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Gynecologic Cancer
May 16, 2013

Obesity and Gynecologic Cancer Etiology and Survival

Publication: American Society of Clinical Oncology Educational Book
The prevalence of overweight and obesity in the United States and elsewhere has increased dramatically in recent decades.1 The actual figures reported vary widely depending on whether they are based on measured or self-reported height and weight information but, regardless of how the data were collected, the trends are the same. Using measured height and weight data from the US National Health and Nutrition Examination Surveys (NHANES), Fig. 1 shows how the probability of a woman aged 18–74 years being obese, defined as a body-mass index (BMI, calculated as weight/height squared) ≥30 kg/m2, has changed over time. Although the probability remained fairly constant at 16% to 17% between 1959 and 1980, it more than doubled over the next 25 years to reach 36% in 2007–2008.2 Furthermore, these figures do not include the approximately 29% of the population now classified as overweight but not obese (BMI 25–29.9 kg/m2). In the 2009–2010 NHANES survey, 65% of all women aged 20 and older were classified as either overweight or obese with 36% classified as obese and 8% as morbidly obese (BMI ≥40 kg/m2).3
Fig 1. Temporal changes in the adjusted probability of obesity, overall and by degree of obesity, among women age 18-74 in the United States. (Drawn from Ljungvall and colleagues 2012.2)
It is well accepted that excess body weight is a risk factor for many chronic diseases including cardiovascular disease, diabetes, and several types of cancer including adenocarcinoma of the esophagus, colorectal, kidney, and postmenopausal breast cancer.4 Obesity has also been associated with reduced survival after a diagnosis of breast cancer.5 However, although it has long been known that obese women have an increased risk of developing endometrial cancer,6 the relation between obesity and risk of other gynecologic cancers and the potential influence of body size on survival among women diagnosed with gynecologic cancer are less well understood.

