Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study
Metformin in early breast cancer: a prospective window of opportunity neoadjuvant study
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DOI：
10.1007/s10549-012-2223-1
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发表时间：
2012-10-01
影响因子：
3.8
通讯作者：
Goodwin, Pamela J.
中科院分区：
文献类型：
--
作者：
Niraula, Saroj;Dowling, Ryan J. O.;Goodwin, Pamela J.
二甲双胍可通过间接（胰岛素介导）或直接（胰岛素非依赖性）机制发挥抗癌作用。我们报告了二甲双胍在可手术乳腺癌妇女中的新辅助“机会之窗”研究结果。新诊断、未经治疗的非糖尿病乳腺癌患者在诊断性空芯针活检后接受二甲双胍500 mg tid治疗，直至最终手术。比较二甲双胍治疗前后的临床（体重、症状和生活质量）和血液[空腹血清胰岛素、血糖、稳态模型评估（HOMA）、C反应蛋白（CRP）和瘦素]属性，以及肿瘤组织中的末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）和Ki 67评分（我们的主要终点）。39名患者完成了研究。平均年龄为51岁，二甲双胍给药的中位时间为18天（范围13-40），直至手术前晚上。51%患有T1癌症，38%患有阳性淋巴结，85%患有ER和/或PgR阳性肿瘤，13%患有HER 2过表达或扩增的肿瘤。分别有50%、50%、41%和32%的患者出现轻度自限性恶心、腹泻、厌食和腹胀，但EORTC 30-QLQ功能量表未观察到显著降低。体重指数（BMI）（-0.5 kg/m（2），p < 0.0001），体重（-1.2 kg，p < 0.0001）和HOMA（-0.21，p = 0.047）显著降低，而胰岛素水平无显著降低（-4.7 pmol/L，p = 0.07）、瘦素（-1.3 ng/mL，p = 0.15）和CRP（-0.2 mg/L，p = 0.35）。浸润性肿瘤组织中Ki 67染色降低（从36.5%至33.5%，p = 0.016），TUNEL染色增加（从0.56至1.05，p = 0.004）。短期术前二甲双胍耐受性良好，并导致与有益抗癌作用一致的临床和细胞变化;需要使用临床终点（如生存期）在充分把握度的临床试验中评价这些结果的临床相关性。
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.