Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
Cancer Prev Res (Phila). 2016 May;9(5):349-56. doi: 10.1158/1940-6207.CAPR-15-0311. Epub 2016 Feb 29.
In breast cancer presurgical trials, the Ki-67 labeling index predicts disease outcome and offers clues to the preventive potential of drugs. We conducted a placebo-controlled trial to evaluate the activity of exemestane and celecoxib before surgery. The main endpoint was the change in Ki-67. Secondary endpoints were the modulation of circulating biomarkers. Postmenopausal women with histologically confirmed estrogen receptor-positive breast cancer were randomly assigned to exemestane 25 mg/day (n = 50), or celecoxib 800 mg/day (n = 50), or placebo (n = 25) for 6 weeks before surgery. Changes in biomarkers were analyzed through an ANCOVA model adjusting for baseline values. Exemestane showed a median absolute 10% reduction in Ki-67 [from 22 (interquartile range, IQR, 16-27), to 8 (IQR 5-18)], and a 15% absolute reduction in PgR expression [from 50 (IQR 3-90) to 15 (IQR -0-30)] after 6 weeks of treatment. Exemestane significantly increased testosterone [median change 0.21 ng/mL, (IQR 0.12-0.35)], decreased SHBG [median change -14.6 nmol/L, (IQR -23.1 to -8.6)], decreased total and HDL cholesterol by -10 mg/dL (IQR -21-2) and -7 mg/dL, (IQR -14 to -2), respectively. Triglycerides were reduced by both agents [median change -0.5 mg/dL (IQR -17.5-13.5) and -8 mg/dL (IQR -28-9) for celecoxib and exemestane, respectively]. Exemestane showed a remarkable antiproliferative effect on breast cancer, whereas celecoxib did not affect breast cancer proliferation. Given the proven preventive efficacy of exemestane, these findings support the use of Ki-67 to explore the optimal exemestane dose and schedule in the prevention setting. Cancer Prev Res; 9(5); 349-56. ©2016 AACR.
在乳腺癌术前试验中，Ki-67 标记指数可预测疾病结局，并为药物的预防潜力提供线索。我们进行了一项安慰剂对照试验，以评估手术前依西美坦和塞来昔布的活性。主要终点是 Ki-67 的变化。次要终点是循环生物标志物的调节。组织学证实雌激素受体阳性乳腺癌的绝经后妇女被随机分配至依西美坦 25mg/天（n=50）、塞来昔布 800mg/天（n=50）或安慰剂（n=25），术前 6 周给药。通过调整基线值的协方差分析模型分析生物标志物的变化。依西美坦显示 Ki-67 中位数绝对值降低 10%[从 22（四分位距 IQR，16-27），到 8（IQR 5-18）]，PgR 表达绝对值降低 15%[从 50（IQR 3-90），到 15（IQR -0-30）]。依西美坦显著增加了睾酮[中位数变化 0.21ng/ml，（IQR 0.12-0.35）]，降低了 SHBG[中位数变化-14.6nmol/L，（IQR -23.1 至-8.6）]，降低了总胆固醇和 HDL 胆固醇分别为 10mg/dL（IQR -21-2）和 7mg/dL（IQR -14-2）。两种药物均降低了甘油三酯[中位数变化分别为-0.5mg/dL（IQR -17.5-13.5）和-8mg/dL（IQR -28-9）]。依西美坦对乳腺癌具有显著的抗增殖作用，而塞来昔布则不影响乳腺癌增殖。鉴于依西美坦已被证实具有预防作用，这些发现支持使用 Ki-67 来探索预防环境中依西美坦的最佳剂量和方案。癌症预防研究；9(5)；349-56。©2016AACR。
