Clinical Trial of Acolbifene in Premenopausal Women at High Risk for Breast Cancer.
Clinical Trial of Acolbifene in Premenopausal Women at High Risk for Breast Cancer.
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DOI：
10.1158/1940-6207.capr-15-0109
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Heckman-Stoddard BM
中科院分区：
文献类型：
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作者：
Fabian CJ;Kimler BF;Zalles CM;Phillips TA;Metheny T;Petroff BK;Havighurst TC;Kim K;Bailey HH;Heckman-Stoddard BM
本研究的目的是评估选择性雌激素受体调节剂（SERM）阿柯菲因作为绝经前妇女乳腺癌预防剂的可行性。为了这样做，我们评估了随机乳晕周围细针抽吸（RPFNA）取样的良性乳腺组织的增殖变化作为主要终点，以及其他风险生物标志物的变化以及客观和主观副作用作为次要终点。25名细胞增生+/−异型性和≥2%乳腺上皮细胞Ki-67染色阳性的女性，每天接受20 mg阿科尔菲尼治疗，持续6-8个月，然后重新评估良性乳腺组织和血液风险生物标志物。尽管生物利用度雌二醇增加，但阿柯芬后Ki-67的中位值从基线时的4.6%（四分位数范围，3.1 - 8.5%）降至1.4% (IQR, 0.6 - 3.5%) （P<0.001； Wilcoxon sign rank检验）。雌激素诱导基因pS2、ER-α和PgR的表达量（RT-qPCR）也显著降低（p≤0.026）。血清IGF-1、IGFBP3、IGF-1与IGFBP3比值或乳腺密度无显著变化。主观副作用很小，没有明显增加潮热、肌肉痉挛、关节痛或疲劳。客观测量显示腰椎骨密度（DEXA）和卵巢囊肿增加，但子宫内膜厚度（超声）没有变化。综上所述，阿柯菲尼与良性乳腺上皮细胞增殖和雌激素诱导基因表达的有利变化相关，但副作用很小，提示IIB期安慰剂对照试验进一步评估其预防乳腺癌的作用。
The purpose of this study was to assess the feasibility of using the selective estrogen receptor modulator (SERM) acolbifene as a breast cancer prevention agent in premenopausal women. In order to do so we assessed change in proliferation in benign breast tissue sampled by random periareolar fine needle aspiration (RPFNA) as a primary endpoint, along with changes in other risk biomarkers and objective and subjective side effects as secondary endpoints. Twenty-five women with cytologic hyperplasia +/− atypia and ≥2% of breast epithelial cells staining positive for Ki-67, received 20 mg acolbifene daily for 6–8 months, and then had benign breast tissue and blood risk biomarkers re-assessed. Ki-67 decreased from a median of 4.6% (interquartile range, 3.1 – 8.5%) at baseline to 1.4% (IQR, 0.6 – 3.5%) after acolbifene (P<0.001; Wilcoxon signed rank test), despite increases in bioavailable estradiol. There were also significant decreases in expression (RT-qPCR) of estrogen inducible genes that code for pS2, ER-α, and PgR (p≤0.026). There was no significant change in serum IGF-1, IGFBP3, IGF-1:IGFBP3 ratio, or mammographic breast density. Subjective side effects were minimal with no significant increase in hot flashes, muscle cramps, arthralgias, or fatigue. Objective measures showed a clinically insignificant decrease in lumbar spine bone density (DEXA) and an increase in ovarian cysts but no change in endometrial thickness (sonography). In summary, acolbifene was associated with favorable changes in benign breast epithelial cell proliferation and estrogen inducible gene expression but minimal side effects, suggesting a Phase IIB placebo-controlled trial evaluating it further for breast cancer prevention.