**4.2 Breast cancer**

There have been a number of studies relating to metformin's effect on biomarkers in breast cancer patients and it has been shown that metformin therapy reduced the levels of insulin, sex hormones and sex hormone-binding globulin, Ki67, caspase-3, p-Akt, obesity, CRP, blood glucose and lipid profile overall [73]. More, in a clinical trial to examine the clinical and biological effects of neoadjuvant metformin on patients with breast cancer, non-diabetic women with untreated breast cancer given 500 mg of metformin three times daily for ≥2 weeks exhibited decreased insulin receptor expression (*P* = 0.04), phosphorylation status of protein kinase B /Akt, extracellular signal-regulated kinase 1/2, AMPK and acetyl coenzyme A carboxylase (*P* = 0.0001, *P* < 0.0001, *P* < 0.005 and *P* = 0.02, respectively) in tumors correlating with decreases in tumor cell proliferation and increases in apoptosis [74]. In T2DM patients with breast cancer, a 2018 meta-analysis of eleven

*Repurposing of Metformin as a Multifaceted and Multitasking Preventative and Treatment… DOI: http://dx.doi.org/10.5772/intechopen.96101*

studies of all-cause mortality found a 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI 0.44–0.70) and concluded that metformin may improve overall survival in this patient subset [75]. Separately in another review, 7 observational studies showed significantly reduced breast cancer risk among T2DM patients on metformin OR = 0.83 (CI 0.71–0.97) [76]. Separately, in a sub-study involving over four hundred diabetic patients in the large phase 3 ALTTL trial of Her2+ breast cancer patients, Her2+ and estrogen receptor positive breast cancer cases on metformin experienced had improved disease free survival, metastasis free disease survival and overall survival over those patients not on metformin over a median of four and a half years [77]. However despite the vast amount of preclinical and epidemiologic data on its benefits in breast cancer, there are no trials in non-diabetic breast cancer patients to date which have unequivocally demonstrated a clinical benefit of metformin.
