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

Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain. Girona Biomedical Research Institute (IDIBGI), Girona, Spain. Unitat de Recerca Biomèdica, Hospital Universitari de Sant Joan, IISPV, Rovira i Virgili University, Reus, Spain. Department of Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. Medical Oncology, Catalan Institute of Oncology, Girona, Spain. Medical Oncology Service, Hospital Universitario Donostia, Donostia-San Sebastián, Spain. Biodonostia Health Research Institute, Donostia-San Sebastián, Spain. Medical Oncology Department, Hospital de Mataró, Mataró, Barcelona, Spain. IOB Institute of Oncology, Hospital Quirónsalud, Madrid and Barcelona, Spain. Medical Oncology Service, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain. Medical Oncology Service, Hospital Universitario de Salamanca, Salamanca, Spain. Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain. Medical Oncology, Hospital Universitari Sant Joan, Reus, Spain. Medical Oncology Service, Hospital Universitario Araba, Vitoria-Gasteiz, Spain. Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain. Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI), Girona, Spain. Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Spain. Clinical Research Unit, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain. Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain.

Aging. 2019;(9):2874-2888
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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.

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Publication Type : Clinical Trial ; Clinical Trial

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