Abstract OT2-6-06: Pre-surgical “window of opportunity” trial of metformin and atorvastatin in newly diagnosed operable breast cancer
Authors: Kalinsky K , Baer L , Tsai WY , Ngan MC , Feldman SM , Taback B , Ananthakrishnan P , Chen-Seetoo M , Hibshoosh H , Crew KD , Maurer MA , Hershman DL 
Published: August 2014

Abstract
Background: Breast cancer requires energy homeostasis shifts with enhanced anabolism to enable rapid growth and continued proliferation. The main energy regulatory system is the AMP-activated kinase (AMPK) pathway triggered by changes in the AMP/ATP ratio. AMPK pathway closely interacts with the PI3K/AKT signaling pathway, with both pathways affecting downstream function of the master regulator mTOR. “Window of opportunity” studies with metformin alone, an AMPK inhibitor, have resulted in mixed results in reducing tumor proliferation in women with early-stage operable breast cancer. Reduction in tumor proliferation has been demonstrated with statins alone (i.e. HMG CoA reductase inhibitors) in pre-surgical trials. Dual therapy with both metformin and atorvastatin demonstrate synergistic activity in preclinical studies in cancer cell lines, showing enhanced anti-proliferative effect. The purpose of this study is to determine the effects of dual therapy with metformin and atorvastatin in women with newly diagnosed BC between breast biopsy and surgery.
Trial Design: Patients (n = 40) will receive metformin 1500mg (500 mg am/1000 mg pm) and atorvastatin 80mg pm, for 2-4 weeks following a diagnostic biopsy and prior to surgery (goal: at least 2 weeks). The main eligibility criteria for this open-label, single-institution, pre-surgical trial include operable stage 0-III BC. Patients must have at least 1 cm of tumor based on palpation or imaging to ensure sufficient pre-treatment tissue. Patients not considered for neoadjuvant chemotherapy are eligible. Specific Aims: Our hypothesis is that pre-surgical metformin plus atorvastatin will result in a significant decrease in the tumor proliferation marker Ki-67. Ki-67 will be log-transformed ln(ki-67), per international guidelines. Secondary objectives include evaluation of functional proteomic changes, such as AMPK/mTOR pathway signaling and apoptosis, by reverse phase protein array (RPPA), as well as assessment of changes in serum insulin, lipids, and markers of the insulin growth factor pathway.
Statistical Methods: Paired t-tests will be calculated to assess modulations in ln(ki-67) before and after treatment. Compared to historical control, we will achieve 80% power with 40 patients, anticipating a -0.523 reduction of ln(ki-67) and standard deviation of 1.15 before and after metformin plus statin (significance level, p = 0.05). We will also be comparing changes in ln(ki-67) in the treated patients to historical controls matched by age, stage, and BMI, using a two-sample t-test at level 0.05. Frequency distributions and summary descriptive statistics will be calculated for all other biomarkers in the two groups. Correlations between all biomarkers and changes in Ki-67 proliferation marker will be analyzed in exploratory fashion. We will also explore differences in modulation of tumor proliferation and functional proteomics in grade III tumors as compared to other tumors. We anticipate accrual 2-3 patient/month, completing the trial within 18 months. Contact information: kk2693@columbia.edu.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-06.