Diabetic patients treated with metformin who have HER2-positive, hormone receptor (HR)–positive breast cancer have prolonged survival compared with diabetic patients not treated with metformin, according to an analysis of the ALTTO trial (ClinicalTrials.gov Identifier: NCT00490139) published in the Journal of Clinical Oncology.1

Patients with diabetes are more likely to have a poor prognosis compared with non-diabetics, and evidence suggests that metformin may have indirect and direct antitumor effects. The purpose of this substudy was to determine if metformin treatment improved breast cancer–related outcomes among patients with diabetes at enrollment.

In the ALTTO trial, 8381 patients with non-metastatic, completely excised HER2-positive breast cancer were randomly assigned to receive 1 year of trastuzumab, lapatinib, their sequence, or their combination. In this substudy, 186 patients had diabetes not treated with metformin, and 260 diabetic patients were treated with metformin.

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With a median follow-up time of 4.5 years, diabetic patients with HR-positive disease not treated with metformin had worse disease-free survival (hazard ratio [HR], 1.40; 95% CI, 1.01-1.94; P = .043), distant disease-free survival (HR, 1.56; 95% CI, 1.10-2.22; P = .013), and overall survival (HR, 1.87; 95% CI, 1.23-2.85; P = .004) compared with patients who received metformin.

There was no difference in outcomes relating to metformin treatment among patients with HR-negative disease.

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The authors suggested that the prolonged survival observed among patients with HR-positive, but not HR-negative, disease may be a result of several mechanisms. Metformin may reverse interactions between the Akt-mTOR pathway — which is downstream of insulin signaling — and hormone receptor signaling, and counteract the hormonal treatment–resistance that occurs via insulin signaling.


  1. Sonnenblick A, Agbor-Tarh D, Bradbury I, et al. Impact of diabetes, insulin, and metformin use on the outcome of patients with human epidermal growth factor receptor 2–positive primary breast cancer: analysis from the ALTTO phase III randomized trial. J Clin Oncol. 2017 March 13. doi: 10.1200/JCO.2016.69.7722 [Epub ahead of print]