Ottawa Hospital Research Institute, University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H 5L3, Canada.
Gynecol Oncol. 2013 Nov;131(2):315-20. doi: 10.1016/j.ygyno.2013.08.004. Epub 2013 Aug 9.
Temsirolimus (TEM) has recently shown activity (NCIC CTG phase II trial) in endometrial cancer (EC). Despite EC having a high rate of PTEN mutation, in this trial activity was independent of PTEN and other molecular markers. We explored whether treatment related toxicity occurring in cycle one was predictive of outcomes.
Patients were those enrolled on two sequential phase II studies of the NCIC CTG that evaluated single agent TEM in women with recurrent or metastatic chemotherapy naïve or treated EC. An exploratory landmark analysis examined the relationship between early treatment related toxicities as well as prior chemotherapy and efficacy outcomes (response, progression, and tumor size shrinkage) in univariate and multivariate analyses. The relationship between molecular markers and outcomes was also reexamined in patients.
Mucositis, diarrhea, decreased absolute neutrophil count, as well as elevated glucose, or cholesterol were not independent predictors of response or progression. Highest fasting triglyceride predicted for a 3.5% tumor shrinkage from baseline. Women previously treated with chemotherapy were at 7.37 times greater risk of progression and experienced 20.9% increased tumor growth compared to chemotherapy naïve women. Molecular markers were not predictors of response or progression.
Except for elevation in fasting triglyceride being associated with minimal tumor shrinkage, no other relationship between efficacy and TEM induced adverse events was found. mTOR inhibition activity in EC seems greatest in chemo-naïve patients. Future studies of mTOR inhibitors in EC should focus on women without prior chemotherapy while continuing to explore molecular mechanisms of benefit.
替西罗莫司（TEM）在子宫内膜癌（EC）中最近显示出活性（NCIC CTG 二期试验）。尽管 EC 具有很高的 PTEN 突变率，但在该试验中，活性与 PTEN 及其他分子标志物无关。我们探讨了在第一个周期中发生的与治疗相关的毒性是否可预测结果。
患者是在 NCIC CTG 评估 Tem 单药治疗复发性或转移性化疗初治或经治 EC 妇女的两项连续二期研究中入组的患者。探索性里程碑分析检查了早期治疗相关毒性以及先前化疗与疗效结局（反应、进展和肿瘤大小缩小）之间的关系，包括单变量和多变量分析。还重新检查了患者的分子标志物与结局之间的关系。
粘膜炎、腹泻、中性粒细胞绝对计数减少以及血糖或胆固醇升高不是反应或进展的独立预测因素。空腹甘油三酯最高预示着从基线开始有 3.5%的肿瘤缩小。与化疗初治的妇女相比，先前接受过化疗的妇女进展的风险高 7.37 倍，肿瘤生长增加 20.9%。分子标志物不是反应或进展的预测因素。
除了空腹甘油三酯升高与肿瘤缩小最小相关外，未发现疗效与 Tem 引起的不良反应之间存在其他关系。mTOR 抑制剂在 EC 中的活性在化疗初治患者中最大。未来在 EC 中进行 mTOR 抑制剂的研究应聚焦于无既往化疗的女性，同时继续探索获益的分子机制。
