Effect of Metformin on Breast Ductal Carcinoma In Situ Proliferation in a Randomized Presurgical Trial

Abstract

Metformin is associated with lower breast cancer risk in epidemiologic studies and showed decreased proliferation in HER2-positive breast cancer in a presurgical trial. To provide insight into its preventive potential, we measured proliferation by Ki-67 labeling index (LI) of intraepithelial lesions surrounding breast cancer. We randomly assigned 200 nondiabetic patients diagnosed with invasive breast cancer in core biopsies to metformin, 1,700 mg or placebo once daily for 28 days before surgery. Upon surgery, five to seven specimens of cancer adjacent ( 1 cm) and distant (>1 cm) tissue were screened for LCIS, ductal carcinoma in situ (DCIS), and ductal hyperplasia (DH). The prevalence of LCIS, DCIS, and DH was 4.5% (9/ 200), 67% (133/200), and 35% (69/200), respectively. Overall, metformin did not affect Ki-67 LI in premalignant disorders. The median posttreatment Ki-67 LI (IQR) in the metformin and placebo arm was, respectively, 15% (5-15) versus 5% (4-6) in LCIS (P ¼ 0.1), 12% (8-20) versus 10% (7-24) in DCIS (P ¼ 0.9), and 3% (1-4) versus 3% (1-4) in DH (P ¼ 0.5). However, posttreatment Ki-67 in HER2-positive DCIS lesions was significantly lower in women randomized to metformin especially when ER was coexpressed: 22% (11-32) versus 35% (30-40) in HER2-positive DCIS (n ¼ 22, P ¼ .06); 12% (7-18) versus 32% (27-42) in ER-positive/HER2-positive DCIS (n ¼ 15, P ¼ .004). Eight of 22 (36%) HER2-positive DCIS were adjacent to HER2-negative invasive breast cancer. In tissue samples obtained following 4 weeks of study drug, proliferation was lower in HER2-positive DCIS for women randomized to metformin versus placebo. An adjuvant trial incorporating metformin in HER2-positive DCIS is warranted. Cancer Prev Res; 8(10); 888-94.Ó2015 AACR.

New insight for metformin against bladder cancer

“…The authors concluded that a lower Ki-67 LI in ductal hyperplasia under metformin in women with abdominal obesity, the hallmark of insulin resistance, in line with cancer tissue. Thus, metformin selectively decreased Ki-67 in Human Epidermal Growth factor Receptor 2 (HER2)-positive cancers and in women with extra markers of insulin resistance [11]. Interestingly, recent study confirmed that patients with low Ki-67 expressions, negative epidermal growth factor receptor staining and preoperative positive urine cytology appear to be more sensitive to intravesical instillations for bladder recurrence prevention after radical nephroureterectomy [12].…”

Body fatness and mTOR pathway activation of breast cancer in the Women’s Circle of Health Study

“…Clinically, it is important to know whether mTOR activation is related to the recurrence of these tumors in obese individuals and whether mTOR inhibition is helpful to prevent recurrence. mTOR inhibition can be achieved with mTOR inhibitors or metformin, an insulin sensitizer that is widely used in the treatment of type II diabetes 42,43 . Metformin reduces breast tumor growth in diet-induced obese mice 44 .…”

Impact of diabetes mellitus on risk of cardiovascular disease and all-cause mortality: Evidence on health outcomes and antidiabetic treatment in United States adults

“…Meanwhile, all-cause mortality includes deaths from cancer as well. Several studies have shown a significant risk reduction in cancer incidence and mortality among diabetic patients on metformin use relative to other antidiabetic drugs use[ 33 ]. Furthermore, in considering that biguanides demonstrate a better safety profile than most oncology drugs in current anticancer drug use, nonconventional routes for administering diabetobiguanides for cancer treatment has been suggested[ 34 ].…”