By Gary Tufel

Obesity has been previously acknowledged as a causative factor for a range of diseases, including cardiac problems and diabetes. Now research has clearly demonstrated obesity’s link to cancer.

According to Colleen Doyle, MS, RD, director of the Nutrition and Physical Activity National Home Office, American Cancer Society, excess weight impacts cancer risk in at least two ways:

1) Those who are overweight tend to have increased levels of circulating hormones known to influence cell growth: estrogen, insulin, and insulin-like growth factors. Adipose tissue produces more estrogen, and can also cause people to become more insulin-resistant. The body compensates by producing even more insulin. The end result of both is higher circulating insulin and estrogen.

2) Being overweight or obese tends to cause gastroesophageal reflux, which increases the risk of esophageal cancer.

Doyle says that there is a clear linear relationship between increasing body-mass index (BMI) and cancer risk. BMI is a measure of obesity using one’s weight (in kilograms) divided by height (in meters squared). A range of 25.0 to 29.9 is considered overweight and values of 30.0 and over are obese for purposes of a study authored by Eugenia E. Calle, MD, director of Analytic Epidemiology for the American Cancer Society, and her research team. This measurement considers differences in weight because of muscle mass and helps to distinguish fat versus muscle weight. “We recommend that people maintain a BMI between 18.5 and 24.9. In the latest and largest study on overweight/obesity and cancer published in the New England Journal of Medicine last year, obesity was associated with higher rates of death in both sexes from cancers of the esophagus, colon and rectum, liver, gallbladder, pancreas, kidney, and from non-Hodgkin’s lymphoma and multiple myeloma, as well as cancers of the stomach and prostate in men and cancers of the breast, uterus, cervix, and ovary in women,” Doyle says.

“What we don’t know is whether losing weight reduces cancer risk; those studies haven’t been done, primarily because there are not large groups of people to follow who have lost weight and maintained that weight over time,” she says. However, in those who intentionally lose weight, there is lower circulating insulin, insulin-like growth factors, and estrogen, so it’s believed that losing weight likely would reduce cancer risk. Therefore, those who are overweight are encouraged to get to a healthy weight.

According to the US Surgeon General, Vice Admiral Richard Carmona, “As we look to the future and where childhood obesity will be in 20 years, it is every bit as threatening to us as is the terrorist threat we face today. It is the threat from within.”

For every country and every age group, obesity has become epidemic; sedentary lifestyles and bad food choices are problematic throughout. Serious concern is expressed by the North American Association for the Study of Obesity, which also cites considerable evidence suggesting that obesity and overweight play an important role in cancer.

The association says that obesity and overweight have been clearly associated with increased risks for kidney cancer in both men and women (twofold increased relative risk), and in women, endometrial cancer (one-and-a-half-fold relative risk) and postmenopausal breast cancer (twofold relative risk). Building evidence suggests that obesity and overweight also are associated with an increased risk of colorectal cancer, gallbladder cancer, and perhaps more modestly, the risk of thyroid cancer in women. For colorectal cancer, the effect of obesity and overweight on risk may be due in part to low physical activity, as consistent evidence exists for a strong protective effect of physical activity against developing colorectal cancer. As mentioned earlier, recent studies suggest that obesity and overweight may also play a role in the increasing incidence of some types of esophageal cancer, possibly through obesity’s association with gastric reflux. For prostate cancer risk, inconsistent findings from studies evaluating obesity may result from limitations in the measurement of obesity, as more consistent results have come from recent studies of biological factors that are more directly associated with specific aspects of body composition (eg, total fat).

The previously mentioned American Cancer Society study could have a profound effect on how Americans view weight, diet, and lifestyles. It evaluated the influence of excess body weight on cancer death risk, and found that increased body weight and increased death rates from cancer of all types were linked. The study covered 16 years and included 900,000 people from all 50 states, the District of Columbia, and Puerto Rico. The average age of participants was 57, and all were 30 years of age and older.

The study looked at BMI as a risk factor for cancer death. In the heaviest group (with a BMI of 40.0 or greater), the study found increased death rates from all cancers of 52% higher (relative risk 1.52) for men and 62% higher (relative risk 1.62) for women. Based on the data, it was estimated that in adults 50 years of age and older, obesity and overweight conditions could account for 14% of cancer deaths in men and 20% in women. For breast cancer, as well as cancer of the uterus, cervix and ovary in women, and for stomach and prostate cancer in men, there was an increasing risk seen as BMI increased.

These findings indicate that 90,000 cancer deaths in the United States could be avoided each year if individuals maintained a lifetime BMI of 25 or under. The implications of this study could have far-reaching influences on cancer prevention, risk reduction, and recommended guidelines for maintaining overall health.

According to the National Institutes of Health, evaluating the influence of obesity on survival from cancer is complicated by a number of factors, including variation in treatment regimens and completeness of vital status follow-up. For most types of cancer, little data exists on this topic, except for breast cancer. Most studies of obesity and breast cancer survival suggest that obese women have poorer survival than leaner women. To date, little is known about the mechanisms that might contribute to this effect and no prospective randomized trials have been conducted.

