Obesity and Cancer

Obesity is a disease in which a person has an unhealthy amount and/or distribution of body fat (1). Compared with people of healthy weight, those with overweight or obesity are at greater risk for many diseases, including diabetes, high blood pressure, cardiovascular disease, stroke, and at least 13 types of cancer, as well as having an elevated risk of death from all causes (2–5). 

To determine if someone has obesity, researchers commonly use a measure known as the body mass index (BMI). BMI is calculated by dividing a person’s weight (in kilograms) by their height (in meters) squared (commonly expressed as kg/m²). BMI provides a more accurate measure of obesity than weight alone, and for most people it is a good (although imperfect) indicator of body fatness. 

The National Heart Lung and Blood Institute has a BMI calculator for adults. The standard weight categories based on BMI for adults ages 20 years or older are:

The Centers for Disease Control and Prevention (CDC) has a BMI percentile calculator for children and teens. Overweight and obesity for people younger than 20 years old, whose BMI can change significantly as they grow, are based on CDC’s BMI-for-age growth charts. 

Measurements that reflect the distribution of body fat are sometimes used along with BMI as indicators of obesity and disease risks. These measurements include waist circumference, waist-to-hip ratio (the waist circumference divided by the hip circumference), waist-to-height ratio, and fat distribution as measured by dual-energy X-ray absorptiometry (DXA or DEXA) or imaging with CT or PET.

These measures are used because the distribution of fat is increasingly understood to be relevant to disease risks. In particular, visceral fat—fat that surrounds internal organs—seems to be more dangerous, in terms of disease risks, than overall fat or subcutaneous fat (the layer just under the skin). 
 

Obesity and severe obesity have become more common in the United States in recent years (7). 

• In 2011, 27.4% of adults ages 18 or older had obesity or severe obesity.
• By contrast, in 2020, 31.9% of adults ages 18 or older had obesity or severe obesity. 

The percentage of children and adolescents ages 2–19 years with obesity or severe obesity has also increased (6). 

• In 2011–2012, 16.9% of 2–19-year-olds had obesity and 5.6% had severe obesity.
• By contrast, in 2017–2018, 19.3% of 2–19-year-olds had obesity and 6.1% had severe obesity. 

According to the CDC, the prevalence of obesity in the United States differs among racial and ethnic groups (7). In 2020, the proportions of adults ages 18 years or older with obesity or severe obesity were:

• Non-Hispanic Black, 41.6% 
• American Indian/Alaska Native, 38.8%
• Hawaiian/Pacific Islander, 38.5%
• Hispanic, 36.6% 
• Non-Hispanic White, 30.7%
• Asian, 11.8% 

In 2017–2018, the proportions of obesity among children and adolescents ages 2–19 years were (6):

• Mexican American, 26.9%
• Hispanic, 25.6%
• Non-Hispanic Black, 24.2%
• Non-Hispanic White, 16.1%
• Non-Hispanic Asian, 8.7%

The prevalence of obesity has increased more quickly recently, possibly due to the COVID-19 pandemic (8). CDC has state-level estimates of adult obesity prevalence in the United States. 

Nearly all of the evidence linking obesity to cancer risk comes from large cohort studies, a type of observational study. However, data from observational studies cannot definitively establish that obesity causes cancer. That is because people with obesity or overweight may differ from people without these conditions in ways other than their body fat, and it is possible that these other differences—rather than their body fat—explain their increased cancer risk.

An International Agency for Research on Cancer (IARC) Working Group concluded that there is consistent evidence that higher amounts of body fat are associated with an increased risk of a number of cancers. The table below shows the risks reported in representative studies. 

People who have a higher BMI at the time their cancer is diagnosed (29) or who have survived cancer (30, 31) have higher risks of developing a second, unrelated cancer (a second primary cancer).

Several possible mechanisms have been suggested to explain how obesity might increase the risks of some cancers (32, 33).

