Metformin with neoadjuvant chemotherapy in localized triple-negative and Her2neu-positive breast cancer: A prospective phase 2 open-label randomized controlled trial (McBETH).
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PURPOSE: HER2-positive and triple-negative breast cancers (TNBC) are aggressive subtypes with poor outcomes. Metformin, a commonly used antidiabetic agent, has demonstrated anticancer potential in preclinical studies. This trial evaluated whether the addition of metformin to neoadjuvant chemotherapy (NACT) improves pathological complete response (pCR) rates in nondiabetic patients with localized HER2-positive or TNBC. PATIENTS AND METHODS: In this open-label, phase 2 randomized controlled trial, 242 chemotherapy-naïve, nondiabetic women aged 18-65 years with localized, resectable HER2-positive or TNBC were randomized 1:1 to receive standard NACT with or without metformin (850 mg orally twice daily until surgery). The primary endpoint was pCR (ypT0/ypN0). Secondary endpoints included subgroup pCR rates, clinical response, breast-conserving surgery rates, adverse events, patient-reported outcomes (ESAS-r), and cognitive function (FACT-Cog v3). RESULTS: A total of 112 patients in the metformin arm and 115 in the standard arm underwent surgery and were included in the efficacy analysis. The metformin group had a higher proportion of advanced T3/T4 tumors (55.4% vs. 42.3%). Overall pCR rates were 43.7% in the metformin group and 41.7% in the control group (p = .75). In the HER2-positive subgroup, pCR was higher with metformin (46.3% vs. 36.5%, p = .27). Breast-conserving surgery rates, clinical response, and patient-reported outcomes were similar between groups. Metformin was well tolerated; fewer patients experienced peripheral neuropathy (37.2% vs. 45.5%), but diarrhea was more frequent (26.6% vs. 10.7%). CONCLUSION: Metformin did not significantly improve pCR when added to standard NACT. However, trends in HER2-positive patients and reduced neuropathy merit further investigation.