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, Javier A Menendez, 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, Javier A Menendez

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.

Keywords: HER2; breast cancer; metformin; trastuzumab.

Conflict of interest statement

CONFLICTS OF INTEREST The authors declared that they have no competing interests.

Figures

Figure 1. METTEN trial profile
Figure 1. METTEN trial profile
CONSORT diagram summarizing disposition of patients in the METTEN study. (mITT: modified intention-to-treat; PP: per-protocol).
Figure 2. METTEN study design
Figure 2. METTEN study design
Stratification factors: age, extent of disease (cT2 cN0-1 vs ≥ cT3 or ≥ cN2), and hormone receptor (HR) status. Primary endpoint: pCR in breast and axilla. (HER2, human epidermal growth factor receptor; LVEF, left ventricular ejection fraction; pCR, pathological complete response).
Figure 3. Circulating serum metformin
Figure 3. Circulating serum metformin
Box plots indicating median (black lines within the boxes), interquartile ranges, whiskers and ranges for post-treatment levels of circulating serum metformin (μmol/L; N = 20). (pCR: pathological complete response).
Figure 4. Left ventricular ejection fraction (LVEF)…
Figure 4. Left ventricular ejection fraction (LVEF) per treatment arm
Box plots indicating median (black lines within the boxes), interquartile ranges, whiskers and ranges for LVEF at baseline, after 12–13 weeks, and at the end of therapy.

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