Obesity-associated cancers: An emergent problem among younger adults

The increasing prevalence and troubling consequences of obesity in the United States have been well-documented.

According to the CDC, the prevalence of obesity in the U.S. has increased among adults from 30.5% between 1999 and 2000 to 42.4% between 2017 and 2018. CDC data also showed an 18.5% prevalence of obesity among those aged 2 to 19 years, with 13.7 million children and adolescents affected.

Clear associations have been shown between obesity and several leading causes of preventable death, including heart disease, stroke and type 2 diabetes.

Obesity also has been linked to several types of cancer. These obesity-associated cancers have increasingly emerged in younger populations, driving a shift in incidence toward this group.

According to a study by Siran M. Koroukian, PhD, and colleagues published in JAMA Network Open, rates of obesity-associated cancers increased substantially among younger age groups between 2000 and 2016. Specifically, the increase of obesity-associated cancers among those aged 50 to 64 years ranged from 25.3% among non-Hispanic white women to 197.8% among Hispanic men.

As researchers seek to understand the mechanisms of obesity-related cancers, obesity is projected to overtake tobacco use as the No. 1 cause of cancer in the United States.

“Thirty-three percent of all current cancers are due to tobacco, and we think 30% of all cancers are now due to the combination of too many calories, not enough exercise and obesity,” Otis W. Brawley, MD, Bloomberg Distinguished Professor of oncology at Johns Hopkins University School of Medicine and a HemOnc Today Editorial Board Member, said in an interview. “We believe within the next 10 years, and probably within the next 5 years, this combination of factors we call ‘energy balance’ is going to be the No. 1 cause of cancer in the United States, surpassing tobacco.”

HemOnc Today spoke with epidemiologists and oncologists about how obesity is driving an increased incidence of some cancers among younger people, the mechanisms driving the association between obesity and cancer, and how clinicians should counsel their patients about weight loss and healthy habits.

‘An increase inside the decline’

In their study, Koroukian and colleagues found that new cases of obesity-associated cancer increased across all groups stratified by sex and race/ethnicity.

In total, the percentage increase in absolute number of obesity-associated cancers from 2000 to 2016 ranged from 7.7% among non-Hispanic white women to 123.4% among Hispanic men.

Of the 13 cancers linked to obesity — which include postmenopausal breast cancer, thyroid cancer, colorectal cancer, meningioma, kidney cancer, multiple myeloma, gallbladder cancer, pancreatic cancer, liver cancer, ovarian cancer, uterine cancer, stomach cancer and adenocarcinoma of the esophagus — eight have increased in incidence among younger patients, according to Nathan A. Berger, MD, the Hanna-Payne professor of experimental medicine, professor of medicine, biochemistry and oncology, and director of the Center for Science, Health and Society at Case Western Reserve University School of Medicine, who was a researcher on the study.

“We’re now seeing cancers usually diagnosed in older people that are beginning to appear in patients who are aged younger than 50 years,” Berger told HemOnc Today. “We think that obesity is accelerating the development of some cancers and that is why they are showing up in younger people.”

Breast, thyroid, colorectal, kidney, uterine, ovarian and stomach cancers, as well as meningioma, have increasingly presented in younger patients, Berger said.

For instance, among those aged 20 to 49 years, thyroid cancer cases increased 179.5% among Hispanic men, 160% among Hispanic women, 111.7% among Black women, 62.1% among non-Hispanic white men, 55.1% among non-Hispanic white women and 27.5% among Black men.

However, the largest increases occurred among those aged 50 to 64 years.

“We think there is also evidence that the development of the other cancers is being accelerated by obesity, but not to the point where they are showing up in young people yet,” Berger said. “They are showing up in middle-aged people.”

Among men aged 50 to 64 years, researchers observed a 200.6% increase in liver cancer cases among non-Hispanic white men, a 227.3% increase among Black men and a 355.9% increase among Hispanic men. For thyroid cancer, these groups saw increases of 157.2%, 172.4% and 300%.

Other notable increases in the 50-to-64 age group occurred for gallbladder and other biliary cancers in Black men (288.9%), Black women (188%) and Hispanic men (216.7%), and for uterine cancer in Hispanic women (232.3%).

Research also has revealed a concerning trend in the growing incidence of colorectal cancer among younger adults.

A study by Levi and colleagues connected that growing incidence with simultaneously increasing rates of obesity.

In an analysis of 1.1 million Israeli Jewish men with 19.5 million person-years of follow-up, the researchers found obesity among adolescents aged 16 to 19 years was associated with a significantly increased risk for colon cancer (HR = 1.53, 95% CI 1.17-2) but not rectal cancer.

