Abstract A07: A phase II study of metformin therapy in ovarian cancer with translational endpoints
Authors: Buckanovich Ronald J. , Chan Daniel , Shank Jessica , Griffith Kent , Fan Huihui , Szulawski Robert , Yang Kun , Reynolds Kevin , Johnston Carolyn , McLean Karen , Uppal Shitanshu , Liu Rebecca , Cabrera Laura , Taylor Sarah , Shen Hui , Mehta Geeta , Coffman Lan 
Published: September 2020

Abstract
Epidemiologic studies suggest that metformin can improve outcomes for patients with ovarian cancer. Preclinical studies suggest metformin may work in part via effects on cancer stem-like cells (CSCs) to maintain platinum sensitivity. We therefore performed a phase II clinical trial evaluating adjuvant metformin therapy in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC). The primary aims were translational studies evaluating the impact of metformin on CSC and chemotherapy resistance. Secondary aims included progression-free and overall survival. Thirty-eight patients with confirmed stage IIC (n=1)/III (n=25)/IV (n=12) EOC were treated with either (i) neoadjuvant metformin followed by primary debulking surgery and adjuvant chemotherapy + metformin, or (ii) three cycles of neoadjuvant chemotherapy and metformin, followed by interval debulking surgery, and adjuvant chemotherapy + metformin. Thirty-two patients (84%) completed six cycles metformin + chemotherapy. Metformin was well tolerated with one grade III/IV treatment-related adverse event (3%). Median PFS was 18.0 months (95% CI 14.0-21.6). Median OS was surprisingly long at 57.9 months (95% CI 28.0 – not estimable). For patients with recurred platinum sensitive disease, response to second-line therapy was 85%. Translational studies comparing metformin-treated tumors and historical controls found that metformin-treated tumors had a 2.6-fold decrease in ALDH+/CD133+ CSC (p&lt;0.0001). Consistent with this, metformin-treated tumor cells (i) had an increased sensitivity to cisplatin in vitro, (ii) maintained cisplatin sensitivity over time (p&lt;0.001), and (iii) demonstrated reduced ability to amplify CSC with serial passages (p&lt;0.001). To understand the mechanism of metformin-induced maintenance of platinum response, we evaluated tumor cells and carcinoma-associated mesenchymal stem cells (CA-MSC), cells in the TME we previously reported could increase “stemness” and chemotherapy resistance. While we could not identify significant changes in bulk tumor cells, analysis of DNA methylation in CA-MSC demonstrated metformin treatment resulted in an epigenetic shift. Suggesting CA-MSC alteration drives metformin impact, compared to control CA-MSC, CA-MSC from metformin-treated patients were unable to drive chemotherapy resistance ex vivo. In conclusion, this is the first prospective study of metformin in EOC patients. Metformin therapy was associated with better than expected overall survival, reduction in CSC number, and epigenetic modification of cells in the TME. This was associated with maintenance of platinum sensitivity in vitro and could explain the better than expected median overall survival. This work supports the use of metformin in phase III studies.
Citation Format: Ronald J. Buckanovich, Daniel Chan, Jessica Shank, Kent Griffith, Huihui Fan, Robert Szulawski, Kun Yang, Kevin Reynolds, Carolyn Johnston, Karen McLean, Shitanshu Uppal, Rebecca Liu, Laura Cabrera, Sarah Taylor, Hui Shen, Geeta Mehta, Lan Coffman. A phase II study of metformin therapy in ovarian cancer with translational endpoints [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A07.