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Research Paper|Volume 11, Issue 9|pp 2874—2888

Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients

Elisabet Cuyàs1,2, Salvador Fernández-Arroyo3, Maria Buxó2, Sonia Pernas4, Joan Dorca5, Isabel Álvarez6,7, Susana Martínez8, Jose Manuel Pérez-Garcia9, Norberto Batista-López10, César A. Rodríguez-Sánchez11,12, Kepa Amillano13, Severina Domínguez14, Maria Luque15, Idoia Morilla4, Agostina Stradella4, Gemma Viñas5, Javier Cortés9,16, Sara Verdura1,2, Joan Brunet5,17,18, Eugeni López-Bonet19, Margarita Garcia20, Samiha Saidani21, Jorge Joven3, Begoña Martin-Castillo21, Javier A. Menendez1,2
  • 1Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain
  • 2Girona Biomedical Research Institute (IDIBGI), Girona, Spain
  • 3Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Rovira i Virgili University, Reus, Spain
  • 4Department of Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
  • 5Medical Oncology, Catalan Institute of Oncology, Girona, Spain
  • 6Medical Oncology Service, Hospital Universitario Donostia, Donostia-San Sebastián, Spain
  • 7Biodonostia Health Research Institute, Donostia-San Sebastián, Spain
  • 8Medical Oncology Department, Hospital de Mataró, Mataró, Barcelona, Spain
  • 9IOB Institute of Oncology, Hospital Quirónsalud, Madrid and Barcelona, Spain
  • 10Medical Oncology Service, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain
  • 11Medical Oncology Service, Hospital Universitario de Salamanca, Salamanca, Spain
  • 12Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
  • 13Medical Oncology, Hospital Universitari Sant Joan, Reus, Spain
  • 14Medical Oncology Service, Hospital Universitario Araba, Vitoria-Gasteiz, Spain
  • 15Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain
  • 16Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
  • 17Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet del Llobregat, Barcelona, Spain
  • 18Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI), Girona, Spain
  • 19Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Spain
  • 20Clinical Research Unit, Catalan Institute of Oncology, L’Hospitalet de Llobregat, Barcelona, Spain
  • 21Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain

* * Equal contribution

Received: April 1, 2019Accepted: May 4, 2019Published: May 9, 2019
https://doi.org/10.18632/aging.101960

Copyright: Cuyàs et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.