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Andrew Dannenberg, M.D., the Meyer Cancer Center's Associate Director of Cancer Prevention, and Clifford Hudis, M.D., of Memorial Sloan Kettering Cancer Center, penned the following piece in JAMA Oncology, as a commentary to accompany this study, which found that overweight and obese women run an increased risk of breast cancer that is not diminished by weight loss.

Dr. Andrew Dannenberg In large part, obesity represents the end result of excess calorie consumption. Because overweight or obesity has always been an issue, some may ask why we are focusing on it now. A unique change is occurring on a global scale. Overweight and obesity are more prevalent than ever in recorded history, rates have been rising in almost every society in which medical records are available, and the number of individuals who are overweight or obese is at an all-time high.

What is causing this unprecedented global phenomenon? The simple answer is that more people are ingesting more calories than they need. Without dwelling on agriculture policy or government support for farming, we can marvel at the global calorie production and distribution machine that feeds and overfeeds so many of Earth’s citizens. (That is not to deny or ignore real pockets of deprivation and starvation, but many are the consequence of war, cruelty, and corruption rather than production deficiencies.)

The measurable result is pretty clear. The Centers for Disease Control and Prevention reported the prevalence of overweight and obesity at the state level, showing that the number of Americans in the highest weight category has risen from 10% to 14% to more than 30% in many regions of the country since 1990. It is predicted that more than 60% of the adult citizens of many states will be in the highest body mass index (BMI) category by 2030.

There are many consequences of being overweight or obese in adulthood, including increased risks of type 2 diabetes mellitus, cardiovascular diseases, arthritis, and diminished quality of life, among many others. A specific issue is the risk of cancer, and an even more specific one is the risk of individual cancers or subtypes. These increased risks of cancer have been largely unknown to the general public. However, it is increasingly evident that a variety of common malignant neoplasms are associated with obesity, and a recent National Cancer Institute projection suggests that increased BMI will replace tobacco as the leading modifiable risk factor for adults in the coming years. This suggests a need for both public awareness and action.

To identify the most effective potential interventions we would need to understand both how overweight and obesity cause (not “are associated with”) malignant diseases (or specific malignant neoplasms) but also which actions—weight loss through diet and calorie restriction being just 1 of many possible ones—are effective at lowering risk. The danger of inaction is before us—a growing public health burden in the form of cancer and other ailments—but which action to take remains far from clear.

The article by Neuhouser et al in this issue of JAMA Oncology is an important contribution. It extends and refines our understanding of one of the risks of overweight and obesity: increased incidence of the most common manifestation of breast cancer (postmenopausal, hormone receptor–positive disease). This team of investigators used data from the Women’s Health Initiative clinical trials (WHI) drawn from more than 67 000 women older than 50 years (but <80 years) from 1993 to 1998 who were followed at 40 US centers for a median of 13 years. They adjudicated all cases of new primary breast cancer (detected clinically or through the use of regular screening mammography) and examined the risks for overweight, obese, and very obese women compared with those who were in the normal weight category. In addition to identifying an increased risk for women who are overweight or obese, their data suggest a dose-response relationship with higher BMI categories associated with greater relative risk. The collection of WHI clinical trials includes some in which estrogen supplementation (alone or with progesterone) was tested, but they note no significant modification of risk with the use of hormone replacement therapy. Finally, they did not detect a change in risk for hormone receptor–negative breast cancers. Considering earlier observations suggesting a protective effect for obesity among premenopausal women, Neuhouser et al help refine our understanding of the risk of overweight and obesity; it is a particular concern for the most common form of breast cancer, hormone receptor–positive postmenopausal disease.

These investigators also made a frustrating observation with regard to weight loss: it was not protective, whereas weight gain (among women who were in the nonoverweight/nonobese category at baseline) raised risk. This challenges the simple suggestion that patients who are overweight or obese should just lose weight to reduce their cancer risk. Weight control (when achieved) may be very effective for many weight-associated illnesses and ailments, but the data suggesting that it will reduce an already elevated risk of breast cancer are limited. We need clinical trials to determine whether weight loss and body composition changes in overweight and obesity will reduce breast cancer risk.

The article by Neuhouser et al, along with other data, is a call for action on several fronts. First, we need to refine our understanding of the why overweight and obesity raise the risks of some cancers. Classically, clear cell endometrial cancer, but also a large number of others, including a range of gastrointestinal primary, prostate, and breast cancers, has been associated with overweight and obesity, but recently so has non-Hodgkin lymphoma. Our group has focused on the importance of subclinical white adipose tissue inflammation and its downstream consequences including induction of aromatase (and hence estrogen synthesis). Changes in levels of numerous circulating factors, including hyperinsulinemia, also correlate with white adipose inflammation. Our findings for white adipose inflammation are consistent with the observations of Neuhouser et al in that we provide a plausible explanation for activation of estrogen receptor signaling after menopause and linked to elevated BMI. But now we need a better understanding of the interrelated roles of not only calorie-restricted diets but also specific dietary composition(s) and various exercise programs deployed in specific patient groups.

One motivation for studies such as the present one by Neuhouser et al is to help us mount effective and efficient medical or community responses to the challenges we identify. Overweight and obesity are a growing global challenge, and the increased burden of malignant disease, to which it contributes, is another one. Their report helps focus our thinking and motivates us to pursue a deeper understanding of why overweight and obesity are a problem so that we can plan more effective and thoughtful responses.

Additional coverage of the study and commentary can be found in The Guardian, Medical News Today, and dailyRx.