This study evaluates the addition melatonin and metformin to toremifene in the treatment of locally advanced breast cancer. Third of patients will receive toremifene, other third will receive combination of melatonin and toremifene and other patients will receive combination of metformin and toremifene.

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.

Inclusion Criteria:

• Age > 18.
• Obtained Inform Concent.
• Morphologically confirmed breast cancer stage IIB, IIIA, IIIB, IIIC ER positive.
• Eastern Collaborative Oncology Group Performance Status Scale 0-2.
• Expected survival > 6 month.
• Adequate liver and bone marrow function.

Exclusion Criteria:

• Systemic treatment for breast cancer.
• Stage IV disease.
• Evidence of liver and bone marrow clinically meaningful disfunction.
• Severe uncontrolled concomitant conditions and diseases.
• Pregnancy or lactation.
• Second malignancy.
• Diabetes mellitus requiring drug therapy.
• Any condition preventing study participation by investigators opinion.