The management of locally advanced breast cancer is complicated issue. Neoadjuvant treatment is often needed to downstage locally advanced ER positive BC tumors prior to surgery. However, many patients do not achieved objective response on treatment. The ability of melatonin and metformin to decrease side effects of chemotherapy had been investigated, moreover, several studies confirm, that this drugs in combination with conventional anti - estrogen treatment may increase objective response. But, this data is still controversial. We hypothesizes that the combinations of melatonin and metformin with conventional anti - estrogen such as toremifene could be more effective than toremifene alone in terms of response rate.