Endometrial cancer, formerly referred to as carcinoma of the uterus, is the most common gynaecological malignancy and the fourth most common cancer of women in the UK. The incidence of endometrial cancer is rising, due in part to fewer hysterectomies, an ageing population and the use of tamoxifen for breast cancer. Other risk factors include obesity, diabetes and insulin resistance. Endometrial cancer is about 2 times as common in diabetes as in non-diabetic controls. Most, but not all, of this excess risk is attributable to the association with obesity and insulin resistance. This article reviews the epidemiology of endometrial cancer, its association with obesity, diabetes and insulin resistance, and the molecular pathways underpinning these associations.
Endometrial cancer is now the most common gynaecological malignancy and the fourth most common cancer affecting women in the United Kingdom. The life-time risk of developing this disease in the UK is 2.35%. Since the early 1990’s, the standardised incidence in England and Wales is reported to have increased from 13.5/100 000 in 1993 to 19.4/100,000 in 2008. In 2009, 7,835 new cases were diagnosed in the United Kingdom and almost 57,000 women were diagnosed with endometrial cancer in Europe.
Mortality from the disease has also increased by 20% over the same time period, despite improvements in overall survival. Uterine-sparing treatments for benign gynaecological disorders, an ageing population and tamoxifen treatment for breast cancer have all contributed to these rates. Other established risk factors include obesity, insulin resistance and diabetes mellitus . This article will examine the contribution of diabetes and insulin resistance to endometrial cancer risk.
Epidemiology of Diabetes and Endometrial Cancer
An association between diabetes and uterine cancer has been noted for more than 50 years. Women with diabetes have a two-fold increased risk of endometrial cancer compared with non-diabetic controls according to a meta-analysis of 16 studies (three cohort and 13 case-control studies) involving more than 96,000 participants and 7,596 endometrial cancer cases (RR 2.10,95%CI 1.75-2.53) (Friberg et al, 2007). Table 1 illustrates studies which have examined the association between diabetes and endometrial cancer risk and have demonstrated an increased relative risk (1.42 -4.1 after multivariate adjustment).
|Study||Study Type||No of cases||No of controls||RR for all women||95% CI||Adjustment factors||RR after multivariate||95% CI|
|O’Mara et al. 1985*||Case- control||479||Hospital matched||2.0||1.3-3.0|
|Lawrence et al. 1989*||Case- control||84||Population matched||1.95||1.1-3.6||n/a||n/a|
|Rubin et al. 1990*||Case- control||196||Population matched||1.8||0.9-3.6||Age||n/a||n/a|
|Brinton et al. 1992*||Case- control||405||297||2.0||1.1, 3.6||Age, weight, menopausal estrogen HRT, OC, years of education, parity.||n/a||n/a|
|La Vecchia et al. 1994*||Case - control||726||7834||3.4||2.7-4.3 (age)||Age, education, smoking, BMI||2.8||2.2, 3.5|
|Inoue et al.1994*||Case- control||143||143||7.75||1.5-40.0||Age, parity, cancer history, hypertension, obesity|
|Maatela et al. 1994*||Case- control||1715||Population matched||Age, place of residence||4.1||2.7, 6.9|
|Goodman et al. 1997*||Case-control||332||511||1.4||0.8,2.5||Age, pregnancy history, OC, unopposed estrogen use, hypertension, tobacco and alcohol use.||n/a||n/a|
|Terry et al. 1999*||Cohort||142||10012||1.6||0.2,11.3||Age, physical activity, weight, parity|
|Weiss et al. 2006*||Case -control||1281||1779||Age, PMH, BMI, county, referent year, tumour aggression||1.58||1.20, 2.07|
|Lindemann et al. 2008*||Cohort||222||36539||3.84||1.92, 5.11 (Age only)||Age, BMI, smoking||3.13||1.92, 5.11|
|Lambe et al. 2011*||Cohort||1070||229667||1.46||1.09-1.96||Age, socioeconomic, fasting status, BMI (subcohort 38065)||1.75||0.82,3.75|
|Attner et al. 2012*||Case-control study||471||3569||1.21||0.87-1.71||Obesity, abnormal lipids.||1.42||0.92, 2.19|
Table 1 : Studies illustrating the association between endometrial cancer and diabetes. ( OC=oral contraceptive use, HRT= hormone replacement therapy, BMI= body mass index).
