Division of Medical Oncology, E.O. Ospedali Galliera, Mura delle Cappuccine 14, Genoa, Italy.
J Clin Oncol. 2012 Jul 20;30(21):2593-600. doi: 10.1200/JCO.2011.39.3769. Epub 2012 May 7.
Metformin 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.
After 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.
Overall, 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] × 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).
Metformin 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.
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相关，但抗肿瘤活性的临床证据尚不清楚。Ki-67 在预处理活检和治疗后手术标本之间的变化具有预后价值，并可能预测乳腺癌的抗肿瘤活性。
肿瘤活检后，我们将 200 名非糖尿病、可手术治疗的乳腺癌女性随机分为二甲双胍 850 mg/每日两次组（n = 100）和安慰剂组（n = 100）。主要观察指标为治疗 4 周后 Ki-67 变化与基线值的差值。
总体而言，二甲双胍对 Ki-67 变化的影响相对于安慰剂不具有统计学意义，4 周后平均比例增加 4.0%（95%CI，-5.6%至 14.4%）。然而，根据胰岛素抵抗（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（交互作用）=.045），药物作用不同，HOMA 大于 2.8 的女性 Ki-67 平均比例降低 10.5%（95%CI，-26.1%至 8.4%），HOMA 小于或等于 2.8 的女性 Ki-67 增加 11.1%（95%CI，-0.6%至 24.2%），差异无统计学意义。还观察到 HOMA 指数与二甲双胍的作用存在不同的相互作用也在 luminal B 肿瘤中（P（交互作用）=.05）。根据体重指数（P =.143）、腰围/臀围比（P =.058）、中度饮酒（P =.005）和 C 反应蛋白（P =.080），也观察到药物作用修饰的类似趋势。
手术前使用二甲双胍总体上并未显著影响 Ki-67，但根据胰岛素抵抗，表现出明显不同的作用，特别是在 luminal B 肿瘤中。我们的发现需要进一步研究二甲双胍在乳腺癌中的作用，并仔细考虑研究人群的代谢特征。