Endometrial Cancer

It is well known that obesity is a major risk factor for endometrial cancer with risk increasing by 50% to 60% for every 5-unit increase in BMI,4 and it has been estimated that 30% to 34% of all endometrial cancers can be attributed to overweight and obesity.7 However, endometrial cancer is not a single disease. Approximately 80% of endometrial cancers are low-grade, endometrioid tumors that are usually restricted to the uterus at diagnosis. These cancers, often described as “type 1” or “estrogen-dependent”, generally arise on a background of endometrial hyperplasia and are associated with greater than 90% 5-year survival. In contrast, high grade serous and clear cell tumors, often described as “type 2” or “nonestrogen-dependent,” are much less common but much more aggressive, with 5-year survival rates of only 40% to 60%. A third group of high-grade endometrioid tumors are sometimes grouped with other endometrioid cancers as type 1, and sometimes with other high-grade cancers as type 2. Early epidemiological studies did not attempt to separate the different histologic types of endometrial cancer; thus most of the available information regarding risk factors, including the strong association with obesity, pertains primarily to the low-grade endometrioid cancers that comprise the majority of any case group. Much less is known about risk factors for the less common high-grade cancers, although clinical series have suggested they are less strongly associated with exposure to estrogen, hence their description as “nonestrogen-dependent.” Data from recent prospective studies suggest that although obesity is most strongly associated with increased risks of endometrioid cancers, it does also increase risk of the more aggressive nonendometrioid cancers, albeit to a lesser extent (Table 1).8,9
Table 1. Relative Risks (RR) and 95% Confidence Intervals (CI) for the Association between Obesity and the Different Histologic Subtypes of Endometrial Cancer
First Author, Year, CountryNo. CasesBMI Comparison (kg/m2)RR (95% CI)
Type 1/Type 2*Type 1*Type 2*
Bjorge, 2007, Norway87164/992≥30 versus 18.5–24.92.69 (2.42–2.98)1.77 (1.44–2.19)
Yang et al, 2012, USA91312/138≥30 versus <302.93 (2.62–3.28)1.83 (1.27–2.63)
* Exact classifications varied but in general Type 1 included all endometrioid cancers and Type 2 included serous, clear cell and other high-grade cancers.
Given the increasing prevalence of obesity worldwide, it is therefore not surprising that age-standardized incidence rates of endometrial cancer have also been rising in many countries, particularly among postmenopausal women (Fig. 2A).10 It is likely that at least a proportion of this change is a result of the increasing prevalence of obesity, as even within countries such as the United States where endometrial cancer rates have been fairly constant over recent years, this overall trend masks an increase in the incidence of the endometrioid cancers that are most strongly associated with obesity (Fig. 2B).11
Fig 2. (A) Incidence rates of endometrial cancer among women age 50 and older, age standardized to the world population. (Drawn from Ferlay and colleagues 2010.10) (B) Overall and subtype-specific incidence rates of endometrial cancer in the United States, age standardized to the 2000 U.S. standard population. (Drawn from Duong and colleagues 2011.11)
Further work has suggested that, although body-life in early adulthood is associated with risk, the strongest associations are with adult weight gain and recent weight,12,13 and there is some evidence that those who report sustained weight loss are no longer at increased risk.12,14 It has also been proposed that the process of “weight cycling,” whereby women repeatedly lose and then regain weight, might further increase cancer risk as a result of the redistribution of body fat from peripheral to central locations and replacement of lean body mass by fat mass. Results are, however, conflicting for endometrial cancer with some, but not all studies reporting increased risks among women who report weight cycling.14
Obesity is also strongly associated with endometrial cancer mortality in the general population15 although this may largely reflect the increased incidence among obese women. Interpreting data assessing the relation between body size and survival among women diagnosed with endometrial cancer is not straightforward. Overall, the majority of women diagnosed with endometrial cancer will not die from their cancer but rather from some other cause. In the US, only 19% of women diagnosed between 1973 and 1988, a period chosen to allow 20 years follow-up, died from their endometrial cancer, compared with 36% from cardiovascular diseases, 20% from other malignancies, and 26% from other causes.16 However, the proportion of endometrial cancer deaths varied dramatically over time, with 50% of deaths in the first 5 years after diagnosis due to endometrial cancer, compared with 13% between 5 and 10 years, and only 2% more than 10 years after diagnosis. As discussed above, the association between obesity and cancer risk is strongest for low-grade cancers. Women diagnosed with high-grade tumors are thus much less likely to be obese than those with low-grade cancers; they are also much more likely to die from their disease, and many of these deaths will occur during the first few years following diagnosis. Short-term studies are thus likely to see lower all-cause mortality among more obese women, with this difference largely attributable to the fact that they have less aggressive disease. In the long-term, however, we would expect studies to show a positive association between obesity and all-cause mortality as cardiovascular disease takes over as the leading cause of death.
There are, thus, two questions to be answered. First, is obesity independently associated with an increased risk of recurrence of, or death from, endometrial cancer? Few studies have presented data with adequate control for subtype and/or grade of disease to address this; however, the few that have, found little evidence for an association.17 One exception was a US-based study that observed a borderline significant association between body size at diagnosis and endometrial-cancer-specific mortality among women with endometrioid tumors (hazard ratio [HR] for a 5 unit increase in BMI, 1.17, 95% confidence interval [CI] 0.98–1.4). This association was, however, driven by the small number of women with high-grade endometrioid tumors (HR 1.39, 95%CI 1.04–1.85; 16 deaths).18 There was no association among women with nonendometrioid tumors. On balance, it seems unlikely that body size has a major influence on the risk of endometrial cancer recurrence or death; however, there are currently insufficient data to draw any definitive conclusions.
The second question is whether obesity is associated with increased mortality from other causes among women diagnosed with endometrial cancer compared with the general population. Studies have variously reported significant inverse, null and significant positive associations between BMI and all-cause mortality following a diagnosis of endometrial cancer,17 but interpretation of these data is hampered by the differing lengths of follow-up and variable control for confounding. Furthermore, none has directly compared survival among women with endometrial cancer relative to women in the general population with a similar distribution of body size. In a recent review of this area, the authors noted that in four studies that reported an association between BMI at diagnosis and all-cause mortality, the magnitude of the association (HR 1.9–2.8 for BMI ≥40 vs. <25 kg/m2) was comparable to that seen among the general population.17

