Abstract PD03-03: Pre-surgical Trial of Metformin in Overweight and Obese, Multi-ethnic Patients with Newly Diagnosed Breast Cancer
Authors: Kalinsky K , Crew KD , Refice S , Wang A , Feldman SM , Taback B , Hibshoosh H , Maurer M , Hershman DL 
Published: August 2014

Abstract
Background: Overweight or obese women with breast cancer (BC) have a higher risk of distant recurrence and death compared to normal weight women. There is increasing evidence that insulin significantly mediates these adverse clinical outcomes. Laboratory and population studies demonstrate that metformin offers a protective BC effect through reduction of serum insulin levels and direct modulation of cellular protein synthesis and growth through AMPK pathway signaling. Our aim is to assess the biologic impact of metformin on blood- and tumor-based markers on insulin, IGF and AMPK/mTOR pathway signaling, and/or proliferation in operable BC patients with a body mass index (BMI) ≥ 25 kg/m2.
Methods: The study was an open-label pre-surgical trial with metformin 1500 mg PO per day (500 mg am/1000 mg pm) for 2–4 weeks prior to surgical resection in 35 overweight or obese patients with invasive BC (n = 25) or ductal carcinoma in situ (n = 10) and no history of diabetes. The primary endpoint was to assess a reduction in tumor proliferation. We have 80% power to detect a 30% decrease in Ki-67 in invasive BCs from baseline to post-metformin values (two-sample t-test, 0.05). Secondary endpoints include changes in BMI and insulin resistance markers, such as fasting serum insulin, lipid panel, glucose, leptin, and adiponectin. Tumor markers will be compared to untreated historical controls matched by age, BMI, and tumor characteristics.
Results: Between Oct 2009 to Aug 2011, we screened 116 patients, enrolling 35 with newly diagnosed BC: 18/34 overweight (27.6: 25.1–29.7) and 16/34 obese (35.9: 30.5–46.4). Hispanic women made up 80% of the population (28/35). The median metformin duration was 22 days (1–64). All took metformin until the evening prior to surgery, except 2 (1 withdrew and 1 stopped early after surgery delay). More than half had a prior diagnosis of hypertension and a third had hypercholesterolemia. In the invasive BC cohort (n = 25), 19/25 (76%) were HR+/HER2−. The most common grade I-II included self-limiting diarrhea, flatulence, abdominal pain, fatigue, and anorexia. Grade III events included abdominal pain (n = 1) and diarrhea (n = 3). The change in blood markers are described in the table. Tumor Ki-67 (immunohistochemistry) and pathway signaling analyses (reverse protein microarray) are ongoing.

Conclusions: Our study is unique to other pre-surgical metformin trials due to the enrichment of overweight/obese BC patients and the ethnically diverse population. We observed a significant decrease in serum cholesterol and leptin with metformin, and a trend toward lower insulin, HOMA, and adiponectin. No significant changes in glucose or IGFP-3 levels are noted. We are awaiting tumor-based biomarker evaluation. Pre-surgical trials can assess an agent's biological effect prior to long-term intervention trials.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-03.