Is Bariatric Surgery Protective against Breast and Endometrial Cancers for Women?

| December 1, 2015

This column is written by medical students and is dedicated to reviewing the science behind obesity and bariatric surgery.

Column Editor: Daniel B. Jones, MD, MS, FASMBS
Professor of Surgery, Harvard Medical School, Vice Chair, Beth Israel Deaconess Medical Center, Boston, Massachusetts

This month: Is Bariatric Surgery Protective against Breast and Endometrial Cancers for Women?

by Elliott Hoel
Medical Student, Harvard Medical School, Boston, Massachusetts

ABSTRACT
Breast and endometrial cancers are leading causes of cancer morbidity and mortality for women in the United States and obesity is an established and important risk factor. Observational evidence suggests a dose-dependent, perhaps causal, relationship between increased adiposity and increased risk of developing breast and endometrial cancers. What remains uncertain is whether weight reduction, particularly by means of bariatric surgery, decreases risk for these cancers. Results from four studies, one prospective and three retrospective, suggest that the risk for cancer is indeed decreased with bariatric surgery for women, though by what mechanism and for what cancers specifically remain less clear.

Bariatric Times. 2015;12(12):10–12.


Introduction
Over the last 40 years, growing evidence has established obesity as an important risk factor for many cancers for both men and women.[1,2] In 2003, Calle et al[3] estimated that obesity was responsible for 14 percent of all cancer deaths in men and 20 percent of all cancer deaths in women in the United States. Obesity is potentially the second largest preventable cause of cancer after smoking.[2] Given that the prevalence of overweight and obesity among men and women in the United States is 69 percent and growing,[4] weight loss interventions such as bariatric surgery can potentially play a large role in reducing the morbidity and mortality caused by cancer.

Among women in the United States, breast cancer is the leading cause of cancer morbidity and the second leading cause of cancer mortality after lung cancer.[5] Uterine cancers are the fourth leading cause of cancer morbidity.[5] In 2009, the World Cancer Research Fund (WCRF) estimated that obesity in women causes 17 percent of incident post-menopausal breast cancers and 50 percent of incident endometrial cancers.[6] For pre-menopausal breast cancers, however, observational evidence shows that excess adiposity provides protective benefit.[7,8] Considering most women who seek bariatric surgery are pre-menopausal, is bariatric surgery protective against breast and endometrial cancers in the long-term overall or is it deleterious? Moreover, what is the evidence that obesity directly causes breast and endometrial cancers and can the increased risk therefore be reduced through weight loss?

Obesity and Cancer
Observational evidence of dose-dependency supports a causal link between excess adiposity and breast and endometrial cancers. Body mass index (BMI) affects breast and endometrial cancers in a progressive fashion. Several studies and meta-analyses have shown robust stepwise increases in risk with increases in BMI.[3,7] For example, Calle et al[3] found that women with a BMI between 35 and 39kg/m2 have a relative risk of death from breast cancer of 1.70 (95% confidence interval 1.33–2.17) as compared with normal weight controls. Women with a BMI of 40kg/m2 or more have a higher relative risk of breast cancer, 2.12 (95% CI 1.41–3.19). BMI had similar dose-dependent effects on the relative risks of uterine cancers.[3] The WCRF also reported through meta-analysis of two sets of studies[2] an eight- and 13-percent increase in risk per 5kg/m2 BMI for breast cancer post-menopause. They also reported a 52-percent and 56-percent increase in risk per 5kg/m2 for endometrial cancer.[2] Calculations assumed a linear relationship between BMI and risk.

Plausible mechanisms have been postulated for how excess adiposity could cause breast and endometrial cancers. One prominent idea is that excess adipose tissue leads to excess endogenous production of estrogens via aromatase activity. The excess estrogens then feed the development of estrogen-sensitive breast and endometrial cancers. The idea has support from several prospective studies showing that increased blood concentrations of estrogens, endogenous and exogenous, are associated with increased risk of breast cancer[9–11] and endometrial cancer[12,13] in post-menopausal women. The idea is also supported by the greater risks of estrogen receptor positive breast cancers[10] and type 1 (hormone sensitive) endometrial cancers[14] as compared with their hormone-insensitive counterparts in individuals with excess adiposity.

