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Oncologist. Jun 2011; 16(6): 726–729.
Published online May 31, 2011. doi:  10.1634/theoncologist.2011-0050
PMCID: PMC3228228
Overweight, Obesity, Diabetes, and Risk of Breast Cancer: Interlocking Pieces of the Puzzle
Carlo La Vecchia,corresponding authorab Sharon H. Giordano,c Gabriel N. Hortobagyi,c and Bruce Chabnerd
aIstituto di Ricerche Farmacologiche “Mario Negri,” Department of Occupational Health, University of Milan, Milan, Italy;
bInternational Prevention Research Institute (i-PRI), Lyon, France;
cUniversity of Texas MD Anderson Cancer Center, Houston, Texas, USA;
dMassachusetts General Hospital, Boston, Massachusetts, USA
corresponding authorCorresponding author.
Correspondence: Carlo La Vecchia, M.D., Istituto di Ricerche Farmacologiche “Mario Negri,” Via Giuseppe La Masa 19, 20156 Milano, Italy. Telephone: 39-02-39014-1; Fax: 39-02-33200231; e-mail: carlo.lavecchia/at/marionegri.it, Web site: http://www.marionegri.it
Disclosures: Carlo La Vecchia: Research funding/contracted research: Associazione Italiana per la Ricerca sul Cancro (AIRC n. 10068); Sharon H. Giordano: Research funding/contracted research: American Cancer Society and the Cancer Prevention Research Institute of Texas; Gabriel N. Hortobagyi: Consultant/advisory role: sanofi-aventis, Allergan, Genentech, Merck, Novartis, Tyvex; Research funding/contracted research: NIH/NCI, Novartis, Susan G. Komen for the Cure; Bruce Chabner: Consultant/advisory role: Sanofi, Allergan, Epizyme, PharmaMar, GlaxoSmithKline, Peregrine, Onyx; Honoraria: Eli Lilly; Research funding/contracted research: U.S. Government; Ownership interest: PharmaMar, Gilead, Epizyme, Human Genome Sciences, Onyx.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.
Received February 25, 2011; Accepted March 27, 2011.
We considered epidemiological data on overweight, diabetes, insulin, and breast cancer. Overweight is inversely related to premenopausal breast cancer, but there is definite evidence that, as compared with normal weight women, the relative risk (RR) for postmenopausal breast cancer is around 1.5 for overweight women and >2 for obese women, and that the association is stronger in elderly women. Overweight and obesity are strongly related to diabetes. Diabetes is associated with postmenopausal breast cancer, too, with summary RRs from meta-analyses of 1.15–1.20, but not with premenopausal breast cancer (RR, 0.9). There is no consistent evidence that fasting insulin is related to breast cancer risk. Thus, although overweight and obesity are strongly related to postmenopausal breast cancer, diabetes is only moderately related to it. Given the extent of the association, and the likely residual confounding by overweight, inference on causality for the diabetes–breast cancer relation remains open to discussion.
Keywords: Breast cancer, Diabetes, Overweight, Risk
There is currently great interest in the relationship between altered metabolism and cancer and in the role of insulin and insulin-like growth factor-1 (IGF-1) pathways in the etiology and progression of human cancers [1, 2]. Overexpression of the IGF-1 receptor (IGFR) and mutations in genes encoding enzymes at multiple steps in the downstream components of the IGFR pathway are found in colon, breast, and prostate cancers, and have become targets for new therapeutic interventions [3]. In addition, epidemiological evidence suggests a relationship between obesity and cancer, type II diabetes and cancer, and possibly insulin levels and cancer [2, 4]. This review summarizes the epidemiological evidence that implicates overweight status, diabetes, and insulin levels as risk factors for of breast cancer.
An elevated body mass index (BMI) in the overweight (25.0–29.9 kg/m2) and obesity (BMI ≥30 kg/m2) ranges has been consistently associated with postmenopausal breast cancer, although it is inversely related to premenopausal breast cancer [57]. Whereas the inverse association between BMI and premenopausal breast cancer has been attributed to more frequent anovulation in obese women [810], the direct relation for postmenopausal breast cancer has generally been attributed to elevated levels and bioavailability of circulating estrogens in overweight postmenopausal women. Elevated circulating estrogen levels result from aromatase-mediated conversion of androgens to estrogens in peripheral adipose tissue, lower levels of sex hormone–binding globin in overweight women [5, 9, 11, 12], as well as, possibly, altered regulation of aromatase expression [13]. Obesity is also associated with high levels of circulating insulin, and insulin resistance is a possible factor in the relationship between obesity and breast cancer risk. However, the few studies providing data on fasting levels of insulin and breast cancer found no consistent association [14].
