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
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Abstract
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
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.
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