Furthermore, the idea is compatible with the observation that excess adiposity is protective in pre-menopausal women. Post-menopause, the majority of estrogens are produced by adipose tissue. Pre-menopause, however, the majority of estrogens are produced by the ovaries. Excess adiposity often disrupts ovarian function, and therefore disrupts the menstrual cycle and the production of estrogens, affording a protective benefit against hormone sensitive cancers.[15,16] On the other hand, some observational data does suggest that obesity can still increase the risk of hormone-insensitive breast cancers in pre-menopausal women.[17] Other plausible mechanisms by which obesity increases the risk of cancers include hyper-inflammatory stress, hyperinsulinemia, and hyper-insulin-like growth factor-1 (IGF1), though these mechanisms are not specific to breast and endometrial cancers.[16]

Evidence for dose-dependency taken together with plausible mechanisms suggest a direct causal link between excess adiposity and increased risk for breast and endometrial cancers. If there is such a link, then the questions that logically follow are 1) whether the increased risk due to excess adiposity is reversible through weight loss and 2) whether bariatric surgery can reduce that risk through weight loss. Bariatric surgery is a proven weight loss intervention for patients with severe obesity, providing dramatic and sustained weight loss.[18] In the United States, 17 percent of women have severe obesity with BMIs of 35kg/m2 or more and potentially qualify for bariatric surgery.[4]

Bariatric Risk Reduction
A number of studies have sought to address whether bariatric surgery can lower cancer incidence. The most compelling of these is the Swedish Obese Subjects (SOS) study.[19] The SOS study, started in 1987, is a prospective cohort study comparing 2,010 men and women with obesity who underwent bariatric surgery with 2,037 matched controls. Women made up 71 percent of the subjects. In 2009, Sjöström et al[19] published data from a 10.9 year median follow-up with subjects that showed that the hazard ratio of developing cancer for women who had undergone bariatric surgery was 0.58 (95% CI 0.44-0.77) as compared with those who had not (Table 1, Figure 1). The cancer benefit held for both women who were pre-menopausal and post-menopausal at the time of their matching examination prior to surgery (HR 0.73 with 95% CI 0.55–0.97 and HR 0.56 with 95% CI 0.36–0.86 respectively). Breast and endometrial cancers were most common among the women (23% and 22%, respectively), but the data were not strong enough to show a significant benefit for either type of cancer individually. Notably, men and women who had undergone surgery had a mean weight loss of 19.9kg, whereas those who did not undergo surgery gained a mean of 1.3kg.[19] No significant protective benefit was found for men who had undergone bariatric surgery over matched controls.

Three other studies (Table 1, Figure 1),[20–22] all retrospective, corroborate these findings on the effect of bariatric surgery on cancer incidence in women. Adams et al[20] found that after a mean follow-up of 12.5 years, the hazard ratio of developing any cancer for women with obesity who had undergone bariatric surgery was 0.73 (95% CI 0.62-0.87). Their data on breast cancer specifically was not significant.[20] Christou et al,[21] however, did find significant data on breast cancer. After a mean follow-up of five years,  they found that the relative risk of breast cancer was 0.17 (95% CI .143–.347) for those who had undergone bariatric surgery as compared with matched controls.[21] Both of these studies showed significant weight loss in both men and women who had undergone bariatric surgery compared to insignificant weight change in controls. Neither showed significant protective benefit against cancer for men.[20,21] In the third study, Ward et al[22] queried a pooled multi-institutional database for women 18 and older and found that the relative risk of uterine cancer was 0.29 (95% CI 0.26–0.32) for all women who had undergone bariatric surgery as compared with obese controls, and 0.19 (95% CI 0.17–0.22) for women who had undergone bariatric surgery and postoperatively maintained normal weight as compared with obese controls.[22]