A direct trend in risk between measures of BMI and postmenopausal breast cancer has long been observed, and the risk appears strongest in older women [5, 6, 9, 15]. Thus, in a pooled analysis of three Italian case–control studies including 3,108 postmenopausal breast cancer cases and 2,604 controls [16], the relative risk (RR) for the highest quintile of BMI (>28.4 kg/m2) was around 1.3 for women aged 50–69 years and rose to 2.1 (95% confidence interval [CI], 1.4–3.2) for those aged ≥70 years. This age-related pattern of risk is similar to that observed for menopausal hormone replacement therapy and is consistent with a duration-risk relationship in exposure to high estrogen levels, and with a greater excess in estrogen levels among overweight elderly women [8]. In the New York University Women's Health cohort study [17], including 109 premenopausal and 150 postmenopausal women with breast cancer, the RR for the highest quintile of BMI was 0.8 (95% CI, 0.5–1.5) in premenopause (BMI >26.4 kg/m2) but 2.4 (95% CI, 1.4–4.1) in postmenopause (BMI >27.5 kg/m2).
In the Women's Health Initiative (WHI) Observational study [18], including 1,030 women with invasive breast cancer, the association between BMI and breast cancer risk was analyzed. Obese women (BMI >31.1 kg/m2) had a RR of 2.5 (95% CI, 1.6–3.3) compared with women with a BMI <22.6 kg/m2. In the National Institutes of Health American Association of Retired Persons Diet and Health Study, which included 2,111 postmenopausal women with breast cancer, the RR for breast cancer was around 1.5 for women with a BMI of 27.5–35 kg/m2 and rose to 2.1 (95% CI, 1.4–3.0) for women with a BMI >40 kg/m2, when compared with women with a BMI of 18.5–22.4 kg/m2. The same study as well as several other case–control [6, 19] and cohort [20] investigations reported a direct association between adult weight gain and postmenopausal breast cancer risk. The contralateral breast cancer risk is also higher in obese postmenopausal women [21]. There is, therefore, convincing evidence that, as compared with normal weight women, the RR for postmenopausal breast cancer is around 1.5 for overweight women (BMI, 25 kg/m2 to 30–32 kg/m2) and >2 for obese women, and that the association is stronger in elderly women.
Overweight and obesity are also strongly related to diabetes. Thus, a key question is to disentangle the independent effects of overweight and of diabetes on postmenopausal breast cancer risk.
Data on diabetes and (postmenopausal) breast cancer are available from at least nine case–control and 15 cohort studies. Their results indicate a modest association between diabetes and breast cancer, and have been summarized in two meta-analyses [14, 22]. These gave summary RRs of breast cancer in diabetic women of 1.15–1.20, similar in case–control and cohort studies, with CIs in the range of 1.1–1.3.
Diabetes has also been associated with excess mortality in women with breast cancer [2325], but the extent of the excess risk has not been satisfactorily quantified.
One of the above-mentioned meta-analyses [14] also considered fasting insulin in relation to breast cancer risk. Among five studies providing data, two [26, 27] found a direct relationship and three [2830] found no consistent association between fasting insulin and breast cancer risk in postmenopausal women. Further, in the WHI 6% random sample of women with a baseline measurement for glucose and insulin, the RR for the highest tertile of insulin was about 2, but this was based on only 190 cases of breast cancer, of which only 75 were invasive [31]. Furthermore, there was no consistent evidence of an association between plasma levels of IGF-1 and breast cancer. Similarly, plasma levels of C-peptide, a cleavage product of endogenous insulin, are not associated with breast cancer risk [14].
The limited information available on diabetes and premenopausal breast cancer (which is unrelated to overweight [58]) does not support a causal role for diabetes in breast cancer. Data on diabetes and premenopausal breast cancer were considered from only three studies in a meta-analysis [22] that gave a RR of 0.91, with, however, a wide CI (0.62–1.34). No distinction, moreover, was made in that study between type I and type II diabetes. The other meta-analysis [14] considered data from two case–control [32, 33] and three cohort [3436] studies, from a total of 4,714 premenopausal women with breast cancer and provided a summary RR of 0.94 (95% CI, 0.80–1.10).
