Interventions to improve insulin resistance for the prevention of endometrial cancer
Description of the condition
Cancer of the womb (uterus) is the most common cancer affecting the female reproductive system in the developed world. Most womb cancers arise from abnormal growth of the womb lining (endometrium) and are termed endometrial cancer. Endometrial hyperplasia is a thickening of the womb lining, which can progress to endometrial cancer, if untreated. Worldwide, endometrial cancer affects 382,000 women per year (Globocan 2019), including over 9000 women in the UK. Its incidence rates have increased by almost three-fifths (57%) in the UK since the early 1990s, with similar trends reported globally (Lortet-Tieulent 2018). Most women diagnosed with endometrial cancer are postmenopausal; 93% of those diagnosed in the UK between 2014 and 2016 were over the age of 50 (CRUK 2019). Increasingly, however, a greater number of younger premenopausal women are being diagnosed with the disease (Unzurrunzaga 2019).
Most of the increase in incidence is due to low-grade Type 1 cancers. These are largely caused by an excess of the sex hormone, oestrogen, unopposed by progesterone (Kaaks 2002). Other risk factors include advancing age, insulin resistance and diabetes (Friberg 2007; Zhang 2013). The common link for all these risk factors is obesity. Worldwide, the prevalence of obesity (body mass index (BMI) > 30 kg/m2) has doubled in the last 30 years. Of the 20 most common tumour types, endometrial cancer has the strongest association with obesity, with a 5 kg/m2 increase in BMI being associated with a 60% increase in endometrial cancer risk. As the risk rises exponentially, a woman with a BMI of 42 kg/m2 has a nine-fold higher chance of developing endometrial cancer compared with a woman with a BMI of 22 kg/m2 (Bhaskaran 2014; Renehan 2008). Several different theories have been proposed to explain the link between obesity and endometrial cancer. These include an excess of endometrial pro-growth factors, including oestrogen, increased inflammation and insulin resistance.
Insulin is a hormone that helps the body process glucose (sugar). Insulin resistance occurs when target tissues (including liver, skeletal muscle and fat) do not respond appropriately to insulin and cannot break down glucose in the blood (Lebovitz 2001). If the pancreas is unable to produce enough compensatory insulin to counteract this, chronic hyperglycaemia (high glucose) and hyperinsulinaemia (high insulin) lead to the development of type 2 diabetes mellitus (T2DM). In obese people, dysregulation of signalling proteins (including tumour-necrosis factor-α (TNF-α) and adiponectin) lead to chronic inflammation and insulin resistance (Calle 2003; Kaaks 2002).
Multiple studies have found an association between prolonged high insulin levels and an increased incidence of cancer, including colorectal, hepatic, pancreatic, breast and endometrial cancers (Friberg 2007; Huxley 2005; Larsson 2005; Michels 2003; Wang 2012). Women with T2DM have a two-fold increased risk of endometrial cancer compared with women without diabetes (Friberg 2007). Whilst most obese women are insulin resistant (Abbasi 2002), insulin resistance and diabetes are additional independent risk factors for endometrial cancer. Insulin resistance alone continues to increase the risk of endometrial cancer, even after adjusting for the effect of obesity (Friberg 2007; Lucenteforte 2007).
Insulin and its related protein, insulin-like growth factor-1 (IGF-1), play important roles in driving proliferation (increased cell numbers), differentiation (changing of one cell type to another) and metabolic (chemical) activity within the normal endometrium (Merritt 2016). They do this by binding to the insulin and IGF-1 receptors, leading to activation of growth signalling pathways, such as PI3K/AKT/mTOR [phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR)] and mitogen-activating protein kinase (MAPK) (Cantrell 2010; Nagamani 1998; Renehan 2006). A rise in insulin and IGF-1 levels is associated with endometrial growth, thus increasing the risk of abnormal endometrial cells and, eventually, cancer formation. Increased expression of insulin and IGF-1 receptors, and over-activation of the associated growth signalling pathways, have been reported in endometrial hyperplasia (McCampbell 2006), and endometrial cancer (McCampbell 2010; Wang 2013).
Early-stage endometrial cancer is treated surgically by removing the uterus, fallopian tubes and ovaries. In women with aggressive or advanced disease, this is followed by radiotherapy or chemotherapy, or both. When endometrial cancer is diagnosed in women of child-bearing potential, these treatments result in infertility, which can be devastating to those who have not completed their families. Most women with endometrial cancer are diagnosed with early stage (FIGO stage I and II) curative disease. Obesity, however, can make surgery more challenging and present increased complications and healthcare costs. (Suidan 2017).
Interventions to prevent endometrial cancer, therefore, would have significant benefits for both the woman and for healthcare systems as a whole. In high-risk women with a familial predisposition for endometrial cancer (Lynch Syndrome), identification of the condition allows familial-based genetics follow-up and access to cancer surveillance programmes (e.g. camera assessments and biopsies of the womb lining). Risk-reducing surgery, in the form of a hysterectomy and removal of tubes and ovaries after the family is complete, is an established method of preventing endometrial cancer in these women.