Ovarian Cancer

Ovarian cancer is a very heterogeneous disease. Approximately 90% of ovarian cancers appear to arise from the epithelial surface of the ovary with the remaining 10% comprising sex-cord stromal tumors and germ cell tumors. Most work to date has focused on the epithelial cancers and further reference to ovarian cancer will refer to this subgroup. The epithelial group can be further subdivided into four major histologic groups including serous cancers, the most aggressive type that comprise 50% to 60% of all invasive epithelial cancers; endometrioid cancers, that resemble their endometrial counterparts; clear cell cancers; and mucinous tumors, that resemble cancers of the endocervix or intestine. Furthermore, these cancers can be frankly invasive or what are described as borderline or low malignant potential cancers that have many of the features of invasive cancer but do not invade the surrounding tissue. It is now well accepted that risk factors for the different histologic subtypes can vary, and that there is further heterogeneity within subtypes. For example, at a molecular level, low-grade invasive serous cancers appear more similar to their borderline counterparts than to high-grade invasive serous cancers. Analysis of risk factors for ovarian cancer must, therefore, take this heterogeneity into account. [Note: the majority of what are commonly described as serous ovarian cancers are now thought to originate from the fallopian tube but, following current convention, these cancers will be considered as ovarian in the following discussion.]
Results from individual studies evaluating the relation between body size and risk of ovarian cancer are inconsistent; however, in a recent analysis that pooled data from 47 studies including more than 25,000 cases, a 5-unit increase in BMI was associated with a significant 5% increase in risk of developing ovarian cancer.19 Subtype-specific analyses suggested that the association was stronger for borderline serous cancers (29% increase per 5 units), endometrioid (8%), and mucinous cancers (12%), with no increase in risk of invasive serous cancers; however, the differences between the subtypes were not statistically significant. Overall, the association was restricted to women who had not used hormone replacement therapy (HRT), with no association among HRT users. A second pooled analysis that included more than 13,000 cases from 15 case-control studies (approximately 1200 cases were also included in the previous analysis), reported very similar subtype-specific data with a significant 24% increase in risk of borderline serous cancers, 19% for mucinous, and 17% for endometrioid cancers with a 5-unit increase in BMI, but again no association with invasive serous cancers (Table 2).20 Stratification by menopausal status and HRT use suggested that the association was stronger among premenopausal women, but among postmenopausal women there was little difference between HRT users and nonusers. Together, these studies suggest that ovarian cancer should be added to the list of obesity-related cancers, but they raise the possibility that obesity only increases risk of some histologic subtypes of ovarian cancer, and not the more aggressive high-grade serous cancers that account for the majority of deaths.
Table 2. Relative Risks (RR) and 95% Confidence Intervals (CI) for the Association between Obesity and the Different Histologic Subtypes of Ovarian Cancer in Two Large Pooled Analyses
RR per 5-Unit Increase in BMI
 Invasive CancersBorderline Cancers
First Author, YearSerousMucinousEndometrioidClear CellSerousMucinous
Collaborative Group on Epidemiological Studies of Ovarian Cancer, 2012191.001.15*1.07*1.051.29*1.06
Olsen et al, 2013200.981.19*1.17*1.061.24*1.09*
* p < 0.05.
Unlike endometrial cancer, the majority of women with ovarian cancer will die from their disease and not from other causes. A recent meta-analysis suggested that greater body size is associated with a poorer outcome, with obese women having a 17% greater risk of dying than their normal-weight counterparts, although there was significant heterogeneity between the results from individual studies.21 The results were similar regardless of whether BMI was measured before diagnosis, at diagnosis, or around the commencement of chemotherapy.

Cervical Cancer

The major risk factor for cervical cancer is infection with a carcinogenic strain of the human papillomavirus (HPV), particularly HPV16 or HPV18; however, not all women infected with these viruses go on to develop cancer, so other factors must also play a role. Several studies have suggested that increasing obesity is associated with increased risks of cervical cancer, particularly adenocarcinoma,22 but others have found no association.23 A positive association between obesity and risk of adenocarcinoma but not squamous cell carcinoma of the cervix would be consistent with observations that rates of adenocarcinoma have been increasing in many countries while rates of squamous cell carcinoma have been falling (Fig. 3).24 It is, however, difficult to separate out the effects of the introduction of cytologic screening, particularly on incidence rates of invasive squamous cell cancer, although it appears screening has been less effective at reducing the incidence of adenocarcinomas. In a series of period-cohort analyses conducted across 13 European countries, Bray and colleagues noted the differing incidence trends but concluded that the patterns were consistent with the idea that both subtypes share a common etiology.25
Fig 3. Age-standardized incidence rates of cervical squamous cell and adenocarcinoma, United States. (Drawn from Wang and colleagues, 2004.24)
Obesity is also associated with cervical cancer mortality in the general population;15 however, recent studies have suggested that among women with cervical cancer, increasing body size is associated with longer survival.26 In these studies, however, the biggest differences have been seen for underweight women who appear to have poorer survival, and it is possible that this is because they have more advanced disease and/or experience more complications during treatment.26 Further data are limited although, as with endometrial cancer, it might be expected that, in the long-term, obesity would be associated with increased all-cause mortality. There is currently little evidence to suggest that recurrence-free and cervical cancer-specific survival differ among overweight and obese women compared with normal weight women.