This increased risk is also observed in patients with insulin resistance; a condition that is common in the obese population. A prospective study of patients with endometrial cancer demonstrated that 30 percent had undiagnosed insulin resistance, which was significantly associated with higher body mass index (P<0.001). A Canadian cohort study analysed data from 541 incident endometrial cancer cases and 961 frequency age-matched controls and demonstrated that markers of insulin resistance such as adiponectin and the homeostasis model assessment ratio (HOMA-IR) are informative regarding endometrial cancer risk. Compared with the lowest quartile, the highest quartile of insulin and HOMA-IR (increased insulin resistance) was associated with 64% (95% CI 1.12,2.40) and 72% (95% CI 1.17,2.53) increased risks of endometrial cancer and the highest quartile of adiponectin (decreased insulin resistance) was associated with a 45% (95% CI 0.37, 0.8) decreased risk. This effect persisted after multivariable adjustment for age, parity, HRT, menopausal hormone use, hypertension, weight and waist-hip ratio.
Prospective investigations measuring fasting indices of insulin resistance are required to capture the full impact of insulin resistance on endometrial cancer. It is likely that previously performed retrospective studies have not had access to fasting serum samples and thus will have underestimated the relationship between these conditions.
Many studies have also shown that patients with endometrial cancer with pre-existing diabetes have a significantly increased overall mortality. A study examining whether mortality after endometrial cancer diagnosis was affected by pre-diagnosis obesity, diabetes and other factors revealed that women with endometrial cancer and diabetes had an increased risk of all-cause mortality compared with women without diabetes (HR 1.7, 95% CI 1.1, 2.5) .
Role of Obesity
Obesity (body mass index >30kg/m2) is also associated with an increased risk of both all cause (HR:1.6, 95% CI 1.0, 2.5) and endometrial cancer (HR: 2.0, 95% CI 0.8-5.1) mortality, compared with normal weight women ( BMI <25kg/m2). In a retrospective cohort study of patients with endometrial cancer, Zanders et al found that after adjusting for age, stage, period of diagnosis, cardiovascular disease and treatment, the 5- year overall survival rate for patients with diabetes and endometrial cancer was significantly lower than for the endometrial cancer patients without diabetes (HR 1.4, 95% CI 1.0-1.8). While this study did not adjust for the effects of body mass index on the survival rate, subcohort analyses demonstrated that endometrial cancer patients with diabetes were diagnosed more often with a higher BMI compared with endometrial cancer patients without diabetes .
The modifying Effect of Obesity on Risk of Endometrial Cancer
Given the effect of obesity on the incidence of both diabetes and endometrial cancer, a number of investigators have adjusted for the modifying effects of obesity. A population based case-control study performed between 1985-1999 found that diabetes was associated with endometrial cancer among women with a body mass index (BMI) less than 35, with odds ratios ranging from 1.6 to 2.5 (OR: 1.8, 95% CI 0.8, 4.1) in lean BMI<25, (OR: 2.5, 96% CI 1.3, 4.6) in overweight BMI 25-30 and (OR:1.6, 95% CI 0.8, 3.1) in moderately obese women BMI 30-<35. However, diabetes appeared not to be related to endometrial cancer among severely obese women (BMI>35) (OR: 1.1, 95% CI 0.6, 2.0). These associations persisted when BMI was added to the regression model as a continuous linear variable to control for residual confounding.
The finding that diabetes was not associated with endometrial cancer among women who were extremely obese may have been due to the substantial prevalence of insulin resistance or undiagnosed diabetes in these women or the relatively small contribution that diabetes makes to endometrial cancer risk in the context of severe obesity.