But overall, while the mechanisms underlying the obesity-cancer relationship are not fully understood, sufficient evidence exists to support recommendations that adults and children maintain reasonable weight for their height and ages for multiple health benefits, including decreasing their risk of cancer, according to the North American Association for the Study of Obesity.

And in the first-quarter 2004 issue of Frontline, the Susan G. Komen Breast Cancer Foundation’s newsletter, Walter Churchill Willett, MD, DrPH, says, “The most important ways of minimizing breast cancer from currently available evidence are to avoid weight gain and to minimize use of postmenopausal hormone replacement therapy (HRT). Based on the Nurses’ Health Study findings, we have estimated that breast cancer risk could be reduced by about one third if most women did not gain weight during midlife and avoided HRT.”

According to the American Cancer Society’s 2002 estimates, cancers linked to obesity among women comprise approximately 51% of all new cancers diagnosed among women in 2002: 2% thyroid cancers (15,800 new cases), 6% uterine cancers (39,300 new cases), 12% colorectal cancers (75,700 new cases), and 31% breast cancers (203,500 new cases). Among men, cancers linked to obesity comprise approximately 14% of new cancers: 3% are kidney cancers (19,100 new cases) and 11% are colorectal cancers (72,600 new cases). In terms of mortality, for women, obesity-related cancers are estimated to comprise 28% of cancer-related deaths in 2002: 15% from breast cancers (39,600 deaths), 2% from uterine cancers (6,600 deaths), and 11% from colorectal cancers (28,800 deaths). Among men, obesity-related cancers are estimated to comprise 13% of cancer-related deaths in 2002: 10% are colorectal cancers (27,800 deaths) and 3% are kidney cancers (7,200 deaths).

Interestingly, obesity may also be somewhat protective against other forms of cancer. Among premenopausal women, heavier women appear to experience modest protection from breast cancer compared to leaner women (0.7-fold relative risk). Lung cancer is also less prevalent among the obese, possibly because of smoking-related effects on metabolism. However, some investigators have argued that smoking or weight loss due to undetected disease may bias reported findings.

One interesting and possibly significant finding recently reported on National Public Radio was the result of work by Texas researchers who found that by using an experimental drug to shrink blood vessels in mice, obesity was reduced by 30%. Although it is far too soon to tell if this has implications for human beings, the drug will be tested on baboons later this year.

Examining the Obesity/Cancer Dynamic
According to Rachel Ballard-Barbesh, MD, associate director, Applied Research Program, National Cancer Institute (NCI), one of the biggest challenges in studying the obesity/cancer dynamic comes in methods of self-reporting. “We’re looking for better biomarkers to measure energy and nutrition intake and expenditure,” she says. One useful product has been double-labeled water, in which both hydrogen and oxygen are labeled with a mildly radioactive isotope, making the water heavier than regular water. People in studies who drink the water can be measured more accurately in terms of energy expenditure. If the energy expenditure is stable, researchers know that any weight gain is from food intake. This is significant, she says, because those who are heavier tend to underestimate their food intake, making their self-reporting unreliable.

“We need more biomarkers of this sort,” Ballard-Barbesh says. “Physical activity monitors are also useful.”

John Miner, MD, chief of the nutrition group, Division of Cancer Prevention, NCI, says that mass spectrometry is useful in examining small molecular weight compounds. In addition, he says calorimetric devices that measure the breakdown of energy in the body or how much is expended are important because if you don’t burn the energy, you store it. Calorimetric devices measure subtle changes in the body’s metabolic rate. In addition, impedance measurement is used to gauge body composition in obesity/cancer studies.

“But more sophisticated measurement is needed,” says Miner. “We need newer techniques to assess energy metabolism, and to measure subtle changes in cells.”

Research Continues
Continuing research on obesity and cancer includes a series of large-scale epidemiologic studies on the influence of obesity and physical inactivity on several major cancers conducted by the Division of Cancer Epidemiology and Genetics (DCEG), one of NCI’s intramural research divisions. These studies include cohort studies within clinical trials, such as the Alpha-Tocopherol Beta-Carotene Study; the Prostate, Lung, Colorectal, and Ovarian Cancer Study; and the Polyp Prevention Trial. In addition, DCEG is studying energy balance in cohort and case-control studies in Sweden, China, and the United States. These include the NIH–AARP (National Institutes of Health–American Association of Retired Persons) Diet and Health Study, a study of nutrition in relation to major cancers among over half a million American men and women. In addition, the Cohort Consortium is a new effort that combines several prospective cohort studies from around the world, and includes information on energy balance-related factors from each cohort.

NCI is also developing and supporting research initiatives to improve the measurement of diet and physical activity in the population to understand health professionals’ knowledge and practices in the area of obesity treatment, and to support the establishment of centers in nutrition, energetics, and physical activity and cancer outcomes. Some of these initiatives are cosponsored with other parts of the NIH.

Gary Tufel is a contributing writer for Clinical Lab Products.