Effect of Metformin on Breast Cancer Metabolism

Summary

Metformin, a drug that has been used since the 1950's in the treatment of diabetes, has recently generated great interest in its anticancer effects based on in vitro, in vivo and clinical studies. This study assesses the pharmacodynamic effects of metformin on breast cancer metabolism. The trial design is based on a 2 centre study 'Early Antiangiogenic Response to Bevacizumab in Primary Breast Cancer' that is about to successfully complete recruitment in Oxford and Mount Vernon hospitals. The study takes advantage of the 2 week window between the first clinic visit and commencement of neoadjuvant chemotherapy. Metformin will be given to patients for at least 2 weeks prior to neoadjuvant chemotherapy with a set of 3 breast core biopsies, a PET-CT scan and blood tests carried out before and after this 2 week period of treatment. Patients will also receive a drink of heavy (deuterated) water, a safe and stable isotope commonly used in clinical lipid metabolism studies, the evening prior to both sets of core biopsies. Having completed the first 2 weeks of metformin patients will have the option of continuing metformin until completion of chemotherapy, at the discretion of the trial physician. The core biopsies will then be used to assess for changes in: * immunohistochemical staining; * gene profiles; * uptake of heavy water into tumour fatty acids using mass spectrometry techniques. The aim is to identify potential biomarkers of response to metformin (and other future cancer metabolism drugs).

Timeline

Start

2011-05

Primary completion

2014-05

Completion

2014-05

Publications

• Ralli GP, Carter RD, McGowan DR, Cheng WC, Liu D, Teoh EJ, Patel N, Gleeson F, Harris AL, Lord SR, Buffa FM, Fenwick JD. Radiogenomic analysis of primary breast cancer reveals [18F]-fluorodeoxglucose dynamic flux-constants are positively associated with immune pathways and outperform static uptake measures in associating with glucose metabolism. Breast Cancer Res. 2022 May 17;24(1):34. doi: 10.1186/s13058-022-01529-9.
• Lord SR, Collins JM, Cheng WC, Haider S, Wigfield S, Gaude E, Fielding BA, Pinnick KE, Harjes U, Segaran A, Jha P, Hoefler G, Pollak MN, Thompson AM, Roy PG, English R, Adams RF, Frezza C, Buffa FM, Karpe F, Harris AL. Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin. Br J Cancer. 2020 Jan;122(2):258-265. doi: 10.1038/s41416-019-0665-5. Epub 2019 Dec 10.
• Lord SR, Cheng WC, Liu D, Gaude E, Haider S, Metcalf T, Patel N, Teoh EJ, Gleeson F, Bradley K, Wigfield S, Zois C, McGowan DR, Ah-See ML, Thompson AM, Sharma A, Bidaut L, Pollak M, Roy PG, Karpe F, James T, English R, Adams RF, Campo L, Ayers L, Snell C, Roxanis I, Frezza C, Fenwick JD, Buffa FM, Harris AL. Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer. Cell Metab. 2018 Nov 6;28(5):679-688.e4. doi: 10.1016/j.cmet.2018.08.021. Epub 2018 Sep 20.

Drugs

Indications