Short-term pre-operative caloric restriction downregulates miR-21 and modulates gut microbiome in breast cancer and prostate cancer patients

Purpose: Calorie restriction (CR) has been shown to improve oncological markers in numerous studies, the mechanism and extent to which it can modulate clinical outcomes remain of interest. In this study, we sought to determine the effect of a 2-5-week preoperative CR intervention on the oncogenic microRNA miR-21, as well as other clinical, microbiome and metabolic markers in patients with breast cancer and prostate cancer. We hypothesized that caloric restriction would lower miR-21-mediated inflammation, inducing a favorable shift in patient characteristics and enhancing anti-tumor responses. Methods: Breast cancer and prostate cancer patients from a large academic medical center were recruited to participate in a 25% reduced calorie diet intervention up to 12 weeks before definitive surgery. Adherence was maintained via a diet journal, regular check-ins, as well as nutritional and behavioral counseling. Clinical labs, weight, body composition, biomarkers and microbiome samples were collected pre and post-intervention. Paired t-tests were used to identify significant clinical parameters. Microbiome data was analyzed with QIIME2 and microbiome pathway analysis was conducted with PiCrust2. Results: From August 2016 to October 2018, 35 patients enrolled in the study and completed the pre-operative CR intervention, lasting an average of 21 days. The intervention resulted in significant weight loss, with an average of 7.8 pounds lost (p<0.0001). Patient fatigue was decreased, as measured by the Promis Fatigue scale (p < 0.01). Leptin (n=23) and IGFBP-3 (n=25) were both significantly decreased (p<0.05). MiR-21 expression was found to be significantly downregulated post-intervention (p<0.05). Microbiome analysis did not find any significant differences in alpha or beta diversity. Picrust2 analysis revealed 10 differentially expressed functional microbiome pathways, with the three greatest changes being decreased benzoyl-CoA degradation, decreased L-arabinose degradation IV, and decreased glycogen degradation. Serum biomarker microarray analysis revealed significantly post-intervention downregulation of Eotaxin 2 and IP 10 chemokines in breast cancer patients (FDR < 0.05), and significant upregulation of IGFBP-1 in prostate cancer patients (FDR < 0.05). Conclusions: This study demonstrates that short term preoperative caloric restriction is feasible and elicits rapid biologic changes in breast and prostate cancer patients, including significant downregulation of the oncogenic miR-21 and modulation of inflammatory chemokines. Microbiome pathway and taxa shifts suggest coordinated host/microbiome adaptation during the intervention. These findings support CR as a low-risk short-term intervention that warrants further investigation to determine the potential impact on long-term cancer outcomes.