Obesity and Cancer: A Current Overview of Epidemiology, Pathogenesis, Outcomes, and Management

Obesity is a common disease and has been associated with several major chronic illnesses including coronary artery disease, diabetes mellitus, hypertension, osteoarthritis, sleep disorders, and mental illnesses, among others. More importantly, there is growing evidence that obesity increases the risk of several solid-organ and hematological malignancies. Obesity has been linked to cancer of the breast, colon and rectum, esophagus, stomach, gallbladder, uterus, pancreas, and ovary, among others. The relationship between obesity and cancer is rather complex. Obesity is not only associated with an increased risk of cancer but may also increase the risk of cancer recurrence and mortality in cancer survivors. Hence, the management of obesity as an early intervention in patients with early-stage cancer is important to improve cancer outcomes. Over the past decade, new evidence of the association between obesity and cancer risk and inferior outcomes has arisen. New drugs that are more effective and relatively safer than the older agents have been approved for weight management in adults with obesity. An increasing number of prospective studies are underway to address various aspects of obesity in cancer patients. This review was undertaken to provide readers updated information on obesity and cancer. The paper first describes the definition of obesity, the epidemiology of obesity and cancer in the general population, the use of new technology in measuring obesity and body fat distribution, and potential biologic mechanisms of the development of cancer in obese individuals. It then reviews recent data on the negative relationship between obesity and cancer outcomes, including the risk of recurrent disease and treatment-related complications. Then, it evaluates the management of obesity using various strategies in cancer survivors where weight reduction is an important adjunct to cancer treatment in reducing the risk of recurrent disease and a new obesity-related primary cancer. It ends with summarizing ongoing clinical trials related to obesity in cancer survivors.

A literature search was performed using PubMed and Google Scholar. In addition, clinical practice guidelines, position papers by professional societies and organizations, and the reference lists of relevant articles were reviewed for identification pertinent articles. Due to the wide scope of this paper, a formal literature search was deemed impractical. The search was mostly limited to papers published in English over the past decade up to September 2022 and was focused on studies that investigated epidemiology, the pathogenesis of cancer in obesity, cancer incidence and the risk of recurrence in obesity, and the management of obesity. As this review addresses several aspects of cancer and obesity, multiple searches using various key words in combination with "obesity" and "cancer" were performed independently to identify key papers relevant to a section. The senior authors reviewed the citations and content of each section and made appropriate changes. Most clinical evidence is derived from meta-analyses and or systematic reviews of observational studies or pooled analyses of clinical trials.

Obesity is characterized by the presence of excess body fat. "Obese" and "obesity" are the terms used by clinicians to describe those individuals with a substantially increased risk of ill-health due to the accumulation of excessive body fat. Although obesity was recognized as a disease by the World Health Organization (WHO) in the late 1940s, it was only during the latter part of the century that the term became significant, after its connection was established with serious illnesses. The WHO has defined obesity as "abnormal or excessive fat accumulation to the extent that health may be impaired". It results from a complex interplay between genetic, environmental, socioeconomic, and behavioral factors. Body mass index (BMI) is the surrogate measurement of excess body fatness. Obesity is commonly described as a BMI or weight to height ratio of greater than or equal to 30 kg/m 2. Individuals with a BMI of 25-29 kg/m 2 are considered overweight. BMIs > 30 kg/m 2 are further classified as follows: class I, a BMI of 30.0-34.9 kg/m 2 ; class II, a BMI of 35.0-39.9 kg/m 2 ; and class III, or extreme obesity, BMI ≥ 40 kg/m 2. Obesity is also referred to as a high waist-hip ratio. Abdominal obesity is defined as a waist-hip ratio above 0.90 in men and above 0.85 in woman. Evidence supports the superiority of a high waist-hip ratio over BMI or waist circumference in predicting cardiometabolic risk; waist circumference and waist-hip ratio have been found comparable to BMI and a better predictor of cancer risk. Anthropometric measures are commonly used in epidemiological studies for body fat measurements; however, they have some limitations. In addition to anthropometric measurements, various other techniques have been used to measure body fat composition and distribution. Dual energy X-ray absorptiometry (DEXA) is one of the standard tests for the direct measurement of whole-body fat and its regional distribution. A DEXA measurement of body fat > 25% in men and >30% in women is considered abnormal. The other techniques include bioelectrical impendence, ultrasound, computed tomography (CT) scans, and magnetic resonance imaging (MRI) scans. These methods and their potential advantages and disadvantages are described in Table 1. Obesity has nearly tripled worldwide since 1975. In 2020, 39 million children under the age of five were either overweight or obese. If current trends continue, it is predicted that by 2025, 2.7 billion adults would be overweight, over 1 billion would be obese, and 177 million will be extremely obese, while approximately 38% of the world's adult population will be overweight by 2030 and another 20% will be obese. A metaanalysis of 230 studies involving more than 30 million individuals showed that excess body weight is associated with an increased risk of all-cause mortality. Globally, it is estimated that obesity attributes to about 4-8% of all cancers with a range of <1% in low-income countries to 7-8% in high-income countries. In the United States, it is estimated that obesity accounts for about 4.7% of new cases of cancer in men and 9.6% new cases of cancer in women. However, the proportion of cancer linked to excess body weight varies according to the underlying cancer, with 51% of all liver or gallbladder cancers and 49.2% of all endometrial cancers in women and 48.8% of all liver or gallbladder cancers and 30.6% of all adenocarcinomas being attributed to obesity. It is estimated that about 21% of all cancers that are linked to obesity could be prevented if the American adult population had a BMI < 25 or a healthy body weight. Among those cancer survivors who are aged 20 years or older, 33.6% have been shown to be obese and 35.6% are reported to be overweight.

