Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer.
Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer.
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DOI：
10.1007/s10549-009-0507-x
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发表时间：
2010-01
影响因子：
3.8
通讯作者：
Esserman, Laura J.
中科院分区：
文献类型：
--
作者：
Garwood, Elisabeth R.;Kumar, Anjali S.;Baehner, Frederick L.;Moore, Dan H.;Au, Alfred;Hylton, Nola;Flowers, Chris I.;Garber, Judy;Lesnikoski, Beth-Ann;Hwang, E. Shelley;Olopade, Olofunmilao;Port, Elisa Rush;Campbell, Michael;Esserman, Laura J.
关键词：
本研究的目的是通过配对的组织、血液和基于成像的生物标志物来确定短期亲脂性他汀类药物暴露对原位和浸润性乳腺癌的生物学影响。在诊断为DCIS或1期乳腺癌的女性中进行了氟伐他汀的围手术期窗口试验。患者在手术前随机接受高剂量（80 mg/天）或低剂量（20 mg/天）氟伐他汀治疗3-6周。在治疗前/后获得组织（诊断性空芯活检/最终手术标本）、血液和磁共振图像。主要终点是Ki-67（增殖）降低。次要终点是裂解的caspase-3（CC 3，细胞凋亡）、MRI肿瘤体积和血清C反应蛋白（CRP，炎症）的变化。计划的亚组分析比较了疾病分级、他汀类药物剂量和雌激素受体状态。入组的45例患者中有40例完成了方案; 29例具有配对Ki-67主要终点数据。高级别肿瘤的增殖降低了7.2%（P = 0.008），这在统计学上大于低级别肿瘤的0.3%降低。CC 3的配对数据显示，38%的受试者肿瘤细胞凋亡增加，41%保持稳定，21%下降。更高级别的肿瘤细胞凋亡增加（60%比13%; P = 0.015）。血清CRP无变化，但胆固醇水平显着降低后，他汀类药物暴露（P<0.001）。氟伐他汀通过减少高级别0/1期乳腺癌的肿瘤增殖和增加凋亡活性显示出可测量的生物学变化。仅在高级别肿瘤中效果明显。这些结果支持进一步评估他汀类药物作为ER阴性高级别乳腺癌的化学预防。
The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3–6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen-receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P<0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.
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