Metformin Improves Outcomes in HER2+ Breast Cancer Patients With Diabetes

Treatment with metformin may improve outcomes in patients with human epidermal growth factor receptor 2 (HER2)–positive primary breast cancer and diabetes, according to an analysis of the phase III ALTTO trial.

“Patients with diabetes and breast cancer were found to have poorer prognoses compared with non-diabetic patients in population-based cohorts,” wrote study authors led by Evandro de Azambuja, MD, PhD, of the Jules Bordet Institute in Brussels. “Preclinical and clinical data have shown that metformin has direct and indirect antitumor effects, especially in breast cancer.”

The ALTTO trial’s primary analysis showed that patients randomized to receive trastuzumab and lapatinib in combination fared better than those receiving only trastuzumab. The new study examined whether patients with diabetes at study entry fared better with metformin treatment; the results were published in the Journal of Clinical Oncology.

Of 8,381 patients included in this analysis, 186 (2.2%) had diabetes at study entry with no metformin treatment, and 260 patients (3.1%) were diabetic and were receiving metformin treatment. After a median follow-up of 4.5 years, there were 1,205 disease-free survival (DFS) events, 929 distant DFS (DDFS) events, and 528 deaths.

Diabetic patients who were not treated with metformin had significantly worse DFS compared with non-diabetic patients, with a multivariate hazard ratio (HR) of 1.40 (95% CI, 1.01–1.94; P = .043). This effect was restricted to hormone receptor–positive disease, in whom the HR was 2.05 (95% CI, 1.32–3.18; P = .001); in hormone receptor–negative patients, the HR was 0.99 (95% CI, 0.61–1.62; P = .982).

Diabetic patients treated with metformin had similar outcomes to non-diabetic patients, with an HR for DFS of 0.97 (95% CI, 0.70–1.35; P = .873); this was similar in hormone receptor–positive and –negative patients.

A similar result was seen for DDFS. Diabetic patients not treated with metformin had an HR for DDFS of 1.56 (95% CI, 1.10–2.22; P = .013), and hormone receptor–positive patients again were the driver of that increase. The metformin group had an HR for DDFS of 0.91 (95% CI, 0.62–1.33; P = .638). The same was true for overall survival, where the non-metformin diabetic group had an HR of 1.87 (95% CI, 1.23–2.85; P = .004), and the metformin group had an HR of 1.15 (95% CI, 0.73–1.81; P = .541).

“Despite the lack of level 1 evidence, we believe that for patients with diabetes and 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,” the authors concluded, adding that patients treated with insulin should be considered at higher risk of recurrence.