Looking at overall cancer incidence and mortality data may obscure these trends, Brawley said, citing a 2017 study by the American Cancer Society that showed a 50% decrease in the overall rate of death due to colorectal cancer in the U.S.

This statistic does not tell the whole story, he said.

“Buried in that data is that for adults aged 35 to 55 years, there was an increase in the death rate,” he said. “There is actually an increase within that decline. So, when you hear about the 29% decrease in cancer death rates from 1991 to 2017, think of obesity as lessening that decline. In other words, if we didn’t have this obesity epidemic, we may very well have had a 35% decline.”

Bailey and colleagues found that although the incidence of colorectal cancer decreased overall (annual percent change [APC], –0.92%; 95% CI, –1.14 to –0.7) between 1975 and 2010, this decrease was driven by those aged 50 to 74 years (APC, –0.97) and those aged 75 years and older (APC, –1.15). Conversely, rates increased among those aged 20 to 24 years (APC, 1.99) and 35 to 49 years (APC, 0.41).

Research conducted by Brawley and colleagues has also found that the decreased mortality rate in the United States varies by region of the country.

“Some of the work we’ve published compares the Northeast vs. the southern United States,” Brawley said, “When we talk about that 50% decline in colorectal cancer deaths, it’s important to know that the decline in colorectal cancer death rates in Massachusetts has been far greater than 50%, and in Mississippi it has been about half of that. These state-by-state variants are, to some extent, due to a failure in access to care.”

Energy balance: A ‘three-legged stool’

The obesity epidemic is on an upward trajectory in the United States, particularly among children, according to Brawley. He said in 1970, only 4% of American children had obesity, compared with 20% in 2010.

This increase in the rate of pediatric obesity is reflected in the distribution of cancer among the younger population.

However, Brawley said the “energy balance” encompasses more than obesity and presents a more complete picture of the problem.

“It’s a three-legged stool,” he said. “It consists of not enough activity, too many calories and obesity.”

Obesogenic diets are a component of the problem even in the absence of obesity, Berger said.

Berger said in his work on animal models, published in Obesity, he has found that high-fat diets can begin to have detrimental effects even before obesity is reached.

“When we look at obesogenic diets, there is no question that these accelerate the development of cancers,” he said. “We also found that in some animals, a high fat-diet accelerates the development of tumors even before the animal becomes obese. So, we’re concerned about obesogenic diets, as well.”

According to Cornelia Ulrich, MS, PhD, professor of population health sciences and Jon M. and Karen Huntsman presidential professor in cancer research at University of Utah, and executive director of Comprehensive Cancer Center at Huntsman Cancer Institute, a person’s degree of physical activity can influence some aspects of cancer risk independent of weight. She noted that regular physical exercise likely improves DNA repair capacity.

“However, inflammation can only be improved through weight loss,” she told HemOnc Today. “So, there are different mechanisms for energy balance. Some of them require weight loss and obesity reduction, while others don’t.”

Due to increased conveniences in the United States over the past 60 years, energy imbalance has become a distinctly American problem, Brawley said.

“We have to think about how our way of life has changed over these decades; it has changed in ways that it hasn’t changed in Western Europe,” Brawley said. “In the 1950s, people walked a great deal. By the 1970s, almost every American family owned a car. Nowadays, we have two or three cars per family. We moved to the suburbs where we need to drive everywhere. That’s not as much of an issue in Europe.”

Meanwhile, Brawley said, the association between automobile use and obesity also has been seen in East Africa, where “dark blue taxis” have decreased the need for walking.

“Conversely, in communities where people walk frequently, there is more energy expenditure, and the obesity problem is not as significant,” he said.

Ulrich noted that these factors in an individual’s environment should be considered when counseling a patient on maintaining a healthy weight.

“Many people think it is solely up to the individual to make the decision to eat healthier and have a healthy weight,” she said. “That’s not how it is. There are numerous factors that influence whether a person will be successful in attaining a healthy weight. These factors have to do with availability, food security and the price of food.”

She added that some environments may be limited in terms of safe areas to walk.

“There’s a lot that has to do with what we call the ‘built environment’ and the safety of the environment,” she said. “Not everyone feels they are able to walk safely to the store in their neighborhoods.”

According to Brawley, the ubiquity of fast-food restaurants and processed foods has also impacted the rates of obesity in the United States. He said 60 years ago, fewer than 60 McDonald’s restaurants existed in the United States. Today, the chain is opening new restaurants at a rate of approximately 60 per week.

