworoger SS. 62.  et al. 2006. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J. Natl. Cancer Inst. 98:1406–15 [Google Scholar]
  63. Rock CL, Flatt SW, Laughlin GA. 63.  et al. 2008. Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol. Biomark. Prev. 17:614–20 [Google Scholar]
  64. Goodwin PJ.64.  2013. Obesity and endocrine therapy: host factors and breast cancer outcome. Breast 22:Suppl. 2S44–47 [Google Scholar]
  65. Lonning PE, Haynes BP, Dowsett M. 65.  2014. Relationship of body mass index with aromatisation and plasma and tissue oestrogen levels in postmenopausal breast cancer patients treated with aromatase inhibitors. Eur. J. Cancer 50:1055–64 [Google Scholar]
  66. Pfeiler G, Konigsberg R, Hadji P. 66.  et al. 2013. Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer. Br. J. Cancer 109:1522–27 [Google Scholar]
  67. Ewertz M, Gray KP, Regan MM. 67.  et al. 2012. Obesity and risk of recurrence or death after adjuvant endocrine therapy with letrozole or tamoxifen in the breast international group 1-98 trial. J. Clin. Oncol. 30:3967–75 [Google Scholar]
  68. Sestak I, Distler W, Forbes JF. 68.  et al. 2010. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J. Clin. Oncol. 28:3411–15 [Google Scholar]
  69. Fagan DH, Yee D. 69.  2008. Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J. Mammary Gland Biol. Neoplasia 13:423–29 [Google Scholar]
  70. Siiteri PK.70.  1978. Steroid hormones and endometrial cancer. Cancer Res. 38:4360–66 [Google Scholar]
  71. Kaaks R, Lukanova A, Kurzer MS. 71.  2002. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol. Biomark. Prev. 11:1531–43 [Google Scholar]
  72. Hanahan D, Weinberg RA. 72.  2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  73. Nieman KM, Romero IL, Van Houten B. 73.  et al. 2013. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim. Biophys. Acta 1831:1533–41 [Google Scholar]
  74. Apovian CM, Bigornia S, Mott M. 74.  et al. 2008. Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler. Thromb. Vasc. Biol. 28:1654–59 [Google Scholar]
  75. Morris PG, Hudis CA, Giri D. 75.  et al. 2011. Inflammation and increased aromatase expression occur in the breast tissue of obese women with breast cancer. Cancer Prev. Res. 4:1021–29 [Google Scholar]
  76. Lashinger LM, Ford NA, Hursting SD. 76.  2014. Interacting inflammatory and growth factor signals underlie the obesity-cancer link. J. Nutr. 144:109–13 [Google Scholar]
  77. Balkwill F, Mantovani A. 77.  2001. Inflammation and cancer: back to Virchow?. Lancet 357:539–45 [Google Scholar]
  78. Coussens LM, Werb Z. 78.  2002. Inflammation and cancer. Nature 420:860–67 [Google Scholar]
  79. Louie SM, Roberts LS, Nomura DK. 79.  2013. Mechanisms linking obesity and cancer. Biochim. Biophys. Acta 1831:1499–508 [Google Scholar]
  80. Wu T, Gao X, Chen M. 80.  et al. 2009. Long-term effectiveness of diet-plus-exercise interventions versus diet-only interventions for weight loss: a meta-analysis. Obes. Rev. 10:313–23 [Google Scholar]
  81. Pi-Sunyer X, Blackburn G, Brancati FL. 81.  et al. 2007. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care 30:1374–83 [Google Scholar]
  82. Barte JC, Veldwijk J, Teixeira PJ. 82.  et al. 2014. Differences in weight loss across different BMI classes: a meta-analysis of the effects of interventions with diet and exercise. Int. J. Behav. Med. 21:784–93 [Google Scholar]
  83. Wadden TA, Volger S, Sarwer DB. 83.  et al. 2011. A two-year randomized trial of obesity treatment in primary care practice. N. Engl. J. Med. 365:1969–79 [Google Scholar]
  84. Wieland LS, Falzon L, Sciamanna CN. 84.  et al. 2012. Interactive computer-based interventions for weight loss or weight maintenance in overweight or obese people. Cochrane Database Syst. Rev. 8:CD007675 [Google Scholar]
  85. Casazza K, Fontaine KR, Astrup A. 85.  et al. 2013. Myths, presumptions, and facts about obesity. N. Engl. J. Med. 368:446–54 [Google Scholar]
  86. Mason C, Foster-Schubert KE, Imayama I. 86.  et al. 2011. Dietary weight loss and exercise effects on insulin resistance in postmenopausal women. Am. J. Prev. Med. 41:366–75 [Google Scholar]
  87. Schauer PR, Bhatt DL, Kirwan JP. 87.  et al. 2014. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N. Engl. J. Med. 370:2002–13 [Google Scholar]
  88. Rao RS, Yanagisawa R, Kini S. 88.  2012. Insulin resistance and bariatric surgery. Obes. Rev. 13:316–28 [Google Scholar]
  89. Sjostrom L, Gummesson A, Sjostrom CD. 89.  et al. 2009. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 10:653–62 [Google Scholar]
  90. Casagrande DS, Rosa DD, Umpierre D. 90.  et al. 2014. Incidence of cancer following bariatric surgery: systematic review and meta-analysis. Obes. Surg. 24:1499–509 [Google Scholar]
  91. Reeves MM, Terranova CO, Eakin EG. 91.  et al. 2014. Weight loss intervention trials in women with breast cancer: a systematic review. Obes. Rev. 15:749–68 [Google Scholar]
  92. Goodwin PJ, Segal RJ, Vallis M. 92.  et al. 2014. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA Trial. J. Clin. Oncol. 32:2231–39 [Google Scholar]
  93. Rock CL, Byers TE, Colditz GA. 93.  et al. 2013. Reducing breast cancer recurrence with weight loss, a vanguard trial: the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) trial. Contemp. Clin. Trials 34:282–95 [Google Scholar]
  94. Rack B, Andergassen U, Neugebauer J. 94.  et al. 2010. The German SUCCESS C study—the first European lifestyle study on breast cancer. Breast Care 5:395–400 [Google Scholar]
  95. Villarini A, Pasanisi P, Traina A. 95.  et al. 2012. Lifestyle and breast cancer recurrences: the DIANA-5 trial. Tumori 98:1–18 [Google Scholar]
  96. 96. Comm. on Eval. Prog. Obes. Prev. Efforts 2013. Evaluating obesity prevention efforts: a plan for measuring progress. Rep. Inst. Med., Natl. Acad., Washington, DC
  97. Sturm R, An R. 97.  2014. Obesity and economic environments. CA Cancer J. Clin. 64:337–50 [Google Scholar]
  98. Woloshin S, Schwartz LM. 98.  2014. The new weight-loss drugs, lorcaserin and phentermine-topiramate: slim pickings?. JAMA Intern. Med. 174:615–19 [Google Scholar]
  99. Dowling RJ, Niraula S, Stambolic V. 99.  et al. 2012. Metformin in cancer: translational challenges. J. Mol. Endocrinol. 48:R31–R43 [Google Scholar]
  100. Hosono K, Endo H, Takahashi H. 100.  et al. 2010. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev. Res. 3:1077–83 [Google Scholar]
  101. Goodwin PJ, Stambolic V, Lemieux J. 101.  et al. 2011. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res. Treat. 126:215–20 [Google Scholar]
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