Metformin improves prognosis of certain breast cancer patients with diabetes
Metformin use may favourably affect the poor prognosis associated with diabetes in patients with human epidermal growth factor receptor 2 (HER2)–positive and hormone receptor (HR)–positive primary breast cancer, according to a substudy of the ALTTO* trial.
In a cohort of adult patients with early-stage, surgically resected HER2-positive breast cancer, diabetic patients who were not treated with metformin showed worse disease-free survival (DFS; multivariable hazard ratio [HR], 1.40; 95 percent CI, 1.01 to 1.94; p=0.043), distant disease-free survival (DDFS; multivariable HR, 1.56; 1.10 to 2.22; p=0.013) and overall survival (OS; multivariable HR, 1.87; 1.23 to 2.85; p=0.004). [J Clin Oncol 2017;doi:10.1200/JCO.2016.69.7722]
The worse outcome in diabetic patients with no metformin treatment (vs diabetic patients with metformin exposure or nondiabetic patients) was limited to HR–positive patients. In patients with HR–negative status, diabetes had no effect on outcomes.
Furthermore, compared with metformin treatment, insulin exposure in diabetic patients with HER2–positive and HR–positive breast cancer was associated with worse outcomes.
The study population comprised 8,381 early-stage, surgically resected HER2-positive breast cancer patients who had been randomized to receive 1 year of trastuzumab alone, lapatinib alone, their sequence or their combination. A total of 446 patients had diabetes, of which 260 were treated with metformin and the remaining 186 were not.
After a median follow-up of 4.5 years, the respective DFS, DDFS and OS events were reported in 4.38, 11.08 and 6.3 percent of patients overall.
“One of the interesting observations of this study is that for patients with HR–positive cancer, the risk of DDFS and death was more than double in patients with diabetes, but this effect was not seen in HR–negative cancers,” the investigators said. “Moreover, patients with diabetes who were not treated with metformin had triple the risk of DDFS and of dying compared with metformin-treated patients, but again this effect was limited to HR–positive cancer.”
They cited several mechanisms underlying the reversal of the worse breast cancer prognosis in diabetic patients with hormone receptor–positive disease, including interactions between the Akt-mTOR pathway (which is the downstream pathway of insulin and insulin growth factor receptors that, in turn, are activated in patients with diabetes) and hormone receptor signalling that occur at different levels to promote cell growth. [Cancer Treat Rev 2014;40:862–871]
“Diabetes and hyperinsulinaemic state can increase hormonal treatment resistance of HER2 tumours via activation of insulin growth factor receptor and its downstream Akt-mTOR pathway, and this effect may be reversed by metformin,” they continued. “As the Akt-mTOR and HR signaling pathways intersect at multiple junctures, with direct and indirect interactions occurring at multiple levels, a vicious cycle driven by the diabetic state and use of insulin could be broken via inhibition of the Akt-mTOR pathway by metformin.”
Despite the existence of potential limitations inherent in an unplanned analysis and the lack of level one evidence, the investigators noted that it is reasonable to recommend metformin treatment for breast cancer patients with diabetes and HER2-positive and HR–positive disease, if treatment has not already been given, in order to avoid insulin use as much as possible.
“As patients with diabetes only comprise approximately 5 percent of patients with breast cancer, a possible future direction could be to use a neoadjuvant adaptive strategy for matching targeted therapies to screen for metformin activity in breast cancer,” they said.
* Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization