banda transcan 2 2016ul

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


Project Coordinator:
Bernardo BONANNI (Italy) Istituto Europeo di Oncologia, Milan


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


Project Abstract:
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.

Final Publishable Summary:
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.

 

(Project funded under JTC 2013)


TRANSCAN News

Launch of the call: JTC 2021
The new TRANSCAN-3 project consortium is launching the first Joint Transnational Call for proposals, co-funded by the European Commission, on:
"Next generation cancer immunotherapy: targeting the tumour microenvironment"

International Networking Event (virtual)
on 22 April 2021 hrs 9:00 CET
will focus on the forthcoming co-funded JTC 2021 on:
"Next generation cancer immunotherapy: targeting the tumour microenvironment" 
the event is organized by TUBITAK under the “Turkey in Horizon 2020 Phase II” Technical Assistance Project
in cooperation with TRANSCAN-3

ERA-NET Cofund TRANSCAN-3:
 Sustained collaboration of national and regional programmes in cancer research
is the new project funded by the European Commission under H2020  which started on 1st March 2021 and will last five years (G. A. no. 964264)

A TRANSCAN-2 brochure, highlighting key achievements, is available for download

 

eu flagship

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 643638.

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