ABSTRACT: Objectives: To evaluate the feasibility of a very low carbohydrate, ketogenic, diet in women with endometrial cancer and obesity, and to assess the effects of this dietary pattern on metabolism and tumor biology. Design: A multicentre, parallel, prospective, randomized, controlled feasibility study in treatment naïve women with endometrial cancer. Participants were randomized in a 2:1 fashion to a very-low carbohydrate (VLCD) diet, or to continue with their standard diet (SD) by the method of random permuted block. Setting: Eight locations from two teaching hospitals in the New York and New Jersey areas. Participants: 19 treatment naïve women with endometrial cancer (stages IA-IIIC2) and obesity. 15 completed the study. Intervention: After initial biopsy and pathology confirmation, participants received 21-28 days of VLCD and weekly nutritional counseling, followed by surgical staging. Main outcome measures: Dietary adherence, rates of attrition, and adverse effects. Changes in circulating concentration of metabolic biomarkers. Changes in immunohistochemical staining and RNA-Sequencing for insulin signaling pathway, cell apoptosis, proliferation, and immunity. Results: Of the 19 participants randomized, 15 finished the trial with an overall attrition rate of 21%. Participants in the VLCD arm reported consuming 91 ± 4% of the meals, leading to a rise in ketone bodies for all participants by day 3 or 4 and an overall weight loss of 5.5 ± 0.8%. The VLCD was well-tolerated with no grade 3/4 adverse events. Fasting plasma glucose and insulin levels were reduced by 22 ± 5.9% and 60 ± 3.8%, respectively. Total cholesterol and low-density lipoprotein (LDL) were increased by 6 ± 2.7% and 17.8 ± 8.9%, respectively. A measure of insulin pathway signaling, p-AKT (Ser473), was significantly decreased in the tumors of participants who consumed the VLCD by immunohistochemistry (p=0.04). CD8+ T cells were found to infiltrate the tumor margins under VLCD compared to SD (p=0.026). Gene Set Enrichment Analysis using RNA-Seq showed enrichment in pathways related to fatty acid oxidation, oxidative phosphorylation, estrogen response, and interferon alpha response (p<0.05 and Normalized Enrichment Score >1.34). Conclusions: A VLCD is feasible and well-tolerated in obese, women with endometrial cancer and leads to significant host and tumor metabolic changes that suggest potential therapeutic benefits that warrant further investigation in larger clinical trials.
