Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial
Dual Effect of Metformin on Breast Cancer Proliferation in a Randomized Presurgical Trial
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DOI：
10.1200/jco.2011.39.3769
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发表时间：
2012-07-20
影响因子：
45.3
通讯作者：
DeCensi, Andrea
中科院分区：
文献类型：
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作者：
Bonanni, Bernardo;Puntoni, Matteo;DeCensi, Andrea
在糖尿病患者的观察性研究中，二甲双胍与乳腺癌风险降低有关，但其抗肿瘤活性的临床证据尚不清楚。Ki-67的变化之间的预处理活检和治疗后的手术标本具有预后价值，并可能预测在乳腺癌的抗肿瘤活性。患者和MethodsAfter肿瘤活检，我们随机分配200名非糖尿病妇女与可手术的乳腺癌二甲双胍850毫克/每天两次（n = 100）或安慰剂（n = 100）。主要结果的措施是武器之间的差异Ki-67 4周后调整基线value. ResultOverall，二甲双胍对Ki-67的变化相对于安慰剂的影响是没有统计学意义的，平均比例增加4.0%（95%CI，-5.6%至14.4%）4周。然而，根据胰岛素抵抗的不同，（稳态模型评估[HOMA]指数> 2.8，空腹血糖[mmol/L] ×胰岛素[mU/L]/22.5; P-相互作用= 0.045），Ki-67的平均比例降低不显著，为10.5%（95% CI，-26.1%至8.4%），HOMA小于或等于2.8的女性无显著性增加11.1%（95% CI，-0.6%至24.2%）。根据HOMA指数，二甲双胍在管腔型B肿瘤中的作用也不同（P-相互作用= 0.05）。根据体重指数，观察到类似的药物效应改变趋势（P = .143），腰围/臀围比（P = 0.058），中度饮酒（P = 0.005）和C反应蛋白（P = .080）.结论术前美托洛尔对Ki-67总体无显著影响，但根据胰岛素抵抗显示出显著不同的影响，特别是在管腔B肿瘤中。我们的研究结果证明了二甲双胍在乳腺癌中的进一步研究，并仔细考虑了研究人群的代谢特征。
PurposeMetformin is associated with reduced breast cancer risk in observational studies in patients with diabetes, but clinical evidence for antitumor activity is unclear. The change in Ki-67 between pretreatment biopsy and post-treatment surgical specimen has prognostic value and may predict antitumor activity in breast cancer.Patients and MethodsAfter tumor biopsy, we randomly allocated 200 nondiabetic women with operable breast cancer to either metformin 850 mg/twice per day (n = 100) or placebo (n = 100). The primary outcome measure was the difference between arms in Ki-67 after 4 weeks adjusted for baseline values.ResultsOverall, the metformin effect on Ki-67 change relative to placebo was not statistically significant, with a mean proportional increase of 4.0% (95% CI, -5.6% to 14.4%) 4 weeks apart. However, there was a different drug effect depending on insulin resistance (homeostasis model assessment [HOMA] index > 2.8, fasting glucose [mmol/L] x insulin [mU/L]/22.5; P-interaction = .045), with a nonsignificant mean proportional decrease in Ki-67 of 10.5% (95% CI, -26.1% to 8.4%) in women with HOMA more than 2.8 and a nonsignificant increase of 11.1% (95% CI, -0.6% to 24.2%) with HOMA less than or equal to 2.8. A different effect of metformin according to HOMA index was noted also in luminal B tumors (P-interaction = .05). Similar trends to drug effect modifications were observed according to body mass index (P = .143), waist/hip girth-ratio (P = .058), moderate alcohol consumption (P = .005), and C-reactive protein (P = .080).ConclusionMetformin before surgery did not significantly affect Ki-67 overall, but showed significantly different effects according to insulin resistance, particularly in luminal B tumors. Our findings warrant further studies of metformin in breast cancer with careful consideration to the metabolic characteristics of the study population.