Table 2 summarises the results of other studies which have evaluated the association between type 2 diabetes and endometrial cancer risk that have controlled for obesity. Where available, the relative risk or odds ratios for the lean and obese group have been presented.
|Study||Study Type||No of cases||No of controls||RR for all women||95% CI||Adjustment factors||RR for lean woman||95% CI||RR Obese women||95% CI|
|Shoff & Newcomb. 1998*||Case-control||723||2291||1.86 (OR)||1.37, 2.52||BMI, unopposed estrogen, OC, pregnancy history||BMI>31.9 2.95 (OR)||1.6, 5.46|
|Parazzini et al. 1999*||Case-control||752||2606||3.1(age>40)||2.3,4.2||Age, education, Quetelet’s index, parity, OCP, HRT, hypertension, smoking||BMI<25 3.0||1.8, 5.2||BMI>30 3.3||1.9,5.8|
|Salazar-Martinez et al. 2000*||Case-control||85||668||3.6||1.7, 7.4||Age, BMI, hypertension, menopausal status, smoking, physical activity, anovulatory index||BMI <25 3.9||0.88, 18.0||8.0||2.8, 22.7|
|Weiderpass et al. 2000*||Case-control||702||2879||1.5||1.0, 2.1||Age, BMI, HRT, OC, parity, age at menopause, smoking, age at menarche,||BMI <30 1.8||1.2-2.8|
|Anderson et al. 2001*||Cohort n=24664||341||2.07||1.45, 2.95||Age, BMI, WHR, ovulatory span, gravidity, HRT, menstrual irregularities, hypertension||BMI <27.41 0.96||0.3-3.04||BMI>27.4 2.36||1.42, 3.90|
|Friberg et al. 2007*||Cohort||225||36548||1.94||1.23, 3.08||Age, BMI, physical activity, HRT, OCP, parity, education, smoking, energy intake||BMI<30 1.55||0.83-2.91||BMI>30 2.65||1.37-5.15|
|Lucenteforte et al. 2007*||Case-control||777||1550||1.7||1.2, 2.5||Age, education, parity, menopausal status, OC, HRT, BMI, physical activity, hypertension||1.4||0.9, 2.4||5.1||3.0, 8.7|
|Saltzman et al. 2007*||Case-control||1303||1799||1.7||1.2,2.3||Age, BMI, HRT,||BMI<25 1.8||0.8-4.1||BMI>35 1.1||0.6,2.0|
A recent cohort study examined the relationship of BMI, diabetes and smoking to endometrial cancer risk in a cohort of 36 761 Norwegian women during 15.7 years of follow-up. There were 222 incident cases of endometrial cancer, and after multivariable adjustment for BMI, diabetes and smoking, diabetes was associated with a three-fold higher risk (RR 3.13, 95% CI: 1.92-5.11). Another large case-control study with 777 endometrial cancer cases and 1550 controls showed that diabetes had a supramultiplicative effect with BMI. Compared with non-diabetic, non obese women (BMI <30kg/m2), the OR was 1.4 (95% CI 0.9, 2.4) for non-obese women with diabetes but rose to 5.1 (95% CI 3.0, 8.7) for obese diabetic women.
Lastly, Attner et al used a large case control study to demonstrate that there was a non-significant increased trend of pre-existing diabetes prior to a diagnosis of endometrial cancer, RR :1.21 (95% CI 0.87-1.71) and when adjusted for obesity and hyperlipidaemia, RR 1.42 (95% CI 0.9-2.19).
Hyperinsulinaemia and endometrial cancer
Insulin resistance occurs when there is a reduced sensitivity of insulin-responsive target tissues (liver, skeletal muscle, adipose tissue) to insulin, leading to increased levels of glucose and insulin in the circulation. Chronic hyperinsulinaemia also increases production of insulin-like growth factor (IGF)1 in the liver and decreases concentrations of insulin-like growth factor binding proteins which increases bioavailable IGF1.
