Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group
Phase II Study of Temsirolimus in Women With Recurrent or Metastatic Endometrial Cancer: A Trial of the NCIC Clinical Trials Group
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DOI：
10.1200/jco.2010.34.1578
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发表时间：
2011-08-20
影响因子：
45.3
通讯作者：
Eisenhauer, Elizabeth A.
中科院分区：
文献类型：
--
作者：
Oza, Amit M.;Elit, Laurie;Eisenhauer, Elizabeth A.
目的磷酸酶和紧张素同源物（PTEN）是一种肿瘤抑制基因，其功能缺失突变在子宫内膜癌的发病过程中很常见，并具有重要意义。PTEN的缺失导致磷脂酰肌醇-3激酶/丝氨酸-苏氨酸激酶/哺乳动物雷帕霉素靶点（PI3K/Akt/mTOR）信号的失调，这可能通过促进血管生成、蛋白质翻译和细胞周期进展，为肿瘤细胞提供选择性生存优势。替西罗莫司是一种抑制mTOR的雷帕霉素酯衍生物，在这种情况下进行了评估。患者和方法序贯II期研究评估了替西莫司在复发或转移化疗或化疗治疗的子宫内膜癌妇女中的单药活性。替西莫司25mg静脉滴注，每周4周为一个周期。结果在首次化疗组中，33例患者接受了中位数为4个周期（范围1至23个周期）的化疗。在29例可评估缓解的患者中，4例（14%）有独立证实的部分缓解，20例（69%）有稳定的疾病作为最佳缓解，中位持续时间为5.1个月（范围，3.7至18.4个月）和9.7个月（范围，2.1至14.6个月）。只有5名患者（18%）有进展性疾病。在化疗组中，27例患者接受了中位数为3个周期（范围为1至6个周期）的治疗。在25例可评估缓解的患者中，1例（4%）有独立证实的部分缓解，12例（48%）病情稳定，中位持续时间为4.3个月（范围3.6至4.9个月）和3.7个月（范围2.4至23.2个月）。PTEN缺失（免疫组织化学和突变分析）和PI3K/Akt/mTOR通路的分子标记与临床结果无关。结论替西莫司对子宫内膜癌mTOR的单药抑制作用较强，首次化疗患者的mTOR抑制作用高于已化疗患者，且与PTEN状态无关。在未来的临床试验设计中应考虑到先前治疗的活性差异。中华临床杂志，29(3):378 - 385。(C) 2011年美国临床肿瘤学会
Purpose Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting.Patients and Methods Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles.Results In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome.Conclusion mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs. J Clin Oncol 29:3278-3285. (C) 2011 by American Society of Clinical Oncology