Conclusion
Collectively, these studies strengthen the causal link between obesity and cancer, specifically breast and endometrial cancers in women, and show that risk is reversible through bariatric surgery. It is important to note that there are limitations to this evidence. The studies that have investigated the effect of bariatric surgery on cancer incidence have not been randomized control trials. This exposes the data to influence from unforeseen confounders. Considering, however, the accumulating evidence of the protective effect of bariatric surgery on overall mortality, diabetes, and cardiovascular risk, such a trial may be unethical.[23] Additionally, the studies have not been large enough to properly analyze subgroups. Only Christou et al[21] and Ward et al[22] have been able to produce significant data on breast[21] and endometrial22 cancer specifically. The studies have also yet to clarify the mechanism by which bariatric surgery reduces the incidence of cancer. Notably, the SOS study found no significant difference in incidence of cancer among subjects when stratified by degree of weight loss.[19] This suggests either that the study did not have the power to detect differences or that bariatric surgery provides most benefit through mechanisms other than just a simple reduction of excess adipose tissue. Other associations were explored by the SOS study, including degree of visceral adiposity as measured by sagittal trunk diameter, and degree of hyperinsulinemia suppression as predicted by type of bariatric surgery, but none were able to conclusively predict differences in incidence of cancer among the different groups and subgroups.[19]

Even with these limitations, current data demonstrate that bariatric surgery is protective against cancers including breast and endometrial cancers for women long-term, regardless of whether they are pre or post-menopause at the time of surgery. Future studies will need larger cohorts to properly assess cancer incidence among subgroups to tease out the protective mechanism of bariatric surgery and whether or not it is modified by degree of weight loss, and to clarify whether bariatric surgery is protective against all cancers for both sexes or just certain cancers for women. For the time being, physicians and female bariatric candidates should feel comfortable, at the very least, adding the protective benefit of bariatric surgery against cancer to the growing list of benefits supported by scientific evidence to be discussed during consultations.

References
1.     International Agency for Research on Cancer. IARC Handbook of Cancer Prevention, Volume 6. Weight Control and Physical Activity. Lyon, France: IARC Press, 2002.
2.     World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington DC: AICR; 2007.
3.     Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–1638.
4.     National Center for Health Statistics. Health, United States, 2014: With Special Feature on Adults Aged 55–64. Hyattsville, MD; 2015.
5.     U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2012 Incidence and Mortality Web-Based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2015. http://www.cdc.gov/uscs. Accessed September 13, 2015.
6.     World Cancer Research Fund/American Institute for Cancer Research. Policy and Action for Cancer Prevention. Food, Nutrition, and Physical Activity: A Global Perspective. Washington DC: AICR; 2009.
7.     World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Breast Cancer, 2010.
8.     Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–578.
9.     Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701–1712.
10.     Ritte R, Lukanova A, Berrino F, et al. Adiposity, hormone replacement therapy use and breast cancer risk by age and hormone receptor status: a large prospective cohort study. Breast Cancer Res. 2012;14(3):R76.
11.     Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95(16):1218–1226. http://www.ncbi.nlm.nih.gov/pubmed/12928347. Accessed September 13, 2015.
12.     Allen NE, Key TJ, Dossus L, et al. Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer. 2008;15(2):485–497.
13.     Allen NE, Tsilidis KK, Key TJ, et al. Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Am J Epidemiol. 2010;172(12):1394–1403.
14.     Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31(20):2607–2618.
15.     Garland M, Hunter DJ, Colditz GA, et al. Menstrual cycle characteristics and history of ovulatory infertility in relation to breast cancer risk in a large cohort of US women. Am J Epidemiol. 1998;147(7):636–643.
16.     Byers T, Sedjo RL. Body fatness as a cause of cancer: epidemiologic clues to biologic mechanisms. Endocr Relat Cancer. 2015;22(3):R125–R134.
17.     Petekkaya I, Sahin U, Gezgen G, et al. Association of breast cancer subtypes and body mass index. Tumori. 99(2):129–133.
18.     Picot J, Jones J, Colquitt JL, et al. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol Assess. 2009;13(41):1–190, 215–357, iii–iv.
19.     Sjöström L, Gummesson A, Sjöström CD, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 2009;10(7):653–662.
20.     Adams TD, Stroup AM, Gress RE, et al. Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring). 2009;17(4):796–802.
21.     Christou N V, Lieberman M, Sampalis F, Sampalis JS. Bariatric surgery reduces cancer risk in morbidly obese patients. Surg Obes Relat Dis. 4(6):691–695.
22.     Ward KK, Roncancio AM, Shah NR, et al. Bariatric surgery decreases the risk of uterine malignancy. Gynecol Oncol. 2014;133(1):63–66.
23.     Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial—a prospective controlled intervention study of bariatric surgery. J Intern Med. 2013;273(3):219–234.

FUNDING: No funding was provided.

FINANCIAL DISCLOSURES: The author reports no conflicts of interest relevant to the content of this article.

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