{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T01:18:52Z","timestamp":1789003132549,"version":"build-2803163510"},"reference-count":35,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"13","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2017,5,1]]},"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p> Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) \u2013positive primary breast cancer in the context of a large, phase III adjuvant trial. <\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p> The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry\u2014with or without metformin treatment\u2014were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p> A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor\u2013positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor\u2013positive breast cancer. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p> Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor\u2013positive breast cancer. <\/jats:p><\/jats:sec>","DOI":"10.1200\/jco.2016.69.7722","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T09:51:18Z","timestamp":1491385878000},"page":"1421-1429","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":134,"title":["Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2\u2013Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial"],"prefix":"10.1200","volume":"35","author":[{"given":"Amir","family":"Sonnenblick","sequence":"first","affiliation":[{"name":"Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Universit\u00e9 Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. Wolff, Johns Hopkins School of..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Agbor-Tarh","sequence":"additional","affiliation":[{"name":"Amir Sonnenblick, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; Dominique Agbor-Tarh and Ian Bradbury, Frontier Science, Kingussie, United Kingdom; Serena Di Cosimo Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; Hatem A. Azim Jr, Martine Piccart-Gebhart and Evandro de Azambuja, Universit\u00e9 Libre de Bruxelles; Debora Fumagalli, Breast International Group, Brussels, Belgium; Severine Sarp, Novartis Pharma AG, Basel, Switzerland; Antonio C. 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