Abstract P1-02-03: Circulating inflammatory markers, growth factors, and tumor associated antigens in women with early stage breast cancer receiving neoadjuvant metformin
Authors: Dowling RJ , Niraula S , Chang MC , Ennis M , Stambolic V , Goodwin PJ 
Published: March 2017

Abstract
Background: Numerous clinical studies have reported that diabetic patients receiving metformin exhibit decreased cancer incidence and cancer related mortality. Metformin's mechanism of anti-tumor action has been attributed to both direct effects on cancer cells and systemic changes in insulin metabolism. Indeed, metformin reduces circulating insulin levels, which may be integral to its effectiveness in the breast cancer (BC) setting where hyperinsulinemia is associated with both recurrence and death. While the impact of metformin on blood glucose and insulin is well documented, its effects on other systemic physiologic and inflammatory factors are unknown. We completed a neoadjuvant "window of opportunity" study of metformin in non-diabetic women with BC and a series of analyses were performed on plasma samples to assess the impact of metformin on circulating inflammatory markers, growth factors, and tumor associated antigens.
Methods: Non-diabetic women with early stage, untreated BC were given metformin 500 mg tid for ≥2 weeks post diagnostic core biopsy until surgery. Fasting blood was collected at diagnosis and surgery to assess circulating markers pre- and post-metformin administration. Plasma was isolated from blood samples and evaluated for CRP, TNF-alpha, IL-6, IL-8, VEGF, EGF, PlGF (placenta growth factor), CA15-3, and SHBG (sex hormone binding globulin). Change scores (post-metformin minus pre-) were calculated and the degree of change characterized by the median change and the rank-biserial correlation. The Wilcoxon signed-rank test was used to test the null hypothesis that the change scores were symmetrically distributed around zero versus more positive or negative change.
Results: A total of 39 patients (mean age 51 years) completed the study and received metformin for a median of 18 days (range 13-40). Metformin was associated with changes in the levels of growth factors, with increases seen in EGF (median increase 1.1 pg/mL, r=0.42, p=0.027) and VEGF (1.7 pg/mL, r=0.31, p=0.09). A reduction in PlGF levels (-0.18 pg/mL, r=-0.6, p=0.0028) was also observed. The tumor associated antigen CA15-3 was significantly reduced after metformin treatment (-0.4 pg/mL, r=-0.56, p=0.0024) and a marker of sex hormone bioavailability (SHBG) was increased (2 nM, r=0.30, p=0.1). For circulating inflammatory markers, a significant increase in the levels of IL-8 (0.8 pg/mL, r=0.36, p=0.048) was observed, but changes in TNF-alpha and IL-6 were minimal (TNF-alpha 0.2 pg/mL, r=0.20, p=0.29; IL-6 0.1 pg/mL, r=0.14, p=0.46) and no change was seen in CRP (0 mg/L, r=-0.05, p=0.93).
Conclusions: Short-term metformin administration was associated with alterations in systemic physiologic and inflammatory factors. Such increases in circulating cytokines and growth factors indicate possible alterations in the inflammatory state of the host and/or tumor. Of note, the reduction seen in the tumor antigen CA15-3 may reflect a disease-modifying effect of metformin in BC.
The authors wish to acknowledge the generous support of the Hold'Em For Life Charity Challenge and the Breast Cancer Research Foundation.
Citation Format: Dowling RJ, Niraula S, Chang MC, Ennis M, Stambolic V, Goodwin PJ. Circulating inflammatory markers, growth factors, and tumor associated antigens in women with early stage breast cancer receiving neoadjuvant metformin [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-03.