Some women are diagnosed with endometrial hyperplasia, a precursor lesion, which, if left untreated, can lead to endometrial cancer. This risk is highest in women with atypical endometrial hyperplasia, where the thickening is accompanied by abnormal cell changes (Kurman 1985; Lacey 2008). Atypical hyperplasia in women who have completed their families is treated surgically, with a hysterectomy, removing the womb and cervix (RCOG/BSGE 2016). Women wishing to retain their fertility, or those unfit for surgery, can be treated by insertion of a progesterone-releasing hormone coil (Mirena coil), oral progestogens and weight loss interventions. Oral progesterones have a number of side-effects, including headaches, mood changes and acne. Longer-term progesterone treatment increases the risk of a thromboembolic event (venous blood clots) and breast cancer (BNF 2019), so may not be suitable for all women. In atypical endometrial hyperplasia, disease regression rates ( i.e. resolution of atypical changes) of up to 86% have been reported (Gallos 2012), however, significant disease recurrences are also recognised.
In the general population, prevention strategies are based on targeting established risk factors. Manipulation of sex hormones, including oral, injectable and intrauterine progestins, has been shown to reduce endometrial cancer risk (Jareid 2018). The combined oral contraceptive pill is also associated with a reduction in the lifetime risk of endometrial cancer (Iversen 2017). Unfortunately, in obese women with a BMI greater than 35 kg/m2, the risks of thromboembolic events outweighs the potential benefit (UK MEC 2009).
Another potential intervention is to specifically focus on a driver of endometrial carcinogenesis (cancer development) in women who are at increased risk; for example, by improving insulin resistance in women with diabetes or obesity, or both. Women with polycystic ovary syndrome (PCOS), a metabolically-driven gynaecological disorder, have a three-fold increased risk of developing endometrial cancer compared to women without PCOS (Haoula 2012). This increase is likely to be driven by a combination of insulin resistance and unopposed oestrogen, leading to reduced or absent menstruation. As insulin resistance is thought to be a key player in the development of PCOS, studies have tested the effect of metformin in the treatment of endometrial hyperplasia. A recent Cochrane Review concluded that the existing evidence is insufficient, and that further research using robust, adequately-powered randomised controlled trials is needed to answer this clinical question (Clement 2017).
Cancer prevention interventions require two key attributes: the ability to predict and identify high risk individuals, and a means of assessing the efficacy of the intervention. Measuring the response in endometrial cancer prevention studies can be problematic. These studies require a large number of subjects and a prolonged follow-up period to detect an absolute decrease in the incidence of cancer. As this approach is often prohibitively expensive, investigators have used endometrial tissue proliferation biomarkers (e.g. the Ki-67 protein) as a surrogate for assessment of response (Kitson 2017). Alternatively, regression of endometrial hyperplasia histology towards normal histology could be used as a measure of response.
Description of the intervention
This review will focus on interventions designed to improve insulin resistance as the primary goal, and will include pharmacological, non-pharmacological and surgical interventions, used alone or in combination. Pharmacological interventions include drugs that act to improve insulin resistance (e.g. metformin, sulphonylureas, thiazolidinediones, insulin), and drugs that induce weight loss through reduction of fat absorption (e.g. orlistat), or appetite suppressants. Non-pharmacological or 'lifestyle' interventions are those which aim to increase physical activity and reduce calories, including diet, exercise and psychological management (examples). Surgical interventions include weight loss (bariatric) surgery, such as procedures designed to limit food intake (e.g. gastric banding), cause malabsorption (e.g. intestinal bypass), or both.
How the intervention might work
Reducing insulin resistance may prevent the development of endometrial cancer by changing the hormonal profile in women at risk. Insulin breaks down glucose for use as an energy source, and maintains blood glucose in a stable range. Insulin resistance in the target tissues (e.g. skeletal muscles, liver cells) leads to an increase in insulin production from the pancreas, to maintain normal glucose levels. Eventually, the pancreas fails to produce sufficient insulin to counteract the high glucose levels, resulting in hyperglycaemia (high blood glucose) and hyperinsulinaemia (high insulin). Hyperglycaemia due to T2DM may facilitate cancer cell growth through the following mechanisms.
Insulin from the pancreas acts on the liver to increase the production of growth factors (IGF-1/2)) and to decrease growth-factor neutralisers (IGF-binding proteins 1 and 2). This results in an excess of growth factors (insulin and/or IGF1/2), which bind to the insulin receptor (IR) and IGF-1 receptors (IGF1R) to activate cancer proliferation pathways [phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) and Ras-Raf-MAPK]. The PI3K-AKT-mTOR and Ras-RAF-MAPK pathways are implicated in the development of endometrial cancer. Activation of these pathways initiates a cascade of signalling events, which promote cellular growth, the development of abnormal blood vessels (angiogenesis) and abnormal migration of cells.