Available data indicate, therefore, that the risk for premenopausal breast cancer is not higher in diabetic subjects. Because at least a fraction of diabetes in premenopausal women is type II, an RR below unity (summary RR, ~0.9) does not support a relevant role of insulin, insulin resistance, and IGF-1 on breast cancer risk, and rather indicates that the modest association between diabetes and postmenopausal breast cancer is partly or largely a result of residual confounding by BMI. Considering the appreciably stronger association between overweight and obesity (RR, 1.5 to >2) and breast cancer risk, compared with that of diabetes (RR, 1.15–1.2), as well as the problems of reliability and validity of information on body mass and the difficulty of accurate allowance for BMI, residual confounding by BMI remains a likely explanation for the association between diabetes and postmenopausal breast cancer.
Overweight and obesity are important determinants of postmenopausal breast cancer risk. It appears, therefore, that excess estrogen availability in overweight postmenopausal women is the key pathogenic mechanism for their excess breast cancer risk [8, 11]. Whether insulin and insulin-related factors have an independent additional role is unclear from the scanty available data.
Diabetes is consistently and strongly related to the risk of colorectal, liver, pancreas, and endometrial cancer [3740]. It is only moderately associated with breast cancer risk in epidemiological data. Given such a moderate association, and the likely presence of residual confounding by overweight, any inference on causality for the diabetes–breast cancer relationship remains speculative and unproven.
Author Contributions
Conception/Design: Carlo La Vecchia, Sharon Giordano, Gabriel N. Horto bagyi, Bruce A. Chabner
Data analysis and interpretation: Carlo La Vecchia, Sharon Giordano, Gabriel N. Hortobagyi, Bruce A. Chabner
Manuscript writing: Carlo La Vecchia, Sharon Giordano, Gabriel N. Horto bagyi
Final approval of manuscript: Carlo La Vecchia, Sharon Giordano, Gabriel N. Hortobagyi, Bruce A. Chabner
Other: Data checking and editing: Carlo La Vecchia
1. Kaelin WG, Jr, Thompson CB. Q&A: Cancer: Clues from cell metabolism. Nature. 2010;465:562–564. [PubMed]
2. Gallagher EJ, LeRoith D. Insulin, insulin resistance, obesity, and cancer. Curr Diab Rep. 2010;10:93–100. [PubMed]
3. Heidegger I, Pircher A, Klocker H, et al. Targeting the insulin-like growth factor network in cancer therapy. Cancer Biol Ther. 2011 Apr 11;15;11(8) [Epub ahead of print], doi: 14689 [pii] [PubMed]
4. Gallagher EJ, Fierz Y, Ferguson RD, et al. The pathway from diabetes and obesity to cancer, on the route to targeted therapy. Endocr Pract. 2010;16:864–873. [PubMed]
5. Hunter DJ, Willett WC. Diet, body size, and breast cancer. Epidemiol Rev. 1993;15:110–132. [PubMed]
6. Franceschi S, Favero A, La Vecchia C, et al. Body size indices and breast cancer risk before and after menopause. Int J Cancer. 1996;67:181–186. [PubMed]
7. Tavani A, Gallus S, La Vecchia C, et al. Risk factors for breast cancer in women under 40 years. Eur J Cancer. 1999;35:1361–1367. [PubMed]
8. Pike MC. Age-related factors in cancers of the breast, ovary, and endometrium. J Chronic Dis. 1987;40(suppl 2):59S–69S. [PubMed]
9. Pike MC, Krailo MD, Henderson BE, et al. ‘Hormonal’ risk factors, ‘breast tissue age’ and the age-incidence of breast cancer. Nature. 1983;303:767–770. [PubMed]
10. La Vecchia C, Decarli A, di Pietro S, et al. Menstrual cycle patterns and the risk of breast disease. Eur J Cancer Clin Oncol. 1985;21:417–422. [PubMed]
11. La Vecchia C. Oestrogens and progestins and breast cancer risk in post-menopausal women. Pharmacol Res. 1995;32:323–324. [PubMed]
12. Stoll BA. Breast cancer: The obesity connection. Br J Cancer. 1994;69:799–801. [PMC free article] [PubMed]
13. Brown KA, Simpson ER. Obesity and breast cancer: Progress to understanding the relationship. Cancer Res. 2010;70:4–7. [PubMed]
14. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: A review of the current evidence. Am J Clin Nutr. 2007;86:s823–s835. [PubMed]
15. Hsieh CC, Trichopoulos D, Katsouyanni K, et al. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: Associations and interactions in an international case-control study. Int J Cancer. 1990;46:796–800. [PubMed]
