Abstract P5-12-02: Metformin decreases Ki67 in HER2+ve ductal carcinoma in situ in a window of opportunity trial
Authors: Bonanni Bernardo , DeCensi Andrea , Guerrieri-Gonzaga Aliana , Pruneri Giancarlo , Puntoni Matteo , Cazzaniga Massimiliano , Vingiani Andrea , Serrano Davide , Gentilini Oreste , Johansson Harriet , Aristarco Valentina , Lazzeroni Matteo , Varicchio Clara , Petrera Marilena , Viale Giuseppe 
Published: May 2015

Abstract
Background: In a presurgical trial in 200 non-diabetic women with breast cancer, we previously showed a heterogeneous effect of metformin on the Ki67, with a decreased proliferation in women with insulin resistance (HOMA&gt;2.8) and an opposite effect in women with HOMA≤ 2.8 (Bonanni et al. JCO 30:2593, 2012). Here we determined the effect of metformin on noninvasive proliferative disorders.
Methods: Patients with operable breast cancer were randomly assigned to metformin, 850 mg or placebo once daily on days 1-3 followed by two 850 mg tablets after dinner on days 4 to 28. A total of 3-5 specimens of adjacent (≤1 cm from tumor) and distant (&gt;1 cm from tumor) tissue were obtained from the surgical specimens to assess systematically the prevalence of LCIS and DCIS adjacent to invasive cancer and of distant ductal hyperplasia (DH) in normal tissue. We also determined the effect of metformin on Ki67 in these lesions overall and by molecular subtype. All HER2 2+ DCIS by IHC were assessed by FISH.
Results: Overall, the prevalence of LCIS, DCIS and DH was 4.5% (9/200), 66% (132/200) and 35% (69/200), respectively. The Ki67 was positively associated with DCIS grade (p-trend&lt;.001). The median levels of Ki67 by treatment arm in different premalignant groups is summarized below
Median (IQR) Ki67 level (%) in premalignant disorders by treatment armPremalignant groupPremalignant subgroupMetformin armPlacebo armp-value*p-interaction‡LCIS (n=9) 15 (5-15)5 (4-6)0.1 DH (n=69) 3 (1-4)3 (1-4)0.5 All DCIS (n=132) 12 (8-20)10 (7-24)0.9 DCIS grade 1/2 (n=108)10 (7-16)10 (6-17)0.90.2 DCIS grade 3 (n=24)33 (25-55)40 (32-40)0.2 HER2+ve (n=22)22 (11-32)35 (30-40)0.060.04 HER2-ve (n=58)16 (10-20)17 (8-26)0.7 ER+ve/HER2+ve (n=15)12 (7-18)32 (27-42)0.0040.001 ER+ve/HER2-ve (n=53)16 (10-20)15 (8-22)0.8 PR+ve/HER2+ve (n=12)18 (12-18)32 (24-44)0.020.05 PR+ve/HER2-ve (n=48)16 (10-20)12 (8-20)0.6 *Wilcoxon rank-sum test; ‡ p-interaction between treatment and DCIS grade or HER2 status from a linear regression model, adjusted for age and BMI.
The effect of metformin on DCIS was different by HER2 status (p-interaction=.04) and, among this molecular subtype, by ER and PR status (p-interaction=.001 and .02, respectively). In HER2+ve DCIS, metformin decreased Ki67 by 40% overall (p=.06), by over 60% in ER+ve/HER2+ve DCIS (p=.004). and by 45% in PR+ve/HER2+ve DCIS (p=.02) There was no effect of metformin in HER2-ve DCIS, regardless of ER or PR status. Metformin did not affect Ki67 in DH overall, but showed a trend towards a decrease in women with abdominal adiposity (p-interaction=.05).
Conclusions: Window of opportunity pre-surgical models provide insight into a drug’s preventive potential by targeting intraepithelial proliferations adjacent to invasive cancer. The model shows a high prevalence of preinvasive lesions (field cancerization) in apparently normal breast tissue adjacent to breast cancer. Metformin selectively decreased Ki67 in HER2+ve DCIS, particularly in the ER+ve subgroup, in line with a selective inhibitory effect on the HER2 pathway observed both in in vitro and in vivo preclinical models. Our results provide the background for a phase III trial of metformin in HER2+ve DCIS (ISRCTN16493703, Supported by AIRC, LILT and Health Ministry 2009-RF-153222).
Citation Format: Bernardo Bonanni, Andrea DeCensi, Aliana Guerrieri-Gonzaga, Giancarlo Pruneri, Matteo Puntoni, Massimiliano Cazzaniga, Andrea Vingiani, Davide Serrano, Oreste Gentilini, Harriet Johansson, Valentina Aristarco, Matteo Lazzeroni, Clara Varicchio, Marilena Petrera, Giuseppe Viale. Metformin decreases Ki67 in HER2+ve ductal carcinoma in situ in a window of opportunity trial [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 P5-12-02.