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

Journal of Translational Medicine

Research

Dorothy D. Sears¹  Paniz Jasbi²  Federica Bellerba³  Sara Gandini³  Harriet Johansson⁴  Bernardo Bonanni⁴  Sheri J. Hartman⁵  Anastasia Chrysovalantou Chatziioannou⁶  Augustin Scalbert⁶  Pekka Keski-Rahkonen⁶  Nivonirina Robinot⁶  Béatrice Vozar⁶  Amarine Trolat⁶ 

[1] College of Health Solutions, Arizona State University, Phoenix, AZ, USA;Moores Cancer Center, UC San Diego, La Jolla, CA, USA;Department of Medicine, UC San Diego, La Jolla, CA, USA;College of Health Solutions, Arizona State University, Phoenix, AZ, USA;School of Molecular Sciences, Arizona State University, Tempe, AZ, USA;Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy;Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Via Giuseppe Ripamonti 435, 20141, Milan, Italy;Herbert Wertheim School of Public Health and Human Longevity Science, UC San Diego, La Jolla, CA, USA;Moores Cancer Center, UC San Diego, La Jolla, CA, USA;International Agency for Research on Cancer, Nutrition and Metabolism Branch, Lyon, France;

关键词: Cancer;    Recurrence;    Metabolic syndrome;    Prevention;    Lipids;    Weight loss;   

DOI  :  10.1186/s12967-022-03809-6

 received in 2022-09-07, accepted in 2022-12-05,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundObesity 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.MethodsFasting 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.ResultsParticipants (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.ConclusionsOur 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 registrationClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.

【 授权许可】

CC BY   
© The Author(s) 2022

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