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

• Published in: Oncotarget Vol. 9; no. 86; pp. 35687 - 35704
• Main Authors: Martin-Castillo, Begoña, Pernas, Sonia, Dorca, Joan, Álvarez, Isabel, Martínez, Susana, Pérez-Garcia, Jose Manuel, Batista-López, Norberto, Rodríguez-Sánchez, César A, Amillano, Kepa, Domínguez, Severina, Luque, Maria, Stradella, Agostina, Morilla, Idoia, Viñas, Gemma, Cortés, Javier, Cuyàs, Elisabet, Verdura, Sara, Fernández-Ochoa, Álvaro, Fernández-Arroyo, Salvador, Segura-Carretero, Antonio, Joven, Jorge, Pérez, Elsa, Bosch, Neus, Garcia, Margarita, López-Bonet, Eugeni, Saidani, Samiha, Buxó, Maria, Menendez, Javier A
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 02-11-2018
• Subjects: Research Paper; trastuzumab; breast cancer; metformin; HER2
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.26286

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],
= 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (
= 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.