Higher levels of IGF-1 have been reported in overweight individuals (Crowe 2011). Even in people of who are not overweight, higher levels correlate with an increased risk of breast, prostate and colorectal cancers, and increased levels of the target receptors (IGF-1 receptor) have been observed (Yu 2000). In these cancers, persistently elevated insulin and/or IGF1/2 are thought to increase tumour growth signalling and metastases. In a further study of women with a disordered proliferative endometrium, endometrial hyperplasia and endometrial cancer, Shan 2014 found insulin resistance and high insulin levels to be key events early in abnormal endometrial growth, and may even be the initiating events in the development of endometrial cancer.
Thus, metformin and other drugs that increase the body's response to insulin have been proposed as potential interventions. Metformin is one of the most widely used oral treatments for T2DM, and is used for PCOS, infertility, obesity and hirsutism (excess hair growth). Metformin is thought to reduce cancer growth in two ways. Firstly, it stops glucose production in the liver, resulting in a decrease in compensatory insulin production and lower levels of insulin in circulation. Secondly, metformin can act at a cellular level through the mitochondria. Mitochondria are found in most cells and control cellular respiration and energy production. Metformin acts to activate the signalling protein AMP-activated protein kinase (AMPK), which directly inhibits the PI3K-AKT-mTOR cancer proliferation pathway.
Some epidemiological studies have reported that people with diabetes who take metformin have a substantially lower cancer burden than people with diabetes treated with other agents (DeCensi 2010; Evans 2005; Gandini 2014). A meta-analysis of 11 studies (involving 766,926 participants) found that metformin use was associated with a 13% reduction in endometrial cancer in women with diabetes (Tang 2017). Human, animal and laboratory models have shown metformin to have direct anti-cancer effects. In rats, it has been shown to reduce endometrial hyperplasia caused by oestrogen (Tas 2013), and reduce activation of the mTOR cancer proliferation pathway (Erdemoglu 2009). Small clinical trials and case reports have demonstrated resolution of simple and atypical hyperplasia (excess cell growth with abnormal cells) following treatment with metformin and/or rosiglitazone, a thiazolidinedione (oral diabetes treatment) (Legro 2007; Session 2003; Shen 2008). The evidence for the role of metformin, however, can be conflicting. An Italian case-control study, which compared 376 diabetic women with endometrial cancer and 7485 age-matched diabetic controls, found no significant association between metformin, sulfonylureas, insulin or other anti-diabetes medications and the risk of endometrial cancer. These discrepancies in the studies' findings could be explained by differences in study design, such as size, indication for metformin use and the dose and durations of treatment. On balance, however, the data suggest that the role of insulin resistance and hyperglycaemia in endometrial cancer merit further investigation.
Public health interventions that decrease the overall prevalence of obesity could have an even greater impact on decreasing endometrial cancer incidence. Intentional weight loss, particularly in women who were obese at baseline, has been reported to lower the risk of endometrial cancer (Luo 2017). These findings are consistent with reports that sustained weight loss after bariatric (weight-loss) surgery has been associated with lower endometrial cancer risk in severely obese women (MacKintosh 2019; McCawley 2009; Sjostrom 2009). Improvements in insulin resistance (as measured by the Homeostatic Model of Insulin Resistance (HOMA-IR), are seen shortly after surgery and, indeed, before any significant weight loss has occurred. This suggests that the metabolic changes following surgery are important, particularly improvement in insulin resistance (Arora 2015; Ward 2014). Sustained weight loss is associated with improvement in both HOMA-IR and HbA1C (glycated haemoglobin, a measure of blood sugar control) (Parikh 2014). It is likely that both non-pharmacological and surgical interventions which lead to weight loss will have a favourable effect on improving insulin resistance.
Why it is important to do this review
The burden of endometrial cancer has increased in the developed world, and is expected to increase in lower income countries as obesity becomes more prevalent (Arnold 2015). Prevention strategies must include targeting the key mechanisms that drive endometrial cancer development. There is a bulk of evidence to support a causative role for insulin resistance in endometrial cancer.
This theme ranked as the most important endometrial cancer research priority for patients, carers and healthcare professionals in a recently completed Womb Cancer Priority Setting Partnership (Wan 2016). This review will establish whether the evidence already exists, or whether well-designed randomised controlled trials are required to provide it. This review will set the scene for high-quality research to assess the feasibility, effectiveness and cost-effectiveness of interventions to reduce insulin resistance (including physical activity and dietary interventions, bariatric surgery or drugs (e.g. metformin, thiazolidinediones, sulphonylureas, insulin) for the prevention of endometrial cancer, in both at-risk groups (women with obesity, insulin resistance and type 2 diabetes, PCOS or atypical hyperplasia) and the general population. There have been no previous Cochrane Reviews on this topic.
To determine the safety and effectiveness of interventions to improve insulin resistance for the prevention of atypical endometrial hyperplasia or endometrial cancer, or both.