Obesity is a well-established predisposing factor for many malignancies, most notably breast and colorectal cancer. Adipocyte tissue and its microenvironment may play a role in carcinogenesis, the development of metastases, and the progression of the disease. However, the underlying mechanism resulting in carcinogenesis is complex and not yet fully understood. Altered fatty acid secretion and metabolism, extracellular matrix remodeling, the secretion of anabolic and sex hormones, immune dysregulation, chronic inflammation, and changes in the gut microbiome have been linked to carcinogenesis, the development of metastases, and the progression of cancer in obesity. It is likely that different mechanisms lead to the development of different cancers. There are three primary biological mechanisms that have been proposed as a risk of the development of malignancy in obese individuals. The first of these mechanisms is related to the concept of adipose tissue acting as an "organ", with the capacity to release chemical mediators and enzymes. Specifically, this mechanism describes increased synthesis of estradiol from androgens due to the presence of aromatase found in peripheral adipose tissue. The overproduction of estrogen by adipose tissue has been linked to an increased risk of developing breast, endometrial, ovarian, and other cancers. A higher BMI is strongly associated with metabolic syndrome, which includes higher fasting levels of insulin, glucose, triglycerides, and residual cholesterol, along with low levels of high-density lipoprotein (HDL) cholesterol. The amount and location of adipose tissue are important factors that influence insulin resistance and dyslipidemia. Higher fatness has a negative metabolic impact that is already noticeable in late childhood and could worsen over time. Additionally, increased body fatness increases systolic and diastolic blood pressure and lowers immunity due to its link to increased pro-inflammatory substances such as interleukin-6. Evidence suggests that weight gain during adulthood is associated with an increased risk of the development of post-menopausal breast, colorectal, endometrial, renal, and high-risk prostate cancers. A large population-based study involving 5.24 million individuals with 166,955 new instances of 22 types of cancer supported strong links between BMI and the most common site-specific cancers. According to studies utilizing Mendelian randomization, increased body fatness is associated with a greater chance of developing ovarian, esophageal, gastric, pancreatic, renal, colorectal, endometrial, and other cancers. Mendelian randomization uses germline genetic variations that are strongly related to potentially modifiable exposures as proxies (or "instrumental variables") for the target risk factor in order to assess causation in observational epidemiology. The International Agency for Research on Cancer (IARC) 2020 report found strong evidence for obesity and the risk of 13 different cancers. Post-menopausal breast, colorectal, endometrial, esophageal, pancreatic, renal, liver, stomach, gallbladder, ovarian, thyroid, multiple myeloma, and meningioma are among the cancers that the obese population is more likely to develop. The evidence of an association between obesity and cancers of the mouth, pharynx and larynx, prostate, and male breast, as well as diffuse large B-cell lymphoma, is moderate. A high risk is shown for three of the most challenging cancers to treat-pancreatic, esophageal, and gallbladder-as well as the two most prevalent malignancies-breast and colorectal cancer. An umbrella review of 204 systematic reviews and meta-analyses investigated the relationship between excess body fat and cancer risk and reported a range from a 9% increase (RR 1.09, 95% confidence interval 1.06 to 1.13) for rectal cancer in men to a 56% (1.56, 1.34 to 1.81) increased risk of biliary tract system cancer with every 5 kg/m 2 increase in BMI. The risk of post-menopausal breast cancer in women who never received hormone replacement therapy was 11% (1.11, 1.09 to 1.13) with every 5 kg of weight gained in adulthood whereas the risk of endometrial cancer increased by 21% for each 0.1 increase in the waist-hip ratio (1.21, 1.13 to 1.29). The association of obesity with the risk of breast cancer is complex, with an inverse or neutral relationship between obesity and breast cancer diagnosed in pre-menopausal and a positive association in post-menopausal women, especially of hormone receptor-positive breast cancer. There is evidence that an increased level of whole body fat measured by dual-energy X-ray absorptiometry in women with a normal BMI is associated with an elevated risk of breast cancer with an adjusted hazard ratio of 1.89 (95% CI, 1.21-2.95) for all invasive breast cancer and 2.21 (95% CI, 1.23-3.67) for hormonereceptor positive breast cancer; there is also a 56% increased risk of developing hormone receptor-positive breast cancer per 5 kg increase in trunk fat. Insulin resistance, breast adipose inflammation, the increased expression of aromatase enzyme, elevated leptin, and the inflammation of breast adipose tissue have all been attributed to obesity-associated postmenopausal breast cancer.

