Abstract A24: Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer

Abstract

Abstract There is great interest in the effects on cancer metabolism of the diabetes drug, metformin and its potential as a cancer treatment. Despite intense investigation it is still not clear as to its metabolic effects on primary human cancer in vivo. 41 patients with primary breast cancer were recruited to a ‘window of opportunity study’ prior to neoadjuvant chemotherapy. Before and after 2 weeks of metformin, dynamic 18F-FDG PET-CT scans were carried out, breast core biopsies of the primary tumour taken for RNASeq, metabolomics and immunohistochemistry analysis and host serum metabolic markers assessed. Metabolomic mass spectrometry analysis revealed an increase in the ADP/ATP and AMP/ATP ratio (fold change 8.6 and 24.9, respectively, p = 0.07 and p = 0.14) after metformin treatment. RNA sequencing of the first 21 paired samples showed upregulation of many genes encoding components of complex 1, and the TCA cycle, glutaminolysis, and glycolysis pathways. Several genes encoding for glucose and glutamine transport were amongst those most consistently upregulated, including GLUT1, SLC38A1 and SLC7A5 (all p<0.0001). Dynamic PET-CT analysis of the first 17 paired scans demonstrated a trend toward a decrease in the variable K2 post-metformin (an estimate of 18F-FDG efflux from tumour intracellular pool back to blood), but with much variability between paired scans (0.70±0.11 vs 0.51±0.05 (p=0.14)). There was a decrease in serum C-peptide (0.56±0.04nmol/L vs 0.48±0.02nmol/L, pre- and post-metformin, p=0.003) consistent with reduced host insulin secretion. This is the first study in the clinical setting to show that metformin can cause an energy stress in cancer cells. The effect on mRNA expression was compatible with direct mitochondrial effects on the cancer cell leading to upregulation of the glutaminolysis and glycolysis pathways. The decrease in efflux of radiolabelled glucose may indicate retention of glucose possibly secondary to changes in blood glucose availability. We expect this study will help define biomarker development and future treatment strategies for metformin, in particular potential combination therapy. Note: This abstract was not presented at the conference. Citation Format: Simon R. Lord, Nilay Patel, D. Liu, J. Fenwick, C. Frezza, S. Henriques da Costa, E. Gaude, Q. Zhang, M. Wakelam, F. Gleeson, S. Haider, F. Buffa, A. L. Harris. Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A24.