Research Papers:

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

Begoña Martin-Castillo _, Sonia Pernas, Joan Dorca, Isabel Álvarez, Susana Martínez, Jose Manuel Pérez-Garcia, Norberto Batista-López, César A. Rodríguez-Sánchez, Kepa Amillano, Severina Domínguez, Maria Luque, Agostina Stradella, Idoia Morilla, Gemma Viñas, Javier Cortés, Elisabet Cuyàs, Sara Verdura, Álvaro Fernández-Ochoa, Salvador Fernández-Arroyo, Antonio Segura-Carretero, Jorge Joven, Elsa Pérez, Neus Bosch, Margarita Garcia, Eugeni López-Bonet, Samiha Saidani, Maria Buxó and Javier A. Menendez

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Oncotarget. 2018; 9:35687-35704. https://doi.org/10.18632/oncotarget.26286

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Begoña Martin-Castillo1,*, Sonia Pernas2,*, Joan Dorca3, Isabel Álvarez4,5, Susana Martínez6, Jose Manuel Pérez-Garcia7, Norberto Batista-López8, César A. Rodríguez-Sánchez9,10, Kepa Amillano11, Severina Domínguez12, Maria Luque13, Agostina Stradella2, Idoia Morilla2, Gemma Viñas3, Javier Cortés14, Elisabet Cuyàs15, Sara Verdura15, Álvaro Fernández-Ochoa16,17, Salvador Fernández-Arroyo18, Antonio Segura-Carretero16,17, Jorge Joven18, Elsa Pérez19, Neus Bosch1,20, Margarita Garcia21, Eugeni López-Bonet22, Samiha Saidani1,20, Maria Buxó20 and Javier A. Menendez14,23

1Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain

2Department of Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain

3Medical Oncology, Catalan Institute of Oncology, Girona, Spain

4Medical Oncology Service, Hospital Universitario Donostia, Donostia-San Sebastián, Spain

5Biodonostia Health Research Institute, Donostia-San Sebastián, Spain

6Medical Oncology Department, Hospital de Mataró, Mataró, Barcelona, Spain

7Baselga Institute of Oncology (IOB), Hospital Quirón, Barcelona, Spain

8Medical Oncology Service, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain

9Medical Oncology Service, Hospital Universitario de Salamanca, Salamanca, Spain

10Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain

11Medical Oncology, Hospital Universitari Sant Joan, Reus, Spain

12Medical Oncology Service, Hospital Universitario Araba, Vitoria-Gasteiz, Spain

13Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain

14Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain

15Metabolism and Cancer Group, Girona Biomedical Research Institute, Girona, Spain

16Department of Analytical Chemistry, University of Granada, Granada, Spain

17Research and Development of Functional Food Centre (CIDAF), Health Science Technological Park, Granada, Spain

18Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain

19Department of Radiology-IDI, Dr. Josep Trueta Hospital of Girona, Girona, Spain

20Girona Biomedical Research Institute (IDIBGI), Girona, Spain

21Clinical Research Unit, Catalan Institute of Oncology, L’Hospitalet de Llobregat, Barcelona, Spain

22Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Spain

23Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain

*These authors contributed equally to this work

Correspondence to:

Begoña Martin-Castillo, email: [email protected]

Javier A. Menendez, email: [email protected], [email protected]

Keywords: metformin; breast cancer; HER2; trastuzumab

Received: August 29, 2018     Accepted: October 21, 2018     Published: November 02, 2018


The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; OR 1.34 [95% CI: 0.46–3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6–8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

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