MetBreCS

A randomized placebo controlled phase II study with Metformin in metabolic-unbalanced breast cancer survivors at higher risk for recurrence

Consortium Project abstract Final Summary

Project Coordinator

Bernardo BONANNI
- Istituto Europeo di Oncologia
- Milan - Italy

Project Partners

Augustin SCALBERT
- International Agency for Research on Cancer (IARC)
- Lyon - France
Gunnar MELLGREN
- University of Bergen, Haukeland University Hospital
- Bergen - Norway

Background: Metabolic unbalanced conditions, which can include the presence of metabolic syndrome, weight gain, central obesity, elevated serum insulin and glucose levels, and insulin resistance, have been strongly associated with breast cancer (BC) recurrence and worse outcomes after treatment. Preclinical and clinical studies have demonstrated the efficacy of metformin, the oral insulin-sensitizing drug most widely prescribed for the treatment of type 2 diabetes, to inhibit the growth of BC cells. In particular, a recent pre-surgical clinical study has shown the efficacy of 4 weeks of metformin to reduce Ki-67 (now fully considered a standard surrogate biomarker to test the activity of candidate drugs) in BC cells specifically in metabolic unbalanced subjects.
Hypothesis: We think that this commonly used and cheap oral anti-diabetic drug, given for 1 year, may decrease epithelial cells proliferation also in healthy, metabolic unbalanced BC survivors. Moreover it may favorably modulate various translational risk factors related to the target tissue and the host characteristics. Thus we hypothesize that these effects may induce a possible reduction of early and late BC recurrence/second primary.
Study design: We propose a randomized, placebo-controlled, phase II study (1 year of accrual, 1 year of treatment, and 1 year of follow-up and analysis of results) with metformin/placebo in 236 pre- and postmenopausal (aged 18-70), metabolic unbalanced (BMI >25 Kg/m2) BC survivors at higher risk for recurrence. We will randomize non-diabetic patients with prior triple negative BC (TNBC), or estrogen receptor (ER) negative progesterone receptor (PgR) negative HER2 positive BC, or Luminal B HER2 positive BC at the end of standard adjuvant therapies (no later than 2 years from the cessation). The Primary Endpoint is the effect of treatment on the change of Ki-67 in contralateral unaffected breast biopsies after 12 months of treatment. Secondary Endpoints are the effects of metformin on a series of circulating and molecular biomarkers, the validation of metformin anticancer-action pathways, and various transcriptomics, epigenomics and metabolomics analyses. Safety and toxicity of the treatment will be additional endpoints.The joint effort of our research consortium will contribute to better elucidate the clinical and molecular effects of metformin and to confirm its role in tertiary prevention of high risk patients.

Preclinical and clinical studies have demonstrated the efficacy of metformin, the oral insulin-sensitizing drug most widely prescribed for the treatment of type 2 diabetes, to inhibit the growth of breast cancer (BC) cells. In particular, a previous pre-surgical clinical study has shown the efficacy of metformin to reduce Ki-67 LI in BC cells in metabolic unbalanced subjects.

We have conducted a randomized, placebo-controlled, phase II study with metformin/placebo in metabolic unbalanced BC survivors at higher risk for recurrence. We hypothesized that metformin decreases epithelial cells proliferation (Ki-67 LI) in breast cells thus inducing a possible reduction of early and late BC recurrence/second primary.

As results, we have shown that metformin favourably modulated the breast cancer risk biomarkers leptin, testosterone, androstenedione and estradiol. In line with its inhibition ability of oxidative phosphorylation at the mitochondrial level, metformin was associated with decreased levels of citrulline, arginine, tyrosine and increased levels of leucine, proline, isoleucine, and alanine. The epigenetics studies have shown that chromosomal regions associated with some genes (LEP, GRIK5, WFS1, HYOU1 and HRAS) were significantly differentially methylated between the metformin and placebo treatment arms of the study. By the use of a panel of genetic polymorphisms we genotyped the single nucleotide polymorphisms (SNPs) of the adiponectin receptor 1. insulin receptor, the organic cation transporter OCT1 and OCT 2, and STK11 in order to show how these may be able to predict metformin response: a clear trend to differential drug response was evidenced according to specific genotypes thus providing information to select participants into subgroups that may best benefit from a specific prevention program.

Our study results contribute to improve the understanding of the biological and clinical effects of metformin and may be relevant for its further application in cancer precision medicine with particular focus on cancer prevention.

Co-funded by the European union

Funded by the European Union under the Horizon Europe Framework Programme - Grant Agreement Nº: 101095654. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them.

Legal Notice | Privacy Policy