Other Cancers

Cancers at other gynecologic sites are rare. Collectively, vaginal and vulvar cancers account for less than 5% of all gynecologic cancers and less is known about their etiology, although they often co-occur with cervical cancer and, like cervical cancer, both are associated with HPV infection. Small studies conducted in the early 1990s suggested a possible association between obesity and risk of vulvar cancer, but no association with survival.27 An association has also been reported between adolescent adiposity and risk of clear cell adenocarcinoma of the vagina among women exposed to diethylstilbestrol in utero.28 There are, however, too few data to draw any reliable conclusions regarding the role of obesity in the etiology of these rare cancers.

Mechanisms

There are several mechanisms whereby obesity might influence risk of and/or survival following gynecologic cancer. Adipose tissue is very hormonally and metabolically active. It converts androgens to estrogen and is the main source of endogenous estrogen among postmenopausal women. It has long been known that exposure of the uterus to estrogen in the absence of progesterone leads to uncontrolled proliferation and development of endometrial hyperplasia, a precursor to the low-grade endometrioid subtype of endometrial cancer. It is almost certainly the higher estrogen levels among overweight and obese women that are at least partially responsible for their increased risks of developing low-grade endometrial cancers; this may also explain some of their increased risk of high-grade endometrial and ovarian cancers. Fat cells also produce a range of adipokines including leptin, adiponectin, and inflammatory mediators such as interleukins 6 and 8.29 Leptin is known to act as a growth factor in breast, endometrial, and prostate cancer cell lines and also promotes angiogenesis.29 It is also possible that insulin resistance and impaired glucose metabolism that often accompany obesity may increase cancer risk and/or have an adverse effect on outcomes. Evidence to support this hypothesis comes from studies suggesting that metformin, a common diabetes medication, is associated with reduced cancer risk and increased survival among patients with cancer.30
There are additional reasons why obesity might influence survival after a diagnosis of ovarian cancer. It is possible that the tumors that develop in bigger women are biologically more aggressive than those in normal weight women, although, as noted above, it appears that the most aggressive subtype of ovarian cancer is not more common among big women. It is also possible that obese women may not receive an appropriate dose of chemotherapeutic drugs for their body size. The most common drug used to treat ovarian cancer is carboplatin, and the dose is calculated based on a patient's body-surface area (BSA). Because the drug is associated with several side effects, clinicians are often reluctant to prescribe the full dose to big women, capping it at a BSA of 1.8 or 2.0. Obesity is also associated with other comorbidities such as diabetes and cardiovascular disease, which may, again, lead to women being treated with reduced doses of chemotherapy. Further work is, however, required to identify whether differential chemotherapy dosing can explain the apparent differences in survival by body size and to evaluate the other possible mechanisms whereby body size might influence outcomes.

Disclosures of Potential Conflicts of Interest

The author(s) indicated no potential conflicts of interest.