16. La Vecchia C, Negri E, Franceschi S, et al. Body mass index and post-menopausal breast cancer: An age-specific analysis. Br J Cancer. 1997;75:441–444. [PMC free article] [PubMed]
17. Sonnenschein E, Toniolo P, Terry MB, et al. Body fat distribution and obesity in pre- and postmenopausal breast cancer. Int J Epidemiol. 1999;28:1026–1031. [PubMed]
18. Morimoto LM, White E, Chen Z, et al. Obesity, body size, and risk of postmenopausal breast cancer: The Women's Health Initiative (United States) Cancer Causes Control. 2002;13:741–751. [PubMed]
19. Trentham-Dietz A, Newcomb PA, Egan KM, et al. Weight change and risk of postmenopausal breast cancer (United States) Cancer Causes Control. 2000;11:533–542. [PubMed]
20. Eliassen AH, Colditz GA, Rosner B, et al. Adult weight change and risk of postmenopausal breast cancer. JAMA. 2006;296:193–201. [PubMed]
21. Majed B, Dozol A, Ribassin-Majed L, et al. Increased risk of contralateral breast cancers among overweight and obese women: A time-dependent association. Breast Cancer Res Treat. 2011;126:729–738. [PubMed]
22. Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: A meta-analysis. Int J Cancer. 2007;121:856–862. [PubMed]
23. Peairs KS, Barone BB, Snyder CF, et al. Diabetes mellitus and breast cancer outcomes: A systematic review and meta-analysis. J Clin Oncol. 2011;29:40–46. [PMC free article] [PubMed]
24. Schrauder MG, Fasching PA, Häberle L, et al. Diabetes and prognosis in a breast cancer cohort. J Cancer Res Clin Oncol. 2010 Dec 5; [Epub ahead of print], doi: 0.1007/s00432-00010-00960-00432. [PubMed]
25. Li CI, Daling JR, Tang MT, et al. Relationship between diabetes and risk of second primary contralateral breast cancer. Breast Cancer Res Treat. 2011;125:545–551. [PMC free article] [PubMed]
26. Del Giudice ME, Fantus IG, Ezzat S, et al. Insulin and related factors in premenopausal breast cancer risk. Breast Cancer Res Treat. 1998;47:111–120. [PubMed]
27. Lawlor DA, Smith GD, Ebrahim S. Hyperinsulinaemia and increased risk of breast cancer: Findings from the British Women's Heart and Health Study. Cancer Causes Control. 2004;15:267–275. [PubMed]
28. Jernström H, Barrett-Connor E. Obesity, weight change, fasting insulin, proinsulin, C-peptide, and insulin-like growth factor-1 levels in women with and without breast cancer: The Rancho Bernardo Study. J Womens Health Gend Based Med. 1999;8:1265–1272. [PubMed]
29. Mink PJ, Shahar E, Rosamond WD, et al. Serum insulin and glucose levels and breast cancer incidence: The atherosclerosis risk in communities study. Am J Epidemiol. 2002;156:349–352. [PubMed]
30. Muti P, Quattrin T, Grant BJ, et al. Fasting glucose is a risk factor for breast cancer: A prospective study. Cancer Epidemiol Biomarkers Prev. 2002;11:1361–1368. [PubMed]
31. Kabat GC, Kim M, Caan BJ, et al. Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer. 2009;125:2704–2710. [PubMed]
32. Talamini R, Franceschi S, Favero A, et al. Selected medical conditions and risk of breast cancer. Br J Cancer. 1997;75:1699–1703. [PMC free article] [PubMed]
33. Weiss HA, Brinton LA, Potischman NA, et al. Breast cancer risk in young women and history of selected medical conditions. Int J Epidemiol. 1999;28:816–823. [PubMed]
34. Weiderpass E, Gridley G, Persson I, et al. Risk of endometrial and breast cancer in patients with diabetes mellitus. Int J Cancer. 1997;71:360–363. [PubMed]
35. Wideroff L, Gridley G, Mellemkjaer L, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst. 1997;89:1360–1365. [PubMed]
36. Michels KB, Solomon CG, Hu FB, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care. 2003;26:1752–1758. [PubMed]
37. La Vecchia C, Negri E, Franceschi S, et al. A case-control study of diabetes mellitus and cancer risk. Br J Cancer. 1994;70:950–953. [PMC free article] [PubMed]
38. La Vecchia C, Negri E, Decarli A, et al. Diabetes mellitus and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 1997;6:1007–1010. [PubMed]
39. Hemminki K, Li X, Sundquist J, et al. Risk of cancer following hospitalization for type 2 diabetes. The Oncologist. 2010;15:548–555. [PMC free article] [PubMed]
40. Renehan A, Smith U, Kirkman MS. Linking diabetes and cancer: A consensus on complexity. Lancet. 2010;375:2201–2202. [PubMed]
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