Can a Low-Carbohydrate Diet Improve Outcomes in Endometrial Cancer?

A study in Nature Communications has revealed a very low-carbohydrate diet (VLCD) intervention can lead to profound physiologic, metabolic, and immune changes in women with obesity and endometrial cancer.

The findings provide additional insight into the link between glycemic load and endometrial cancer development. They also further inform understanding of the biological processes underlying whole-body metabolism, antitumor immunity, and tumor phosphatidylinositol 3-kinase (PI3K) signaling, a key regulator of cell growth, survival, and metabolism that is frequently dysregulated in endometrial cancer.

“Excess body fat is a known risk factor for endometrial cancer,” says senior study author Marcus D. Goncalves, MD, PhD, the Clarissa and Edgar Bronfman, Jr. Associate Professor of Endocrinology and director of NYU Langone Health’s Holman Division of Endocrinology, Diabetes, and Metabolism. “Our study explores the link between glycemic load, obesity, and endometrial cancer.”

Revisiting the Biology

Obesity is strongly associated with increased endometrial cancer risk, while also inducing a range of systemic changes that promote tumorigenesis. These changes, which include chronic inflammation, hyperinsulinemia, and hormonal imbalances, could explain why endometrial cancer is so closely tied to obesity.

Importantly, however, is the role of insulin, which promotes endometrial mucosal growth, mainly in the proliferative phase of the endometrial cycle, where insulin-like growth factor (IGF) signaling also plays a vital role.

“Both insulin and IGF-1 bind to the same receptors on the cell surface to activate PI3K signaling pathways, which drive tumorigenesis and growth within the uterine epithelia,” explains Dr. Goncalves.

Given this biological understanding, the researchers hypothesized that diets with high glycemic load, which are known to trigger hyperinsulinemia, could predispose patients to endometrial cancer. As such, diets that lower insulin might limit the effects of obesity on tumor growth.

Feasibility Study: VLCD vs. Standard Diet

To test their hypothesis, the researchers recruited 19 treatment-naive women with obesity and endometrial cancer. The participants were randomized to receive either a VLCD intervention or a standard diet during a presurgical window between diagnosis and surgical staging, which lasted up to 28 days.

“For the intervention arm, meals were prepared in a specialized kitchen before being delivered to the patients,” notes Ezequiel C. Dantas, MD, PhD, an assistant professor of medicine in the Holman Division of Endocrinology, Diabetes, and Metabolism, and co-investigator on the study with Dr. Goncalves.

A total of 15 patients completed the study, including nine in the VLCD intervention arm and six in the standard diet arm, and no patient withdrew due to difficulty adhering to the VLCD.

Overall, the VLCD intervention had marked effects on body weight and measures of systemic glucose and lipid metabolism. Participants’ weight decreased by 5.5 percent, fasting glucose levels fell by 22 percent, and insulin levels dropped by 60 percent. Total cholesterol and low-density lipoprotein (LDL), however, rose by 6 and 17.8 percent, respectively, which warrants further study, Dr. Goncalves says. “Although elevated LDL is generally considered a cardiovascular risk factor, its significance must be weighed against the potential benefits of effective cancer treatment.”

Additionally, further analysis revealed meaningful changes in the tumor microenvironment. Notably, there was increased enrichment and infiltration of CD8+ T-cells surrounding the tumor. These cells play a critical role in recognizing and destroying abnormal cells and are central for an effective antitumor immune response. However, the histology showed that these cells could not enter the tumor itself to exert this cytotoxic activity.

“The insulin-lowering diet was highly effective, safe, and feasible,” Dr. Dantas says. “Dietary changes affected tumor histology dramatically.”

Diet and Drug Strategies

The findings highlight the profound effects that diet can have on antitumor immunity and metabolism, which may help in treating endometrial cancer.

According to the researchers, these data suggest even a short duration of VLCD is sufficient to modify CD8+ T-cell infiltration. However, further investigations are needed to characterize the potential therapeutic benefits and feasibility of pairing dietary interventions with pharmacological treatments.

“We might be able to combine dietary interventions with other insulin-lowering drugs like GLP-1 receptor agonists to treat endometrial cancer,” Dr. Goncalves says.

Disclosures

Dr. Dantas reports intellectual property with Weill Cornell Medicine. Dr. Goncalves is a cofounder and holds equity in Faeth Therapeutics; reports consulting or advisory roles with Genentech Inc.; and patents, royalties, and other intellectual property with Faeth Therapeutics and Weill Cornell Medicine.