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Open Access 01-12-2022 | Breast Cancer | Research

Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials

Authors: Federica Bellerba, Anastasia Chrysovalantou Chatziioannou, Paniz Jasbi, Nivonirina Robinot, Pekka Keski-Rahkonen, Amarine Trolat, Béatrice Vozar, Sheri J. Hartman, Augustin Scalbert, Bernardo Bonanni, Harriet Johansson, Dorothy D. Sears, Sara Gandini

Published in: Journal of Translational Medicine | Issue 1/2022

Abstract

Background

Obesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment.

Methods

Fasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment.

Results

Participants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism.

Conclusions

Our results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies.

Trial registration

ClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.

Available only for authorised users

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Title: Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials
Authors: Federica Bellerba
Anastasia Chrysovalantou Chatziioannou
Paniz Jasbi
Nivonirina Robinot
Pekka Keski-Rahkonen
Amarine Trolat
Béatrice Vozar
Sheri J. Hartman
Augustin Scalbert
Bernardo Bonanni
Harriet Johansson
Dorothy D. Sears
Sara Gandini
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Breast Cancer
Metformin
Breast Cancer
Theophylline
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03809-6

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Keynote webinar | Spotlight on medication adherence

Springer Medicine

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Other articles of this Issue 1/2022

NAD(P)H: quinone oxidoreductase 1 attenuates oxidative stress and apoptosis by regulating Sirt1 in diabetic nephropathy

Assessing the causal association between human blood metabolites and the risk of epilepsy

Tumor angiogenesis at baseline identified by 18F-Alfatide II PET/CT may predict survival among patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy

A narrative review of the moderating effects and repercussion of exercise intervention on osteoporosis: ingenious involvement of gut microbiota and its metabolites

Identifying CCR5 coreceptor populations permissive for HIV-1 entry and productive infection: implications for in vivo studies

Membrane progesterone receptor α (mPRα) enhances hypoxia-induced vascular endothelial growth factor secretion and angiogenesis in lung adenocarcinoma through STAT3 signaling

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