Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer
Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer
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DOI：
10.1093/annonc/mdu124
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发表时间：
2014-06-01
影响因子：
50.5
通讯作者：
Meric-Bernstam, F.
中科院分区：
文献类型：
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作者：
Gonzalez-Angulo, A. M.;Akcakanat, A.;Meric-Bernstam, F.
依维莫司在体外和体内协同增强紫杉烷诱导的乳腺癌细胞的细胞毒性，此外还表现出直接的抗增殖活性。我们的目的是确定在三阴性乳腺癌（TNBC）的标准新辅助化疗中添加依维莫司的药效学变化和反应。在随机分配至T-FEC的原发性TNBC患者中的II期研究（紫杉醇80 mg/m（2）静脉注射，每周一次，持续12周，随后是5-氟尿嘧啶500 mg/m（2），表阿霉素100 mg/m（2），和环磷酰胺500 mg/m2，每3周一次，共4个周期）与TR-FEC（紫杉醇80 mg/m2静脉注射和依维莫司30 mg PO每周一次，共12周，随后FEC）。在基线、48小时、12周和手术时通过反相蛋白阵列（RPPA）收集肿瘤样品以评估PI 3 K/AKT/mTOR通路中的分子变化。临床终点包括12周临床有效率（12周RR）、病理完全缓解（pCR）和毒性。登记了62例患者，其中50例随机分组，27例接受T-FEC，23例接受TR-FEC。中位年龄为48岁（范围31-75岁）。TR-FEC组在48 h时mTOR通路表达下调，T-FEC组和TR-FEC组的1周RR分别为29.6%和47.8%（P = 0.075），pCR分别为25.9%和30.4%（P = 0.76）。在TR-FEC组中，48 h mTOR下调与12周RR无关（P = 0.58）。两组的主要NCI 3/4级毒性包括贫血、中性粒细胞减少、皮疹/脱屑和呕吐。TR-FEC组有1例3级肺炎，无3/4级口腔炎发生，紫杉醇加依维莫司耐受性良好。依维莫司下调mTOR信号，但在TR-FEC组中，48 h mTOR下调与12周RR无关。
Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC).Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity.Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred.The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group.