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Written by: Aislinn Antrim, Assistant Managing Editor

Evidence has shown that reversing pro-cancer effects requires significant weight loss as well as substantial metabolic reprogramming.

Although weight loss can certainly have overall health benefits, experts said more research is needed to understand whether it can improve the pro-cancer effects of obesity. Three experts discussed the issue in a session at the 2023 San Antonio Breast Cancer Symposium (SABCS), happening December 5 to 9 in Texas.

Obesity is a driver across many different cancer types, said presenter Stephen D. Hursting, PhD, MPH, professor, Department of Nutrition, UNC Chapel-Hill Gillings School of Global Public Health. A 2018 American Institute for Cancer/World Cancer Research Fund identified 12 cancer types strongly driven by obesity, and the International Agency for Research on Cancer identified 13 types. However, Hursting said the data is still unclear about whether weight loss can reverse these pro-cancer effects.

“This question just hasn’t been adequately addressed…as of 2017,” Hursting said. “There are a lot of efforts underway. I can’t wait for the [Breast Cancer Weight Loss trial], one of the large trials really looking at this question.”

In animal models, calorie restriction has shown sufficient evidence in reducing cancer risk. However, there is limited preclinical evidence that intentional weight loss can reverse the pro-cancer effects of obesity. Hursting said there have been a few studies over the last 5 years, but it still needs further research.

“That is, I think, a clear message…that we, as the cancer research community, need to pivot from the question of whether obesity can be seen as a risk factor for many risk factors—that is certainly well established,” Hursting said. “The question, then, is what are we going to do? How can we reduce the impact of chronic obesity on cancer?”

Thus far, evidence has shown that reversing pro-cancer effects requires significant weight loss as well as substantial metabolic reprogramming. Hursting said inhibiting the mammalian target of rapamycin (mTOR) signaling pathway in addition to weight loss and anti-inflammatory agents could help.

There are several approaches to achieving significant weight loss: bariatric surgery, calorie restriction, and medications. Although bariatric surgery is the most consistent anti-cancer weight loss intervention, Hursting acknowledged that it is invasive, has potential complications, expensive, and most patients do not qualify. Calorie restriction can also be highly effective, but is incredibly difficult for patients to adhere to.

That leaves medications, and Hursting said the new incretin-based therapies appear to be incredibly effective. Semaglutide (Wegovy; Novo Nordisk) is a single agonist (glucagon-like peptide 1 [GLP-1] receptor) approved for both type 2 diabetes and weight loss. The newest FDA approval is tirzepatide (Zepbound; Lilly), a dual GLP-1 and gastric inhibitor polypeptide receptor (GIPR) agonist. Data from the SURMOUNT-1 trial showed that it was extremely effective for weight loss (approximately 21%) at the maximum 15 mg dose.

“Incretin drugs are really promising; I think these have the potential to be game changers…but they won’t work for everyone,” Hursting concluded. “These are relatively new drugs, so what are their long-term effects? They’re also forever drugs, so rapid weight gain is a real problem [and] we need to find a way to get people off of these at some point and in an effective way.”

Presenter Randy Seeley, PhD, Henry King Ransom Endowed Professor of Surery, University of Michigan School of Medicine, further discussed the mechanisms of action for these newer incretin and dual-incretin drugs to produce substantial weight loss. Ultimately, Seeley said weight is a complex combination of the environment as well as genetics.

“[Researchers] get into this back and forth about whether weight is regulated by the environment or by genetics, and the answer is both,” Seeley said.

Although a common explanation for bariatric surgery is that it reduces weight by making the stomach too small to hold large amounts of food, Seeley said this isn’t entirely true. Instead, it changes the “set point” for body weight, which is dictated by the brain.

Studies of liraglutide in rats have shown a similar effect. In one study, a group of rats maintained a normal diet, while a second group had reduced calories, and a third group had a high-fat diet. After removing the drug, the rats that were underweight almost immediately gained weight and matched the weight of the normally-fed rats, while the high-fat diet rats immediately lost weight and matched the weight of the others. Seeley said this demonstrates the “set point” and how it is impacted by medications.

Finally, expert Kerry S. Courneya, OC, PhD, FACHS, Canada Research Chair in Physical Activity and Cancer, Canadian Institutes of Health Research, discussed the impact of exercise on breast cancer outcomes. Although most research approaches this from a public health or survivorship perspective, Courneya said his research examines exercise as an actual treatment for breast cancer. To do that, he and his colleagues developed a framework that was published in Frontiers in Oncology in 2022.

Thus far, there have been no adequately powered randomized clinical trials of exercise with a breast cancer outcome, although there have been some secondary analyses of small exercise trials with breast cancer outcomes. Most studies in exercise and breast cancer outcomes are observational cohorts, few of which are designed to examine exercise and its impact on breast cancer outcomes.

Courneya said there are approximately 50 preclinical studies that have examined exercise, and these typically find that exercise slows the growth and spread of tumors and disease over the course of time. However, Courneya cautioned that no studies have seen complete responses, shrinking, or stabilized disease, so the best-case scenarios are slowing progression. About a quarter of these studies have shown no effects at all, and tumors actually have grown more quickly in about 10% of the studies, highlighting the research needed in specific tumor types.

In the 40 to 50 observational human studies of exercise and breast cancer outcomes, Courneya said researchers typically do a single measure of pre-diagnosis or post-diagnosis physical activity and link it to 1 clinical outcome. Both pre- and post-diagnosis exercise have been linked with a lower risk of death from breast cancer, but these studies have several limitations. Notably, Courneya said clinically relevant time periods are avoided or mixed, treatment combinations and sequencing are ignored, and treatment response and early events are missed with these trial designs.

Courneya concluded with several recommendations to improve the knowledge base on exercise and breast cancer outcomes. He urged clinicians to recruit clinically homogeneous samples, collect detailed cancer treatment data, assess exercise in relation to cancer treatments, include early cancer-specific outcomes, and analyze subgroups based on cancer treatments (including individual treatments, combinations, and sequences).

Hursting SD, Seeley R, Courneya KS. Overcoming Obesity-Associated Breast Cancer Risk. Presented at: San Antonio Breast Cancer Symposium. December 5-9, 2023.