Abstract SS-01: Metformin effects on breast preneoplasia
Authors: DeCensi Andrea , Aristarco Valentina , Lazzeroni Matteo , Varricchio Clara , Bonanni Bernardo , Puntoni Matteo , Pruneri Giancarlo , Cazzaniga Massimiliano , Vingiani Andrea , Serrano Davide , Guerrieri-Gonzaga Aliana , Gentilini Oreste , Johansson Harriet 
Published: January 2014

Abstract
Background: Metformin has been associated with a significant reduction in cancer incidence and mortality in diabetic patients relative to other antidiabetic drugs, including positive results specifically in breast cancer. In a recent window-of-opportunity trial in 200 non-diabetic women with breast cancer, we showed a heterogeneous effect of metformin on breast cancer proliferation (Ki-67 labeling index) depending on insulin resistance, with a trend to a decreased proliferation in women with insulin resistance (HOMA&gt;2.8) and an opposite trend in women with normal insulin sensitivity (Bonanni et al. JCO 30:2593, 2012). Here we performed an exploratory study to determine whether metformin has antiproliferative effects on adjacent lobular or ductal intraepithelial neoplasia (LIN or DIN) and on distant ductal hyperplasia and whether these effects are different according to specific host and tumor characteristics. Previous studies showed that Ki-67 LI in atypical lesions predicts subsequent breast cancer risk.
Methods: Baseline core biopsies of tumor tissue and blood samples were obtained at study entry and before surgery for pre/post-treatment comparisons. Patients were randomly assigned to metformin, 850 mg or placebo once daily on day 1-3 followed by two 850 mg tablets from day 4 to 28. At the time of surgical removal of the tumor, three to five specimens of adjacent (≥1 cm from the tumor) and distant (&gt;1 cm from the tumor) grossly normal tissue (i.e., the surgical margins of quadrantectomy or lumpectomy, or the grossly free quadrants from mastectomy specimens) were obtained to assess systematically the prevalence of LIN or DIN and ductal hyperplasia.
Results: Overall, the prevalence of LIN, DIN and ductal hyperplasia was 4.5% (9/200), 66.5% (133/200) and 35% (69/200), respectively. The Ki-67 LI was positively associated with DIN grade (p-trend&lt;0.001). The median (and IQ range) Ki-67 LI distribution of LIN+DIN was 12% (8-20) and 10% (6-22) on metformin and placebo, respectively (p=0.6), nor was there a significant difference of Ki-67 LI in any subgroup between treatment arms. However, compared with placebo, metformin exhibited different effects on Ki-67 according to DIN grade (delta=+4.4% in DIN1 vs -27.9% in DIN3, p-interaction=0.09), cancer HER2 status (median 12% vs. 10% in HER2-ve and 28% vs. 35% in HER2+ve, p-interaction=0.03), abdominal circumference (p=0.08), and BMI (p=0.17).
Conclusions: Our findings illustrate the notion that the window of opportunity pre-surgical model provides insight into a drug's preventive potential by targeting tumor adjacent dysplastic (or intraepithelial neoplastic) cells and distant ductal hyperplastic cells. The model unravels the existence of the field cancerization effect in apparently normal breast tissue. Similar to our results on breast cancer tissue, metformin had no overall significant effect on breast preneoplasia proliferation but exhibited heterogeneous effects depending upon specific host and preneoplasia characteristics. Further studies are necessary to better understand the clinical implications of these findings. (Supported by the Italian Association for Cancer Research and Italian Ministry of Health 2009-RF-1532226).
Citation Format: Andrea DeCensi, Valentina Aristarco, Matteo Lazzeroni, Clara Varricchio, Bernardo Bonanni, Matteo Puntoni, Giancarlo Pruneri, Massimiliano Cazzaniga, Andrea Vingiani, Davide Serrano, Aliana Guerrieri-Gonzaga, Oreste Gentilini, Harriet Johansson. Metformin effects on breast preneoplasia. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr SS-01.