The Effect of Neoadjuvant Metformin on Breast Cancer Related Genes Clinical Trial – A Preliminary Result.

Abstract

Abstract Other authoring group: Dougal Adamson, Lee Baker, Douglas C Brown, Sally Chalmers, Amanda Degabriele, Janet Flinn, Kenneth Fowler, Avril Gunning, Grahame Hardie, Julie Lindsay, Gillian Little, Denis McLean, Robert Murdoch, Colin Purdie, Marta Reis, Valerie Walker.IntroductionMetformin, used in the treatment of diabetes for 50 years, has been linked to a reduced incidence of breast cancer and to an enhanced pathological response when administered concurrent with neoadjuvant chemotherapy. It has been postulated that the anti-neoplastic effect of metformin is through activation of AMP-activated protein Kinase (AMPK). The aim of this open label, randomised clinical trial was to investigate the effect of neoadjuvant metformin on gene expression in primary breast cancer.MethodsNon-diabetic women with histologically proven, operable, primary invasive breast cancer of ≥1cm in size were offered the trial following regional Research Ethics Committee approval.The trial had 2 arms, A and B: in arm A (8 patients), patients had core biopsies at three time points: one at presentation; one after a week of no treatment (internal control); and a further biopsy at the time of definitive surgery after at least 2 weeks of metformin. In trial arm B (47 patients), patients had core biopsies at two time points: one before randomisation to either take metformin or not, and one at the time of definitive breast surgery. Metformin was given as 500mg o.d. orally for one week, increased to 1g b.d. orally for at least another week and until the day prior to excisional breast surgery.RNA was extracted from formalin fixed cores and examined using a Disease-Specific Array for breast cancer on an Affymetrix platform (ALMAC Diagnostics Group, Craigavon, UK). Subsequent confirmatory polymerase chain reaction and immunohistochemistry techniques were used to examine the histological material.ResultsType of results expected:[Change of target gene expression in response to neoadjuvant metformin; symptomatic drug toxicities; potential for therapeutic effects of metformin in non-diabetic patients in vivo.]Results from the first arm:The triplet of core biopsies from 6/8 (75%) of the A arm patients passed the GeneGhip QC and data integrity assessment. Patients were 41-65 (mean: 53) years, with IDC NST, grade II-III, and all ER positive. 270 genes were differentially expressed significantly by wounding, and 63 by metformin. Among the genes significantly over-expressed by metformin were AMPK-beta and PI3K; and those down regulated by metformin were AMPK-gamma and ADCY1. Samples from the B arm patients are in analysis.ConclusionThe gene expression changes identified in response to neoadjuvant metformin suggest that metformin improves DNA damage recognition and repair and regulates cancer cell metabolism. These results suggest mechanisms by which metformin could be efficacious in the treatment of breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3145.