Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial
Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial
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DOI：
10.1007/s10549-014-3141-1
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发表时间：
2014-11-01
影响因子：
3.8
通讯作者：
Pollak, Michael N.
中科院分区：
文献类型：
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作者：
DeCensi, Andrea;Puntoni, Matteo;Pollak, Michael N.
在观察性研究中，二甲双胍治疗糖尿病与乳腺癌风险降低相关，但尚不清楚该药物是否具有临床抗肿瘤活性。在最近的一项术前试验中，我们发现二甲双胍对乳腺癌增殖（ki-67）的异质性影响取决于胰岛素抵抗（HOMA指数）。在这里，我们确定了胰岛素抵抗的其他血清生物标志物，肿瘤亚型和药物浓度与二甲双胍对ki-67反应的关系。200名非糖尿病女性在乳腺癌手术前被随机分配接受二甲双胍（850 mg/bid）或安慰剂治疗4周。通过比较基线活检（ki-67和肿瘤亚型）和血清标志物（HOMA指数、C肽、IGF-I、IGFBP-1、IGFBP-3、游离IGF-I、hs-CRP、脂联素）获得的数据，评估ki-67对二甲双胍的反应，并在确定性手术时进行相同测量。对于在末次给药后24小时内采集血样的患者，测量二甲双胍水平。与安慰剂相比，二甲双胍显著降低了HOMA > 2.8的女性、IGFBP-1最低五分位数、IGFBP-3最高四分位数、游离IGF-I低、hs-CRP最高三分位数和HER 2阳性肿瘤患者的ki-67。在HOMA指数> 2.8的女性中，药物水平与ki-67降低呈正相关，而在HOMA < 2.8的女性中没有观察到趋势（p-相互作用= 0.07）。在常规抗糖尿病剂量下，二甲双胍对非糖尿病乳腺癌患者肿瘤ki-67的影响因宿主和肿瘤特征而异。这些发现与设计二甲双胍预防和治疗乳腺癌的试验有关。
Treatment of diabetics with metformin is associated with decreased breast cancer risk in observational studies, but it remains unclear if this drug has clinical antineoplastic activity. In a recent presurgical trial, we found a heterogeneous effect of metformin on breast cancer proliferation (ki-67) depending upon insulin resistance (HOMA index). Here, we determined the associations of additional serum biomarkers of insulin resistance, tumor subtype, and drug concentration with ki-67 response to metformin. Two-hundred non-diabetic women were randomly allocated to metformin (850 mg/bid) or placebo for 4 weeks prior to breast cancer surgery. The ki-67 response to metformin was assessed comparing data obtained from baseline biopsy (ki-67 and tumor subtype) and serum markers (HOMA index, C-peptide, IGF-I, IGFBP-1, IGFBP-3, free IGF-I, hs-CRP, adiponectin) with the same measurements at definitive surgery. For patients with a blood sample taken within 24 h from last drug intake, metformin level was measured. Compared with placebo, metformin significantly decreased ki-67 in women with HOMA > 2.8, those in the lowest IGFBP-1 quintile, those in the highest IGFBP-3 quartile, those with low free IGF-I, those in the top hs-CRP tertile, and those with HER2-positive tumors. In women with HOMA index > 2.8, drug levels were positively correlated with the ki-67 decrease, whereas no trend was noted in women with HOMA < 2.8 (p-interaction = 0.07). At conventional antidiabetic doses, the effect of metformin on tumor ki-67 of non-diabetic breast cancer patients varies with host and tumor characteristics. These findings are relevant to design breast cancer prevention and treatment trials with metformin.