• Fat tissue (also called adipose tissue) produces excess amounts of estrogen, high levels of which have been associated with increased risks of breast, endometrial, ovarian, and some other cancers.
• People with obesity often have increased blood levels of insulin and insulin-like growth factor-1 (IGF-1). High levels of insulin, a condition known as hyperinsulinemia, is due to insulin resistance and precedes the development of type 2 diabetes, another known cancer risk factor. High levels of insulin and IGF-1 may promote the development of colon, kidney, prostate, and endometrial cancers (34).
• People with obesity often have chronic inflammatory conditions such as gallstones or non-alcoholic fatty liver disease. These conditions can cause oxidative stress, which leads to DNA damage (35) and increases the risk of biliary tract and other cancers (36).
• Fat cells produce hormones called adipokines that can stimulate or inhibit cell growth. For example, the level of an adipokine called leptin in the blood increases with increasing body fat, and high levels of leptin can promote aberrant cell proliferation. Another adipokine, adiponectin, is less abundant in people with obesity than in people with a healthy weight and may have antiproliferative effects that protect against tumor growth.
• Fat cells may also have direct and indirect effects on other cell growth and metabolic regulators, including mammalian target of rapamycin (mTOR) and AMP-activated protein kinase.

Other possible mechanisms by which obesity could affect cancer risk include impaired tumor immunity and changes in the mechanical properties of the scaffolding tissue that surrounds developing tumors (37).

In addition to biological effects, obesity can lead to difficulties in screening and management. For example, women with overweight or obesity have an increased risk of cervical cancer compared with women of healthy weight, likely due to less effective cervical cancer screening in these individuals (38).

A nationwide cross-sectional study using BMI and cancer incidence data from the US Cancer Statistics database estimated that each year in 2011 to 2015 among people ages 30 and older, about 37,670 new cancer cases in men (4.7%) and 74,690 new cancer cases in women (9.6%) were due to excess body weight (overweight, obesity, or severe obesity) (39). The percentage of cases attributed to excess body weight varied widely across cancer types and was as high as 51% for liver or gallbladder cancer and 49.2% for endometrial cancer in women and 48.8% for liver or gallbladder cancer and 30.6% for esophageal adenocarcinoma in men.

Globally, a 2019 study found that in 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases), with the burden of these cancer cases higher for women (368,500 cases) than for men (175,800 cases) (40). The proportion of cancers due to excess body weight varied from less than 1% in low-income countries to 7% or 8% in some high-income Western countries and in Middle Eastern and Northern African countries.

Most of the data about whether losing weight reduces cancer risk comes from cohort and case–control studies. Observational studies of obesity and cancer risk should be interpreted with caution because they cannot definitively establish that obesity causes cancer and people who lose weight may differ in other ways from people who do not.

Some of these studies have found decreased risks of breast, endometrial, colon, and prostate cancers among people with obesity who had lost weight. For example, in one large prospective study of postmenopausal women, intentional loss of more than 5% of body weight was associated with lower risk of obesity-related cancers, especially endometrial cancer (41). However, unintentional weight loss was not associated with cancer risk in this study. 

A follow-up study of weight and breast cancer in the Women’s Health Initiative (42) found that, for women who were already overweight or obese at the beginning of the study, weight change (either gain or loss) was not associated with breast cancer risk during follow-up. However, in a study that pooled data from 10 cohorts, sustained weight loss was associated with lower breast cancer risk among women 50 years and older (43).

To better understand the relationship between weight loss among people with obesity and cancer risk, some researchers are examining cancer risk in people with obesity who have undergone bariatric surgery (surgery performed on the stomach or intestines to provide maximum and sustained weight loss). Studies have found that bariatric surgery among people with obesity, particularly women, is associated with reduced risks of cancer overall (44); of hormone-related cancers, such as breast, endometrial, and prostate cancers (45); and of obesity-related cancers, such as postmenopausal breast cancer, endometrial cancer, and colon cancer (46).

Most of the evidence about obesity in cancer survivors comes from people who were diagnosed with breast, prostate, or colorectal cancer. Research indicates that obesity may worsen several aspects of cancer survivorship, including quality of life, cancer recurrence, cancer progression, prognosis (survival), and risk of certain second primary cancers (29, 30, 47, 48).

