Metformin May Extend Survival In Diabetes Patients with Triple-Positive Primary Breast Cancer

Diabetes patients with human epidermal growth factor receptor 2-positive, hormone receptor-positive primary breast cancer may benefit from metformin

medwireNews: A substudy of the ALTTO trial adds support to the hypothesis that metformin use may be protective in breast cancer patients with diabetes, finding improved survival outcomes in women with triple-positive primary disease who used the antidiabetes agent.

“Despite the lack of level one evidence, we believe that for patients with diabetes and [human epidermal growth factor receptor] HER2-positive and hormone receptor–positive disease, it is reasonable to recommend metformin treatment if patients have not already received treatment and to avoid as much as possible insulin use”, say Evandro de Azambuja, from Institut Jules Bordet in Brussels, Belgium, and co-investigators.

“From a prognostic point of view, patients with diabetes and HER2-positive and hormone receptor–positive disease who are treated with insulin should be considered at higher risk of recurrence”, they emphasize.

The current analysis includes data for 8381 patients who were randomly assigned to receive 1 year of trastuzumab or lapatinib therapy or the two agents in sequence or combination, including 2.2% of participants who had diabetes but no metformin treatment and 3.1% of patients who had used metformin for diabetes.

After a median of 4.5 years of follow-up, diabetes patients who were not treated with metformin had significantly poorer disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) than patients without diabetes. The hazard ratios (HRs) for these outcomes were 1.40, 1.56 and 1.87, respectively, after adjusting for timing of chemotherapy, hormone receptor status, lymph node status and other factors.

By contrast, patients with diabetes who had been prescribed metformin did not have significantly poorer DFS, DDFS or OS compared with the controls, the team reports in the Journal of Clinical Oncology.

Further analysis suggested that the increased risk of poor survival in diabetes patients who had not used metformin was only present in women who had hormone receptor-positive tumours. For example, the HR for DFS versus controls was a significant 2.05 for hormone receptor-positive patients versus a nonsignificant 0.99 in their hormone receptor-negative counterparts.

Moreover, when the researchers examined the impact of diabetes treatments, they found that metformin use was beneficial in diabetes patients with HER2-positive, hormone receptor-positive breast cancer, with a significant HR of 0.70 for DFS compared with diabetes patients not given metformin.

But insulin was associated with poorer outcomes in hormone receptor-positive diabetes patients with a significant HR for DFS of 2.29 compared with nonusers of insulin, whereas no association was found for hormone receptor-negative individuals.

“As ALLTO, like most clinical trials, tends to have a healthier population and likely a lower incidence of patients with diabetes than the general population, it would be important to address the hypotheses raised in this study with a larger group of patients who are more indicative of the real world”, the researchers caution.

“Another future direction would be to perform a large registry study that will observe prospectively patients with diabetes and HER2-positive breast cancer”, they recommend.

Nevertheless, the authors conclude that, while their analyses were unplanned, “our data provide evidence that the prognostic impact of diabetes and metformin treatment is also relevant in patients who were treated with the current standard adjuvant treatment.”


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; Advance online publication 13 March 2017. DOI: 10.1200/JCO.2016.69.7722

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