Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study

Abstract

Metformin may exert anti-cancer effects through indirect (insulin-mediated) or direct (insulin-independent) mechanisms. We report results of a neoadjuvant "window of opportunity" study of metformin in women with operable breast cancer. Newly diagnosed, untreated, non-diabetic breast cancer patients received metformin 500 mg tid after diagnostic core biopsy until definitive surgery. Clinical (weight, symptoms, and quality of life) and blood [fasting serum insulin, glucose, homeostasis model assessment (HOMA), C-reactive protein (CRP), and leptin] attributes were compared pre- and post-metformin as were terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and Ki67 scores (our primary endpoint) in tumor tissue. Thirty-nine patients completed the study. Mean age was 51 years, and metformin was administered for a median of 18 days (range 13-40) up to the evening prior to surgery. 51 % had T1 cancers, 38 % had positive nodes, 85 % had ER and/or PgR positive tumors, and 13 % had HER2 overexpressing or amplified tumors. Mild, self-limiting nausea, diarrhea, anorexia, and abdominal bloating were present in 50, 50, 41, and 32 % of patients, respectively, but no significant decreases were seen on the EORTC30-QLQ function scales. Body mass index (BMI) (-0.5 kg/m(2), p < 0.0001), weight (-1.2 kg, p < 0.0001), and HOMA (-0.21, p = 0.047) decreased significantly while non-significant decreases were seen in insulin (-4.7 pmol/L, p = 0.07), leptin (-1.3 ng/mL, p = 0.15) and CRP (-0.2 mg/L, p = 0.35). Ki67 staining in invasive tumor tissue decreased (from 36.5 to 33.5 %, p = 0.016) and TUNEL staining increased (from 0.56 to 1.05, p = 0.004). Short-term preoperative metformin was well tolerated and resulted in clinical and cellular changes consistent with beneficial anti-cancer effects; evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical endpoints such as survival is needed.

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

“…Overall, these prospective, preoperative window studies in breast cancer (62,64,65), despite reservations about trial design and methodology, demonstrate that metformin is safe for women with primary breast cancer and confirm the attraction of metformin as a therapeutic agent.…”

“…A second, single-center, preoperative window-of-opportunity placebo-controlled trial of similar size confirmed the reduction in Ki-67 with metformin use over 2 weeks, again not associated with BMI, and provided enhanced evidence for the systemic insulin-mediated effects (64). The need for meticulous trial design was flagged by a subsequent trial (65) where failure to continue metformin up to the time of surgery and using core samples at diagnosis versus resection specimens (66) make data interpretation difficult.…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…This study also provided preliminary evidence that circulating metformin level is a variable that infl uences antiproliferative activity. A third similar study ( 107 ) was smaller ( n = 39), not placebo-controlled, and also compared tissue from needle biopsies with surgical specimens. Nonsignifi cant declines in insulin level together with signifi cantly increased apoptosis and reduced proliferation were observed.…”

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression

“…Hyperinsulinemia, insulin resistance (IR) [7,8,10], and enhanced levels of insulin-like growth factor-1 (IGF-1) [11] have all been proposed as the underlying causative mechanisms, mainly on the basis of in vitro and animal studies supporting a role for insulin, insulin receptor, and IGFs in BC initiation [12][13][14] and progression [15]. These experimental findings are strengthened by indirect observations that metformin, a biguanide oral hypoglycemic agent capable of lowering insulin levels and improving IR, also might The Oncologist 2016;21:1041-1049 www.TheOncologist.com ©AlphaMed Press 2016 be effective in reducing BC incidence [8] and may beneficially act on proliferation and apoptosis markers in early BC stages [16][17][18]. Accordingly, metformin is being investigated in an adjuvant trial investigating invasive cancer-free survival in nondiabetic women with early breast cancer (National Cancer Institute of Canada Clinical Trials Group MA.32); the primary outcome measure is expected to be released late in 2017 [19].…”