Evidence supports the suggestion that obesity is not only associated with an increased risk of cancer but may also increase the risk of recurrence in early-stage cancer and be correlated with inferior outcomes. Crosstalk between cancer cells and adipose tissue via hyperinsulinemia, proinflammatory cytokines, adipokines, and extracellular matrix proteins promotes metastases. In particular, central obesity that results from the deposition of visceral adipose tissue has been linked to progression. A systematic review and meta-analysis of 230 cohort studies showed that overweight and obesity have been associated with an increased risk of all-cause mortality. Obesity has also been associated with inferior outcomes in some malignancies. Nevertheless, the relationship between obesity and cancer outcomes are not as clearly understood. The variability between each malignancy and even among subtypes lends to variability in the analysis of a causal relationship. A systematic review and a meta-analysis of 203 studies involving 6.3 million cancer patients showed that obesity was associated with an increased overall and cancer-specific mortality. In general, obesity is associated with a 14% increased risk of overall mortality (hazard ratio [HR] for overall survival 1.14; 95% CI, 1.09-1.19; p < 0.001) and 17% increased risk of cancer-specific mortality (HR for cancer-specific survival, 1.17; 95% CI, 1.12-1.23; p < 0.001). Furthermore, obesity was associated with a 13% increased risk of recurrence (HR for recurrence, 1.13; 95% CI, 1.07-1.19; p < 0.001). Obese patients with breast, colorectal, or uterine cancers had an overall poor survival. Obesity in patients with breast, colorectal, prostate, and pancreatic cancers was associated with high cancer-specific mortality and obese patients with breast, colorectal, prostate, and gastroesophageal cancers had high recurrence rates. Conversely, obese patients with melanoma, lung, and kidney cancer had better survival compared with non-obese patients. The inferior outcomes in obese patients noted in certain cancers could be due to several factors, such as an underlying metabolic syndrome, hormonal factors related to some endocrine-dependent cancers, low physical activity, and undertreatment. Significantly, the practice of dose-capping in obese patients discussed below is relevant to all cancer types. Moreover, other standard therapies have been associated with poorer outcomes in obese cancer patients. For example, surgical resections among obese patients have been shown to result in an increased incidence of post-operative complications including wound infection, prolonged operative time, and a greater risk of blood loss. Evidence supports the suggestion that patients with gastrointestinal cancer following radical surgery have inferior long-term survival if they experience operative complications. In addition, radiation therapy has been shown to have poorer results among obese patients; this has been attributed to the labor of daily setup along with the freedom of movement of the tumor within the fat of the patient.

Obesity is a one of the major but preventable global health crises that has been linked to major chronic illness and several cancers, with increased morbidity and mortality. Among the various cancers, breast, colorectal, endometrial, esophageal, pancreatic, renal, hepatic, stomach, gallbladder, ovarian, and thyroid cancer, as well as multiple myeloma and meningioma, are strongly associated with obesity. The underlying mechanism of obesity causing cancer is incompletely understood and involves adipokines, inflammation, an altered extracellular matrix, altered fatty acid metabolism, and the secretion of insulin-like growth factors and estrogen. Weight-reducing strategies in obesity-associated cancers are important interventions as a component of cancer care in reducing cancer-specific and overall mortality in cancer survivors with excess body weight. Regular exercise and diet, in conjunction with behavior therapy, are the primary elements of weight reducing strategies. More data are needed regarding the efficacy and safety of pharmacologic and surgical interventions as a major weight reduction strategy in cancer survivors.

The pathogenesis of cancer development and recurrence in obesity is multifaceted and heterogeneous for different cancers and is also not fully understood. Further studies are warranted to fully understand the mechanisms specific to each cancer and to identify future targets for primary and secondary cancer prevention. While several studies have demonstrated a correlation between obesity and negative cancer outcomes, further studies are warranted using novel clinical and molecular markers. Some of the limitations of the current literature include the use of a fixed BMI threshold of 30 kg/m 2 to distinguish between obese and non-obese individuals, insufficient information about the timing of obesity, and a lack of adjustment for psychosocial, genetic, environmental, and behavioral factors. Due to the limitations associated with anthropometric measurements, the routine use of novel methods that are more accurate in measuring body fat and its distribution are important for future studies in cancer and obesity.