Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment.

Abstract The antidiabetic drug metformin has antitumor effects. We examined the outcome of 177 patients with type 2 diabetes mellitus who received surgery for breast cancer. Among them, 49 patients were treated with metformin. In those patients, recurrence in distant organs was less frequent and postoperative disease-free survival tended to be better than in those without metformin intake. In patients who received preoperative systemic therapy, the rate of pathologic complete response was higher in patients who were also treated with metformin ( P < 0.05). Multiplex immunohistochemical staining of resected tumors revealed that the density of tumor-associated macrophages (TAMs), especially of CD68(+)CD163(+) M2-type TAMs, was lower in tumors treated with metformin. In contrast, the rate of the CD8(+) phenotype among CD3(+) tumor-infiltrating lymphocytes was higher in the metformin-treated group. The results suggest that metformin can change the immune microenvironment from a protumorigenic to an antitumorigenic status, thus supporting a favorable outcome in patients with breast cancer and type 2 diabetes mellitus.