Division of Medical Oncology and Hematology, Department of Medicine, Mount Sinai Hospital and Princess Margaret Hospital, University of Toronto, 1284-600 University Avenue, Toronto, ON M5G 1X5, Canada.
Breast Cancer Res Treat. 2012 Oct;135(3):821-30. doi: 10.1007/s10549-012-2223-1. Epub 2012 Aug 30.
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.
二甲双胍可能通过间接（胰岛素介导）或直接（胰岛素非依赖）机制发挥抗癌作用。我们报告了一项新辅助“机会之窗”研究的结果，该研究评估了二甲双胍在可手术乳腺癌女性中的作用。新诊断的、未经治疗的、非糖尿病乳腺癌患者在接受诊断性核心活检后接受二甲双胍 500mg tid 治疗，直至确定性手术。比较了临床（体重、症状和生活质量）和血液（空腹血清胰岛素、葡萄糖、稳态模型评估（HOMA）、C 反应蛋白（CRP）和瘦素）特征，以及肿瘤组织中端粒末端转移酶介导的 dUTP 缺口末端标记（TUNEL）和 Ki67 评分（我们的主要终点）。39 例患者完成了研究。平均年龄为 51 岁，二甲双胍中位治疗时间为 18 天（范围 13-40），直至手术前一晚。51%的患者为 T1 期癌症，38%的患者有阳性淋巴结，85%的患者有 ER 和/或 PgR 阳性肿瘤，13%的患者有 HER2 过表达或扩增肿瘤。50%的患者出现轻度、自限性恶心，50%的患者出现腹泻，41%的患者出现厌食，32%的患者出现腹部肿胀，但 EORTC30-QLQ 功能量表未见显著下降。体重指数（BMI）（-0.5kg/m2，p<0.0001）、体重（-1.2kg，p<0.0001）和 HOMA（-0.21，p=0.047）显著下降，而胰岛素（-4.7pmol/L，p=0.07）、瘦素（-1.3ng/mL，p=0.15）和 CRP（-0.2mg/L，p=0.35）的下降无统计学意义。浸润性肿瘤组织中的 Ki67 染色减少（从 36.5%减少到 33.5%，p=0.016），TUNEL 染色增加（从 0.56 增加到 1.05，p=0.004）。短期术前二甲双胍耐受良好，导致临床和细胞变化与有益的抗癌作用一致；需要使用生存等临床终点的适当大样本临床试验来评估这些发现的临床相关性。
