Abstract P3-07-22: Presurgical Trial of Metformin plus Atorvastatin in Women with Operable Breast Cancer

Abstract Introduction: Metformin is an oral anti-diabetic agent that exhibits direct anti-proliferative effects on pre-clinical models through activation of the AMPK pathway. However, pre-surgical studies of metformin alone among women with operable breast cancer have not consistently shown reductions in tumor proliferation, and adjuvant metformin in women with high-risk operable breast cancer did not improve invasive disease-free survival compared with placebo. Dysregulation of the mevalonate pathway of cholesterol synthesis can also lead to cell proliferation, and inhibition of HMG-CoA reductase by statins can decrease tumor proliferation. There is close interaction between the AMPK and mevalonate pathways, and dual therapy with a statin and metformin might be synergistic to decrease cell proliferation. We evaluated the effect of combination therapy with metformin plus atorvastatin on markers of proliferation (i.e. Ki67 proliferation index) in women with operable breast cancer. Methods: We conducted an open-label, single-arm presurgical “window of opportunity” study of metformin plus atorvastatin in non-diabetic women age 21+ years with newly-diagnosed stage 0-III operable breast cancer at Columbia University Irving Medical Center (CUIMC). Enrolled patients received metformin 1500mg oral [p.o.] daily (500mg in the morning/1000mg in the afternoon) and atorvastatin 80mg p.o. nightly for up to 4 weeks before breast surgery. The primary endpoint was change in Ki67 proliferation index from baseline (diagnostic biopsy) to post-treatment (surgical specimen). Secondary endpoints included change in body mass index (BMI), waist and hip circumferences, tumor assessment of AMPK/mTOR signaling and apoptosis, and reduction of fasting markers of the insulin growth factor pathway. Paired t-tests were conducted to assess difference in ln(Ki67) pre- and post-therapy, as well as differences in absolute Ki67, BMI, and waist/hip circumferences pre- and post-therapy, at a level of significance of 0.05. Results: Between Nov. 2013 and Jan. 2018, 22 women were enrolled, and two withdrew consent prior to study treatment. Among evaluable participants (n=20), 45% were Hispanic with median age 56 years (range, 33-73) and median baseline BMI 28.4 kg/m2 (range, 22.5-45.8). All had hormone receptor-positive (HR+), HER2-negative breast cancer, and 16 (80%) had invasive cancer. Median time on study treatment was 11 days (range, 5-29). Changes in Ki67 and anthropomorphic measures are shown in Table 1. There was no significant change in BMI, waist or hip circumference with study treatment. Among women with available Ki67 measurements (n=11), there was no significant difference in pre- and post-treatment ln(Ki67) (p=0.25). There was a numeric decrease in absolute Ki67, though statistical significance was not reached (p=0.09). Discussion: There was a numeric reduction in absolute Ki-67 with presurgical metformin plus atorvastatin in patients with newly diagnosed HR+/HER2- breast cancer, although our analysis was limited by small sample size and statistical significance was not achieved. There was no difference in ln(Ki67) or anthropometric measurements. Analyses of additional tissue and serum biomarkers, including markers of insulin resistance, are ongoing to identify associations with absolute Ki67 Table 1 Citation Format: Julia E. McGuinness, Katherine D. Crew, Meghna S. Trivedi, Melissa K. Accordino, Shing M. Lee, Hua Guo, Hanina Hibshoosh, Dawn Hershman, Kevin Kalinsky. Presurgical Trial of Metformin plus Atorvastatin in Women with Operable Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-22.