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.
Highlights
Metformin, a biguanide derivative that reduces insulin levels, has long been a cornerstone in the treatment of type 2 diabetes (T2D)
Primary endpoint was the rate of pathological complete response in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% confidence intervals (CIs): 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; odds ratios (ORs) 1.34 [95% CI: 0.46–3.89], P = 0.589)
The study closed prematurely with a reduced sample size after 84 of 244 planned patients were randomly assigned: 41 enrolled patients were allocated to the metformin group and 43 patients to the non-metformin group
Summary
A biguanide derivative that reduces insulin levels, has long been a cornerstone in the treatment of type 2 diabetes (T2D). Notwithstanding the limitations of observational studies, many have consistently indicated that metformin can reduce the incidence, outcome, and mortality of BC in patients with T2D [1,2,3]. The extensive clinical experience accumulated from patients with T2D prescribed metformin, together with its well characterized and modest toxicity profile [7, 8], has significantly shortened the clinical evaluation path of metformin in cancer prevention and treatment [9,10,11]. Many clinical studies, including proof-of-principle studies in the prevention setting and phase 2 trials in the adjuvant and metastatic settings, have been planned and/or are currently under way to test the causal nature of the suggested correlation between metformin and clinical benefit in cancer
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