The insulin receptor (IR) and IGF-1 receptor (IGF-1R) pathways are closely linked and both insulin and IGF1/2 can bind to them with different affinities. Receptor activation triggers the activation of insulin receptor substrate-1 (IRS-1), which in turn acts on the anti-apoptotic and pro-proliferative targets of the PI3K/AKT and MAPK signalling pathways. These receptors are upstream of the mTOR pathway and in epithelial cells result in growth and enhanced survival (Figure 1). Negative feedback loops also exist and the phosphorylated form of the mTOR target protein, Grb10 is a negative regulator of insulin signalling and IGF1.
AMP-activated protein kinase (AMPK) is a cellular metabolic regulator which inhibits signalling through the PI3K/AKT/mTOR pathway and serves as a counterbalance to AKT and ERK activity. It is frequently inactivated in environments with an excess of energy (i.e. obesity and insulin resistance). This may represent an additional driver for tumourigenesis through the mTOR pathway. LKB1, a serine/threonine kinase phosphorylates and activates AMPK , thus mutations in LKBI lead to activation of the mTOR pathway. Studies in Type 1 endometrial cancers demonstrated a loss of expression or functional deficiency of the LKB1 gene in up to 65% of tumours .
The PI3K/AKT/mTOR pathway is frequently upregulated in endometrial cancer. The phosphatase and tensin homolog (PTEN) phosphatase dephosphorylates PI3K substrates and acts as a PI3K antagonist and tumour suppressor gene. PTEN inactivation occurs in over 40% of type I endometrial cancers and is thought to be an early event in the development of some endometrial carcinomas. Thus, the combination of elevated insulin and IGF-1 and loss of PTEN leads to constitutive activation of the PI3K/AKT/mTOR pathway and facilitates endometrial cancer growth in individuals with diabetes.
The oncogenetic potential of insulin and insulin-like growth factor (IGF) are recognised; insulin or insulin-like growth factor (IGF)-1 stimulate in vitro proliferation of breast cancer cells and reduced IGF signalling can lead to decreased tumour growth in mouse models. Insulin has been shown to stimulate the growth of endometrial stromal cells by binding to insulin receptors on endometrial cells. High levels of insulin have been shown to potentiate the effect of oestrogen on endometrial proliferation in an obese rat model. In this model, oestrogen induced significantly higher expression of the proproliferative genes, cyclin A and c-myc in the endometrium of obese rates, as compared with what had been observed in lean control animals.
Role of Oestrogens
Oestrogen has proliferative effects on the endometrium and can promote the growth of endometrial cancer cells by both directly and indirectly affecting gene transcription. 17β-estradiol activates the PI3K and mitogen-activated protein kinase (MAPK) pathways, which are implicated in many cancers including endometrial cancer. Oestrogen also promotes the local production of IGF-1, further driving these pathways. The enzyme aromatase converts androgens to oestrone and oestradiol, thus adipose tissue represents the primary source of circulating oestrogen in postmenopausal women.
Role of Adipose Tissue
Adipose tissue is metabolically active and secretes inflammatory cytokines, which have been implicated in the development of cancers. Leptin is the central mediator of the feedback loop that regulates appetite and energy homeostasis and has been reported to stimulate proliferation in endometrial cancer cells. Adiponectin is inversely related to BMI and has been reported to reduce serum glucose concentration by activation of AMPK and peroxisome proliferator-activated receptor-α. Adiponectin treatment also induces apoptosis in endometrial cancer cells (HEC-1A and RL95-2), suggesting a protective effect against endometrial cancer .
Diabetes is independently related to endometrial cancer risk. This association is partly, but not wholly explained by co-existing obesity. From a public health point of view, diabetes mellitus and obesity represent conditions that can be targeted to help reduce the disease burden of endometrial cancer. They are also important co-morbidities for other common cancers and their prevention may have a substantial health impact on both malignant and non-malignant disease processes.
A better understanding of the impact of diabetes mellitus on tumorigenesis will not only help to identify therapeutic options but also select patients at risk of cancer who may benefit from screening, chemoprevention and lifestyle modification measures.
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