“However, it’s beyond just the issue of fast food; there are McDonald’s restaurants in Germany and France,” he said. “It’s our way of living.”

Brawley discussed the CDC’s Built Environment and Health initiative, a former program that awarded grants to communities for redevelopment projects related to physical activity and health. Brawley said this program was able to facilitate environments where residents are more active.

“These are the kinds of communities where people are able to walk to the grocery store and might not use their car for weeks at a time,” he said.

Mechanisms of the association

Although the mechanism of the link between obesity and certain cancers is not fully understood, there is evidence to support various possibilities.

“Excess fat can promote several carcinogenic pathways involved in inflammation, oxidative stress and angiogenesis, for example,” Susan M. Gapstur, PhD, MPH, who served as senior vice president of behavioral and epidemiology research at American Cancer Society at the time of the interview, told HemOnc Today. “There is also growing evidence showing that excess body fat can affect the gut microbiome.”

Several studies have sought to characterize the effects of obesity on the gut microbiome and, ultimately, on colorectal cancer, Ulrich said.

“The microbiome is this entire, tremendous population of bacteria in our gut and other surfaces; we are using very crude measures to understand the microbiome at this point,” she said. “For example, for the entire colorectal cancer association, researchers looked at the presence of one bacterium called Fusobacterium nucleatum. There’s a lot more that has to do with the diversity and interplay of the different species that we haven’t really understood yet. We’re just beginning, through sequencing of both the bacteria and the metabolites, to learn more about how to measure the microbiota.”

Ulrich acknowledged much remains to be learned about the role of obesity in triggering certain cancers.

“We clearly know that inflammation is systemically elevated in obesity, and that’s an important aspect. We know the microbiome is different with obesity, as well,” she said. “There are also effects on DNA repair capacity in immunology. There are many, many different mechanisms through which obesity can impact cancer.”

Ulrich said BMI is one of the strongest predictive factors of elevated systemic inflammation, noting the correlation between C-reactive protein and serum amyloid A with BMI. Additionally, she said visceral obesity, which involves the fat stored inside the abdominal cavity, is now thought to play a particularly important role in the development of cancer.

“You can’t see this from the outside — you need a CT scan to see the distribution of fat,” she said. “Two people who look equally chubby on the outside may look very different on the inside. Visceral obesity is something we’re starting to explore much more.”

The ’obesity paradox’

Although healthy diet and exercise habits are recommended for patients and survivors of obesity-associated cancers, some research has suggested that excess body weight may have a protective effect during treatment of various cancers.

Known as the “obesity paradox,” this concept holds that high BMI is associated with decreased mortality.

For instance, Jennifer L. McQuade, MD, instructor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues evaluated data of 1,918 patients with metastatic melanoma who received targeted therapy, immunotherapy or chemotherapy. They found that patients with obesity had improved PFS (adjusted HR = 0.77; 95% CI, 0.66-0.9) and OS (adjusted HR = 0.74; 95% CI, 0.58-0.95) compared with those who had normal BMI.

However, the survival benefit appeared limited to those treated with targeted therapy and immunotherapy. In that group, obesity appeared associated with a near doubling of OS (HR = 0.53; 95% CI, 0.4-0.7) among men, but not women.

Patients with obesity were more likely to take metformin, aspirin, statins and beta-blockers, but the improvement in outcomes occurred independently of those drugs, McQuade told HemOnc Today at the time the study was published.

“We next examined treatment tolerance as a potential mechanism, such as whether patients with obesity are better able to tolerate treatment,” she added. “However, we did not see any difference in the rate of adverse events between those with normal BMI and [patients with obesity]. More telling, we saw the BMI association among patients treated with immunotherapy and targeted therapy — which do not typically cause weight loss — and not with chemotherapy, which does cause weight loss.

“We found BMI does not really matter among women; women do well regardless of BMI,” she added. “Men with obesity had similar survival outcomes as women. Men with normal BMI had much worse outcomes. Thus, it appears that obesity overcomes the survival disadvantage associated with male sex in melanoma.”

However, according to an article by Park and colleagues, evidence has suggested that the obesity paradox can be explained by methodological flaws in studies, including confounding, reverse causation and collider stratification bias, a type of selection bias that can yield false associations.

“From my understanding, it’s not necessarily obesity with a BMI greater than 30 that is beneficial, it’s more the moderate overweight with between 25 mg/m² and 30 mg/m²,” Ulrich said. “That may also have to do simply with the fact that you are able to sustain long periods of low food intake and treatment effects better if you are a little bit more adipose. There are a lot of confounding factors that we haven’t fully elucidated.”

