三受体阴性乳腺癌女性患者中，紫杉醇序贯FEC的标准新辅助化疗与紫杉醇联合依维莫司序贯FEC的开放标签随机临床试验†
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†.
作者信息
Gonzalez-Angulo A M, Akcakanat A, Liu S, Green M C, Murray J L, Chen H, Palla S L, Koenig K B, Brewster A M, Valero V, Ibrahim N K, Moulder-Thompson S, Litton J K, Tarco E, Moore J, Flores P, Crawford D, Dryden M J, Symmans W F, Sahin A, Giordano S H, Pusztai L, Do K-A, Mills G B, Hortobagyi G N, Meric-Bernstam F
机构信息
Department of Breast Medical Oncology Department of Systems Biology
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
出版信息
Ann Oncol. 2014 Jun;25(6):1122-7. doi: 10.1093/annonc/mdu124. Epub 2014 Mar 24.
BACKGROUND
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).
PATIENTS AND METHODS
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.
RESULTS
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.
CONCLUSION
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.
CLINICAL TRIAL NUMBER
NCT00499603.
背景
依维莫司除了具有直接的抗增殖活性外，还能在体外和体内协同增强紫杉烷对乳腺癌细胞的细胞毒性。我们旨在确定在三阴性乳腺癌（TNBC）中，将依维莫司添加到标准新辅助化疗中的药效学变化及反应。
患者与方法
对原发性TNBC患者进行II期研究，随机分为T-FEC组（紫杉醇80mg/m²静脉注射，每周1次，共12周，随后每3周给予5-氟尿嘧啶500mg/m²、表柔比星100mg/m²和环磷酰胺500mg/m²，共4个周期）和TR-FEC组（紫杉醇80mg/m²静脉注射，依维莫司30mg口服，每周1次，共12周，随后给予FEC）。在基线、48小时、12周及手术时采集肿瘤样本，通过反相蛋白阵列（RPPA）评估PI3K/AKT/mTOR通路的分子变化。临床终点包括12周临床缓解率（12周RR）、病理完全缓解（pCR）和毒性。
结果
登记62例患者，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小时时mTOR通路下调。T-FEC组和TR-FEC组通过超声评估的12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）。TR-FEC组48小时时mTOR下调与12周RR无关（P = 0.58）。两组主要的美国国立癌症研究所（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。未发生3/4级口腔炎。
结论
将依维莫司添加到紫杉醇中耐受性良好。依维莫司下调mTOR信号，但TR-FEC组48小时时mTOR下调与12周RR无关。
临床试验编号
NCT00499603。
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