Background: Metformin has been associated with decreased breast cancer (BC) incidence in diabetic patients in epidemiological studies. Moreover, this drug results in initiation of an AMPK-dependent energy stress response which can adversely affect survival of breast cancer cell lines and inhibition of PI3K/Akt/mTOR signaling leading to reduced proliferation of BC cell lines.

Methods: We conducted a randomized, pre-surgical, phase IIb, placebo-controlled, biomarker trial in women with stage I-III BC candidate to elective surgery. The primary endpoint was the change in cell proliferation in malignant, dysplastic and hyperplastic tissue as measured by Ki-67 labeling index (LI). With 150 subjects, the study was 80% powered to test for the interaction between metformin activity and ER status. Two interim analyses are being planned after 100 and 200 women enrolled. Results: As of June 18, 2010, 175 subjects have been randomized and 162 have completed treatment. Here we report data on the first 100 women enrolled. At the symposium, full data on the first 200 women enrolled will be available. As of December 31, 2009, a total of 163 women were screened, 26 were not eligible and 40 refused to participate, 6 dropped out during the study for AEs (n=2) or refusal to continue treatment (n=4), thus leaving 95 subjects assessable for the primary endpoint. The main subject and tumor characteristics blinded as to the allocated arm were mean age 52 (31-77), Pre/postmenopause, 54/41, mean BMI, 23.6 (18.0-40.2). At baseline, median Ki-67LI was 18% (range 4%-65%) at biopsy and 19% (4%-70%) after 4 weeks at surgery. All adverse events except for 1 SAE were grade 1 or 2, consisting of G2 nausea and G2 diarrhea in 4% and 6% of the cases, respectively. The prevalence of ductal intraepithelial neoplasia was 91% (median Ki-67 LI, 10%) in samples both adjacent and distant from the tumor, whereas the prevalence of ductal hyperplasia was 77% (median Ki-67LI, 2%) in samples distant from the tumor. Conclusions: Our preliminary results show the feasibility, high compliance and safety of a metformin trial in breast cancer patients. Assessment of tissue and circulating biomarkers is currently ongoing to characterize the whole spectrum of metformin activity in malignant and dysplastic tissue.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-02.