Counseling patients

When advising a patient with an obesity-associated cancer, the oncologist is in an unusual position: because the patient has already developed cancer, preventive efforts are no longer applicable.

However, lifestyle changes can play an essential role in improving patients’ outcomes and helping them remain healthy throughout their survivorship.

“Weight loss can influence the carcinogenic biologic pathways in a positive direction,” Gapstur said. “The evidence we have seen suggests that just as high BMI is linked to these carcinogenic pathways, weight loss may have an opposite and beneficial effect.”

However, Gapstur noted that clinicians should be cautious and consider each case individually when discussing lifestyle changes with patients who are receiving cancer treatment.

“Some patients diagnosed with cancer have already lost weight due to their cancer, and the treatment can have some adverse effects, as well,” Gapstur said. “So, we want to be very, very careful that patients work with trained dieticians and their oncologists to make sure their nutritional needs are being met.”

Ulrich said physical activity is likely to be beneficial to patients with obesity-associated cancers, even if weight loss is not the goal.

“I think at this point, we can say with near certainty that exercise is helpful to patients with cancer, period, as part of an adjuvant therapy,” she said. “It may or may not help with body composition, but at a minimum it helps with the fatigue of cancer treatment. It maintains function and decreases the likelihood of needing to go into a nursing home. So, there’s probably no harm done through exercise.”

Berger said survivors of obesity-associated cancers should be encouraged to maintain a healthy weight and increase their physical activity.

“Once people have cancer and it is cured or is treated by surgery or radiation or goes into remission, they should be on a low-fat diet,” he said. “They ought to be trying to reduce their weight and prevent recurrences.”

When considering weight loss for a patient with an obesity-associated cancer, clinicians should devise ways to specifically target visceral fat, which has been shown to elevate cancer risk and worsen outcomes, Ulrich said.

“We did studies, for example, with [postmenopausal women with obesity and overweight] who exercised for a year and lost only about 1.2 kg of weight,” she said. “But, they reduced their intra-abdominal fat and their visceral fat by more than 10%, and you could see that overall, their biomarkers were moving toward a significantly better risk profile. Even if people don’t lose weight, if they can change their body composition through strength training, they may be better off that way.”

Ulrich added that as rates of obesity and obesity-associated cancers among young people continue to increase, clinicians should take care not to dismiss any concerns or symptoms these patients may have.

“With this epidemic of young-onset colorectal cancer, we need to have physicians taking any sort of symptoms in a young patient seriously,” she said. “We’ve had so many cases where a young patient has presented with bleeding and they didn’t have a colonoscopy as part of follow-up, because it would seem so unlikely for it to be cancer. We can’t make that assumption anymore. Responding rapidly to these symptoms is an important first step.

References:

Bailey CE, et al. JAMA Surg. 2015;doi:10.1001/jamasurg.2014.1756.

Berger NA. Obesity (Silver Spring). 2018;doi:10.1002/oby.22137.

CDC. Childhood obesity facts. Available at: www.cdc.gov/obesity/data/childhood.html. Accessed Nov. 16, 2020.

CDC. Prevalence of obesity and severe obesity among adults: United States, 2017-2018. February 2020. Available at: www.cdc.gov/nchs/products/databriefs/db360.htm. Accessed Nov. 16, 2020.

Koroukian SM, et al. JAMA Netw Open. 2019;doi:10.1001/jamanetworkopen.2019.9261.

Levi Z, et al. Cancer Epidemiol Biomarkers Prev. 2011;doi:10.1158/1055-9965.EPI-11-0531.

McQuade JL, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30078-0.

Park Y, et al. Cancer Res. 2018; doi:10.1158/0008-5472.CAN-17-3043.

Qin Y, et al. Genome Biol. 2018;doi:10.1186/s13059-018-1389-1.

Siegel RL et al. JAMA. 2017;doi:10.1001/jama.2017.7630.

For more information:

Nathan A. Berger, MD, can be reached at Case Comprehensive Cancer Center, 10900 Euclid Ave., Cleveland, OH 44106-4971; email: nab@case.edu.

Otis W. Brawley, MD, can be reached at Johns Hopkins Bloomberg School of Public Health, 1550 Orleans St., Suite 1M16, Baltimore, MD 21287; email: otis.brawley@jhu.edu.

Susan M. Gapstur, PhD, MPH, can be reached sueg1050@gmail.com.

Cornelia Ulrich, MS, PhD, can be reached at Huntsman Cancer Institute, 2000 Circle of Hope, Room 4725, Salt Lake City, UT 84112: email: neli@hci.utah.edu.