Metformin, the widely prescribed oral hypoglycemic drug, is well known for its established efficacy, favorable safety profile, and low cost. Metformin has recently received increasing attention because of its potential antitumorigenic effects that are thought to be independent of its hypoglycemic effects. It has been extensively studied in preclinical models, which have implicated several molecular pathways in its antitumor activity.

Metformin was proved to have anti-proliferative and apoptotic effects on tumor cells.Moreover, metformin enhances the T-cell mediated immune response to tumor tissue and fights metastases. Also, epidemiological studies have shown that metformin, but not other antidiabetic drugs, reduces cancer incidence and improves survivability in diabetic cancer patients.

The proposed research in this application will investigate two prime questions with regards to the combined use of metformin together with traditional neoadjuvant chemotherapy in breast cancer patients. First, the hypothesis that the simultaneous use of metformin along with doxorubicin/cyclophosphamide/paclitaxel neoadjuvant protocol produces better antitumor outcomes will be tested. Second, the study will examine if the improved apoptotic effect of such regimen is paralleled by exaggerated stimulatory influences on apoptosis biomarkers.

1. Ethical committee approval will be obtained from Ethics committee of Faculty of Pharmacy, Damanhour University.

2. All participants should agree to take part in this clinical study and will provide informed consent.

3. Sixty female breast cancer patients, who are candidates for neoadjuvant chemotherapy, will be recruited from the Medical Research Institute, Oncology department, Alexandria University, Alexandria.

4. The 60 participants will be randomly assigned into 2 arms:

   • Control arm (n=30): will be treated with AC-Taxol regimen (AC: Doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV) for 4 cycles every 3 weeks. Subsequent Taxol cycles (Paclitaxel 80mg/m2 IV) once weekly for 12 weeks.
   • Metformin arm (n=30): will be treated with the AC-Taxol regimen mentioned above together with Metformin 850 mg tablets orally twice per day (1700 mg/day).

5. All patients will be submitted to:

   • Full patient history and clinical examination.
   • Routine follow up before each chemotherapy cycle (complete blood picture, liver function tests, renal function tests).
   • Routine Echocardiography before each chemotherapy cycle.

6. All patients will be monitored for the incidence of chemotherapy toxicities during neoadjuvant therapy.

7. After completion of the neoadjuvant therapy, participants will undergo surgical tumor removal. The excised tumor will be collected, and the expression of apoptosis biomarkers and the pathologic complete response (pCR) will be assessed.

8. Patients demographic data will be recorded with respect to age, weight and disease history.

9. Statistical tests appropriate to the study design will be conducted to evaluate the significance of the results.

10. Results, conclusion, discussion and recommendations will be given.

Inclusion Criteria:

1. Females ≥ 18 years of age and < 65 years.
2. Unilateral or bilateral primary carcinoma of the breast confirmed.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2.
4. Clinically measurable tumor size who are candidates for neoadjuvant therapy.
5. No evidence of distant metastasis.
6. Normal renal and liver functions.
7. Non-diabetics.

Exclusion Criteria:

1. Pregnant or breastfeeding women.
2. Prior cancer chemotherapy.
3. Heart disease or reduced cardiac output with left ventricular ejection fraction < 50%.
4. Metastatic breast cancer patients.
5. Patients with hepatic impairment.
6. Patients with renal impairment.
7. Diabetics.

Summary of all relevant data will be shared