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

Abstract

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 ) -positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and MethodsThe 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-with or without metformin treatment-were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. ResultsA 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-positive 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-positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor-positive breast cancer.

Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development

“…This can be viewed as proof of principle that metformin can be used to modify the metabolic milieu of tumor stroma. Metformin has shown promising activity in multiple human malignancies including breast, non-small cell lung, prostate, endometrial, pancreatic, colorectal, and renal cell cancers and clinical trials of metformin alone and in combination with standard therapies are underway in multiple tumor types [83] [84] [85]. …”

Long‐term metformin use may improve clinical outcomes in diabetic patients with non‐alcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis

“…Beyond its glucose-lowering effect, metformin has shown anti-inflammatory and anti-tumour effects on different types of cells and animal models, which have been hypothesised to underlie the influence of metformin on all-cause mortality and cancer in the context of clinical studies. Metformin exerts it functions on multiple pathways, including decrease in insulin-like growth factor-1, activation AMP-activated protein kinase, inhibition of mammalian target rapamycin (mTOR), downregulating c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappa-B pathways, and reduction in endogenous production of reactive oxygen species (ROS) and associated DNA damage 34,[38][39][40][41][42]. A potentially important observation of our study was that metformin combined with vitamin E may improve patient's outcomes beyond that are observed with either of them individually.…”

Onco-metabolism: defining the prognostic significance of obesity and diabetes in women with brain metastases from breast cancer

“…For example, a secondary analysis of the ALLTO trial suggested a potential benefit and detriment of metformin and insulin, respectively, in diabetic patients with HER2+ cancer [40]. Observational studies have found a decreased risk of breast cancer death associated with statin-use [41, 42], although no definitive cause-effect relationships have been reported.…”