Abstract P6-13-04: Metformin for the treatment of ductal carcinoma in situ (DCIS)

Abstract

Abstract BACKGROUND: Each year about 60,000 new cases of breast ductal carcinoma in situ (DCIS) are diagnosed in the United States. DCIS significantly increases the risk of invasive breast cancer. To reduce this risk, tamoxifen is offered to patients with ER-positive DCIS in the adjuvant setting. In contrast, no adjuvant therapy exists for ER-negative DCIS. Metformin is a frontline therapy for type 2 diabetes and its safety and side effect profiles are well documented. Preclinical, epidemiologic, and retrospective data all support an antitumor effect of metformin in breast cancer. Metformin may act via activation of AMP kinase (AMPK), a sensor of cellular energy, which in turn inhibits mTOR activity and shuts down global protein synthesis. Previous data from our group showed that metformin treatment is associated with a higher rate of pathologic complete response in diabetic breast cancer patients receiving preoperative chemotherapy. In the current study, using preclinical models, we explored the effects of metformin in DCIS and its progression to invasive breast cancer. EXPERIMENTAL DESIGN AND METHODS: We tested the anti-tumor activity of metformin in terms of proliferation and invasion using both DCIS cell lines and a mouse intraductal (MIND) transplantation model previously developed by us. The latter involves intraductal injection of human DCIS cells into mouse mammary glands, and importantly recapitulates the progression of DCIS to invasive cancer seen in human breast cancer. Western blot and immunofluorescent staining for AMP kinase, mTOR, and other relevant targets, as well as flow cytometry, were used to investigate mechanism. RESULTS: Metformin significantly inhibited cell proliferation, migration, and invasion in all DCIS cell lines tested. In the mouse model, using metformin at a dose that is readily achievable in human patients, metformin significantly reduced the tumor burden in terms of median number of ducts filled, from 11 to 2 using DCIS.com cells (p < 0.001) and from 10 to 3 using SUM.225 cells (p = 0.004). In addition, importantly, metformin inhibited the progression of DCIS lesions to invasive breast cancer significantly, with a reduction in invasive lesions from 74 to 17% (p = 0.003). In mechanistic studies, metformin showed activation of AMPK and subsequent inactivation of mTOR and other downstream targets. Treatment with metformin did not lead to significant cell cycle arrest but rather to increased cell death. We found that cell death by apoptosis increased only modestly with metformin treatment, while cell death by necrosis increased significantly. CONCLUSION: Metformin inhibits the growth of DCIS and its progression to invasive breast cancer. To our knowledge, this is the first reported evidence of metformin’s anti-tumor activity in DCIS. Our data support the exciting prospect of developing metformin clinically for the treatment of DCIS. Citation Format: Atreyi Dasgupta, David G Edwards, Frances S Kittrell, Susan G Hilsenbeck, Daniel Medina, Sao Jiralerspong. Metformin for the treatment of ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-04.