References

1.
Finucane MM, Stevens GA, Cowan MJ, et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet. 2011;377:557-567.
2.
Ljungvall A, Zimmerman FJ. Bigger bodies: Long-term trends and disparities in obesity and body-mass index among U.S. adults, 1960-2008. Soc Sci Med. 2012;75:109-119.
3.
Flegal KM, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA. 2012;307:491-497.
4.
World Cancer Res Fund/American Institute for Cancer Res, Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington DC: American Institute Cancer Res. 2007.
5.
Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat. 2010;123:627-635.
6.
Wynder EL, Escher GC, Mantel N. An epidemiological investigation of cancer of the endometrium. Cancer. 1966;19:489-520.
7.
Renehan AG, Soerjomataram I, Tyson M, et al. Incident cancer burden attributable to excess body mass index in 30 European countries. Int J Cancer. 2010;126:692-702.
8.
Bjorge T, Engeland A, Tretli S, et al. Body size in relation to cancer of the uterine corpus in 1 million Norwegian women. Int J Cancer. 2007;120:378-383.
9.
Yang HP, Wentzensen N, Trabert B, et al. Endometrial cancer risk factors by 2 main histologic subtypes: the NIH-AARP diet and health study. Am J Epidemiol. 2012.
10.
Ferlay J, Parkin D, Curado M, et al. Cancer Incidence in Five Continents, Volumes I to IX: IARC CancerBase No. 9. Available from http://ci5.iarc.fr Lyon, France; 2010. Available from: International Agency for Research on Cancer, 2010.
11.
Duong LM, Wilson RJ, Ajani UA, et al. Trends in endometrial cancer incidence rates in the United States, 1999-2006. J Womens Health (Larchmt). 2011;20:1157-1163.
12.
Trentham-Dietz A, Nichols H, Hampton J, et al. Weight change and risk of endometrial cancer. Int J Epidemiol. 2006;35:151-158.
13.
Yang TY, Cairns BJ, Allen N, et al. Postmenopausal endometrial cancer risk and body size in early life and middle age: prospective cohort study. Br J Cancer. 2012;107:169-175.
14.
Nagle C, Marquart L, Bain C, et al. Impact of weight change and weight cycling on risk of different subtypes of endometrial cancer. Eur J Cancer. In press.
15.
Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625-1638.
16.
Ward KK, Shah NR, Saenz CC, et al. Cardiovascular disease is the leading cause of death among endometrial cancer patients. Gynecol Oncol. 2012;126:176-9.
17.
Arem H, Irwin ML. Obesity and endometrial cancer survival: a systematic review. Int J Obes. 2012.
18.
Arem H, Chlebowski R, Stefanick ML, et al. Body mass index, physical activity, and survival after endometrial cancer diagnosis: results from the Women's Health Initiative. Gynecol Oncol. 2013;128:181-186.
19.
Collaborative Group on Epidemiological Studies of Ovarian Cancer. Ovarian cancer and body size: individual participant meta-analysis including 25157 women with ovarian cancer from 47 epidemiological studies. PLoS Medicine. 2012;9:e1001200.
20.
Olsen C, Nagle C, Whiteman D, et al. Obesity and risk of ovarian cancer subtypes: evidence from the Ovarian Cancer Association Consortium. Endocr Rel Cancer. In press.
21.
Protani MM, Nagle CM, Webb PM. Obesity and ovarian cancer survival: a systematic review and meta-analysis. Cancer Prev Res. 2012;5:901-10.
22.
Lacey JV, Jr., Swanson CA, Brinton LA, et al. Obesity as a potential risk factor for adenocarcinomas and squamous cell carcinomas of the uterine cervix. Cancer. 2003;98:814-821.
23.
Tornberg SA, Carstensen JM. Relationship between Quetelet's index and cancer of breast and female genital tract in 47,000 women followed for 25 years. Br J Cancer. 1994;69:358-361.
24.
Wang SS, Sherman ME, Hildesheim A, et al. Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976-2000. Cancer. 2004;100:1035-1044.
25.
Bray F, Carstensen B, Moller H, et al. Incidence trends of adenocarcinoma of the cervix in 13 European countries. Cancer Epidemiol Biomarkers Prev. 2005;14:2191-2199.
26.
Kizer NT, Thaker PH, Gao F, et al. The effects of body mass index on complications and survival outcomes in patients with cervical carcinoma undergoing curative chemoradiation therapy. Cancer. 2011;117:948-956.
27.
Kirschner CV, Yordan EL, De Geest K, et al. Smoking, obesity, and survival in squamous cell carcinoma of the vulva. Gynecol Oncol. 1995;56:79-84.
28.
Sharp GB, Cole P. Identification of risk factors for diethylstilbestrol-associated clear cell adenocarcinoma of the vagina: similarities to endometrial cancer. Am J Epidemiol. 1991;134:1316-1324.
29.
Parekh N, Okada T, Lu-Yao GL. Obesity, insulin resistance, and cancer prognosis: implications for practice for providing care among cancer survivors. J Am Diet Assoc. 2009;109:1346-1353.
30.
Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9:33.

Information & Authors

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American Society of Clinical Oncology Educational Book
Pages: e222 - e228

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Published online: May 16, 2013

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Penelope M. Webb, MA, DPhil
From the Queensland Institute of Medical Research, Brisbane, Australia.

Notes

78879
Corresponding author: Penelope M. Webb, MA, DPhil, Queensland Institute of Medical Research, Gynaecological Cancers Group, 300 Herston Rd., Herston, Brisbane 4006, Australia; email: [email protected].

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American Society of Clinical Oncology Educational Book 2013 :33, e222-e228

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