For example, obesity is associated with increased risks of treatment-related lymphedema in breast cancer survivors (49) and of incontinence in prostate cancer survivors treated with radical prostatectomy (50). In a large clinical trial of patients with stage II and stage III rectal cancer, those with a higher baseline BMI (particularly men) had an increased risk of local recurrence (51). Death from multiple myeloma is 50% more likely for people with the highest levels of obesity compared with people at healthy weight (52).

Most studies of this question have focused on breast cancer. Several randomized clinical trials in breast cancer survivors have reported weight loss interventions that resulted in both weight loss and beneficial changes in biomarkers that have been linked to the association between obesity and prognosis (53, 54). 

However, there is little evidence about whether weight loss reduces the risk of breast cancer recurrence or death (55). The NCI-sponsored Breast Cancer WEight Loss (BWEL) Study, an ongoing randomized phase III trial, is examining whether participating in a weight loss program after breast cancer diagnosis affects invasive disease-free survival and recurrence in overweight and obese women (56).

Many studies are exploring mechanisms that link obesity and cancer (34, 57). One research area involves understanding the role of the microbes that live in the human gastrointestinal tract (collectively called the gut microbiota, or microbiome) in both type 2 diabetes and obesity. Both diseases are associated with dysbiosis, an imbalance in the community of these microbes. For example, the gut microbiomes of people with obesity differ from and are less diverse than those of people of healthy weight. Imbalances in the gut microbiota are associated with inflammation, altered metabolism, and genotoxicity, which may in turn be related to cancer. 

Researchers are also studying how obesity alters the tumor microenvironment, which may play a role in cancer progression. For example, studies in mouse models show that obesity (induced by feeding mice a high-fat diet) creates a competition for lipids between tumor cells and T cells that makes the T cells less effective at fighting the cancer (58). 

Another area of investigation is the role of insulin receptor signaling in cancer. Many cancer cells express elevated levels of IR-A, a form of the insulin receptor that has a high affinity for insulin and related growth factors. Researchers are investigating how these factors contribute to metabolic disease and cancer and whether they may be useful targets for therapeutic interventions to prevent obesity-related cancers.

Investigators are also exploring whether the associations of obesity with cancer risk and outcomes vary by race or ethnicity (59). Also, researchers are investigating whether different cutoffs for overweight and obesity should be used for different racial/ethnic groups. For example, the World Health Organization (WHO) has suggested the alternate thresholds of 23.0 and 27.5 kg/m² for overweight and obesity for people of Asian ancestry (60).

The NCI Cohort Consortium is an extramural–intramural partnership that combines more than 50 prospective cohort studies from around the world with more than seven million participants. The studies are gathering information on body mass index, waist circumference, and other measures of adiposity from each cohort. The large size of the consortium will allow researchers to get a better sense of how obesity-related factors relate to less common cancers, such as cancers of the thyroid, gallbladder, head and neck, and kidney.

Another area of study is focused on developing more precise and effective interventions to prevent weight gain and weight regain after weight loss. This area of research includes two NIH-based initiatives—the Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) Core Measures (61) and the Trans-NIH Consortium of Randomized Controlled Trials of Lifestyle Weight Loss Interventions (62)—both of which aim to identify predictors of successful weight loss and maintenance and to incorporate information on genetic, psychosocial, behavioral, biological, and environmental factors into predictive profiles to enable more precise and, ultimately, more effective weight loss interventions.

NCI supports research on obesity and cancer risk through a variety of activities, including large cooperative initiatives, web and data resources, epidemiologic and basic science studies, and dissemination and implementation resources. For example, the Transdisciplinary Research on Energetics and Cancer (TREC) initiative supports ongoing training workshops for postdocs and early career investigators to enhance the ability to produce innovative and impactful transdisciplinary research in energetics and cancer and clinical care. The Trans-NCI Obesity and Cancer Working Group promotes the exchange of information and cross-cutting interests in obesity and cancer research within NCI by identifying and sharing state-of-the-science knowledge about obesity and cancer to document what is known and what is needed to move the science forward.