1. Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients
- Author
-
Susana Martínez, Javier A. Menendez, Jose Perez-Garcia, Margarita Garcia, Maria Buxó, Jorge Joven, Kepa Amillano, César A Rodríguez-Sánchez, M. Luque, Javier Cortes, Gemma Viñas, Sara Verdura, Begoña Martin-Castillo, Eugeni López-Bonet, Agostina Stradella, Samiha Saidani, Elisabet Cuyàs, N. Batista-López, Joan Dorca, Salvador Fernández-Arroyo, Severina Domínguez, Joan Brunet, Sonia Pernas, Idoia Morilla, Isabel Alvarez, Institut Català de la Salut, [Cuyàs E] Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain. Girona Biomedical Research Institute (IDIBGI), Girona, Spain. [Fernández-Arroyo S] Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Rovira i Virgili University, Reus, Spain. [Buxó M] Girona Biomedical Research Institute (IDIBGI), Girona, Spain. [Pernas S] Department of Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain. [Dorca J] Medical Oncology, Catalan Institute of Oncology, Girona, Spain. [Álvarez I] Medical Oncology Service, Hospital Universitario Donostia, Donostia-San Sebastián, Spain. Biodonostia Health Research Institute, Donostia-San Sebastián, Spain. [Cortés J] IOB Institute of Oncology, Hospital Quirónsalud, Madrid and Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, and Hospital Universitari Vall d'Hebron
- Subjects
Aging ,Homocysteine ,Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES] ,Breast Neoplasms ,Pharmacology ,Cancer -- Treatment ,Càncer de mama ,chemistry.chemical_compound ,Therapeutic index ,Breast cancer ,Organic Chemicals::Amidines::Guanidines::Biguanides::Metformin [CHEMICALS AND DRUGS] ,breast cancer ,Mama - Càncer ,Trastuzumab ,medicine ,Humans ,Hypoglycemic Agents ,Breast -- Cancer ,Metformina ,Nutrició ,Nutrition ,Otros calificadores::Otros calificadores::/metabolismo [Otros calificadores] ,neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES] ,3-Hydroxybutyric Acid ,business.industry ,compuestos orgánicos::amidinas::guanidinas::biguanidas::metformina [COMPUESTOS QUÍMICOS Y DROGAS] ,Cancer ,Other subheadings::Other subheadings::/metabolism [Other subheadings] ,Cell Biology ,homocysteine ,Middle Aged ,medicine.disease ,Metabolisme ,Metformin ,Regimen ,chemistry ,ketogenic diet ,ketone bodies ,Mama -- Càncer ,Biomarker (medicine) ,Folic Acid Antagonists ,Cèl·lules canceroses ,Female ,Càncer -- Tractament ,business ,medicine.drug ,Research Paper - Abstract
Homocisteïna; Càncer de mama; Dieta cetogènica Homocisteína; Cáncer de mama; Dieta cetogénica Homocysteine; Breast cancer; Ketogenic diet Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the “drug plus diet” approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body β-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response. This work was supported by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad (EC10-125, Ayudas para el Fomento de la Investigación Clínica Independiente to Begoña Martin-Castillo). Work in the Menendez laboratory is supported by the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P, Plan Nacional de l+D+I, founded by the European Regional Development Fund [EU FEDER], Spain) and by an unrestricted research grant from the Fundació Oncolliga Girona (Lliga catalana d’ajuda al malalt de càncer, Girona).
- Published
- 2019