Abstract 5493: Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) sensitivity in breast cancer stem cells and non-stem breast cancer cells

Abstract

Abstract Incorporating cancer stem cells (CSCs)-targeting therapies into current therapies could prevent cancer progression, recurrence and metastasis. An anti-diabetic, AMPK-activating drug, metformin has been shown to kill CSCs and reduces cancer incidence and cancer related death. This study aimed to evaluate the combination treatment of metformin or other AMPK/mTOR-acting drugs with chemotherapy on breast CSCs and non-CSCs in the pre-clinical and clinical settings. We investigated the combination effect of metformin, AICAR, A-769662, or rapamycin with doxorubicin, cisplatin, paclitaxel, or FEC on breast CSCs (mammospheres) and non-CSCs in vitro. The study was extended clinically in a pilot study of ten non-diabetic locally advanced breast cancer patients treated with metformin and neoadjuvant FEC chemotherapy. Nine patients treated with FEC only were identified as historical controls. ESA+/CD44+/CD24-/low (CSCs) population of the tumor samples and tumor response were evaluated. In contrast to other drugs, metformin exhibited higher sensitivity in CSCs compared to attached cell lines. Metformin combined with FEC demonstrated a synergistic effect on breast CSCs and non-CSCs. Patients receiving metformin/FEC neoadjuvant therapy showed a significant reduction in CSCs proportion (P=0.008). Proportion of CSCs after treatment with metformin/FEC was significantly lower compared with the FEC-only neoadjuvant group (P=0.008). Five out of nine patients (56%) receiving metformin/FEC therapy showed a clinical response versus one out of eight (13%) patients in the FEC-only group. In conclusion, metformin synergizes FEC sensitivity in both CSCs and non-CSCs in breast cancer cell lines. Combination treatment of metformin and FEC reduces CSCs in primary tumor from non-diabetic locally advanced breast cancer patients. These results indicate that neoadjuvant metformin/FEC may be a potential treatment option for breast cancer patients and warrants further clinical investigations. Citation Format: Sian Siu Soo, Char Hong Ng, Rozita Abdul Malik, Yew Ching Teh, Boon Shing Tan, Gwo Fuang Ho, Mee Hoong See, Nur Aishah Mohd Taib, Cheng Har Yip, Soo Hwang Teo, Chee Onn Leong. Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) sensitivity in breast cancer stem cells and non-stem breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2014-5493