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

2018; Impact Journals LLC; Volume: 9; Issue: 86 Linguagem: Inglês

10.18632/oncotarget.26286

1949-2553

Begoña Martı́n-Castillo, Sònia Pernas, Joan Dorca, Isabel Álvarez, Susana Torres, José Manuel Pérez-García, Norberto Batista-López, César Augusto Rodríguez‐Sánchez, Kepa Amillano, Severina Domínguez, M. 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‐Sierra, Margarita García, Eugeni López‐Bonet, Samiha Saidani, María Buxó, Javier A. Menéndez,

Advanced Breast Cancer Therapies

// Begoña Martin-Castillo 1, * , Sonia Pernas 2, * , Joan Dorca 3 , Isabel Álvarez 4, 5 , Susana Martínez 6 , Jose Manuel Pérez-Garcia 7 , Norberto Batista-López 8 , César A. Rodríguez-Sánchez 9, 10 , Kepa Amillano 11 , Severina Domínguez 12 , Maria Luque 13 , Agostina Stradella 2 , Idoia Morilla 2 , Gemma Viñas 3 , Javier Cortés 14 , Elisabet Cuyàs 15 , Sara Verdura 15 , Álvaro Fernández-Ochoa 16, 17 , Salvador Fernández-Arroyo 18 , Antonio Segura-Carretero 16, 17 , Jorge Joven 18 , Elsa Pérez 19 , Neus Bosch 1, 20 , Margarita Garcia 21 , Eugeni López-Bonet 22 , Samiha Saidani 1, 20 , Maria Buxó 20 and Javier A. Menendez 14, 23 1 Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain 2 Department of Medical Oncology, Breast Unit, Catalan Institute of Oncology-Hospital Universitari de Bellvitge-Bellvitge Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain 3 Medical Oncology, Catalan Institute of Oncology, Girona, Spain 4 Medical Oncology Service, Hospital Universitario Donostia, Donostia-San Sebastián, Spain 5 Biodonostia Health Research Institute, Donostia-San Sebastián, Spain 6 Medical Oncology Department, Hospital de Mataró, Mataró, Barcelona, Spain 7 Baselga Institute of Oncology (IOB), Hospital Quirón, Barcelona, Spain 8 Medical Oncology Service, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain 9 Medical Oncology Service, Hospital Universitario de Salamanca, Salamanca, Spain 10 Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain 11 Medical Oncology, Hospital Universitari Sant Joan, Reus, Spain 12 Medical Oncology Service, Hospital Universitario Araba, Vitoria-Gasteiz, Spain 13 Department of Medical Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain 14 Department of Medical Oncology, Ramón y Cajal University Hospital, Madrid, Spain 15 Metabolism and Cancer Group, Girona Biomedical Research Institute, Girona, Spain 16 Department of Analytical Chemistry, University of Granada, Granada, Spain 17 Research and Development of Functional Food Centre (CIDAF), Health Science Technological Park, Granada, Spain 18 Unitat de Recerca Biomèdica, Hospital Universitari Sant Joan, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Reus, Spain 19 Department of Radiology-IDI, Dr. Josep Trueta Hospital of Girona, Girona, Spain 20 Girona Biomedical Research Institute (IDIBGI), Girona, Spain 21 Clinical Research Unit, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain 22 Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Spain 23 Program 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: bmartin@iconcologia.net Javier A. Menendez, email: jmenendez@iconcologia.net , jmenendez@idibgi.org Keywords: metformin; breast cancer; HER2; trastuzumab Received: August 29, 2018 Accepted: October 21, 2018 Published: November 02, 2018 ABSTRACT 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.