Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma
Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma
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DOI：
10.3816/cgc.2007.n.020
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发表时间：
2007-09-01
影响因子：
3.2
通讯作者：
Atkins, Michael
中科院分区：
文献类型：
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作者：
Cho, Daniel;Signoretti, Sabina;Atkins, Michael
目的：与其他分子靶向药物类似，雷帕霉素的哺乳动物靶向抑制剂替西罗莫司在治疗晚期肾癌方面显示出良好的活性。然而，似乎只有一小部分患者产生了显著的肿瘤反应。为了确定对替西罗莫司疗效的潜在预测因素，对泰西莫司治疗晚期肾癌的11期随机试验中的一组患者的肿瘤样本进行了研究。患者和方法：对接受替西罗莫司治疗的患者的石蜡包埋组织切片进行碳酸氢酶IX、磷酸S6、磷酸化Akt(PACT)以及磷酸酶和张力蛋白同源物的免疫组织化学染色。表达水平与对替西罗莫司的客观反应(部分缓解[PR]、轻微缓解[MR])和临床受益(PR、MR、SD>；=4个周期)相关。此外，还进行了von Hippel-Lindau(VHL)突变分析，并与疗效相关。结果：从20名肿瘤反应和磷酸S6和碳酸氢酶IX染色均可评估的患者身上获得了组织标本。此外，19个样本可评估为PAKT，18个样本可评估为磷酸酶和张力蛋白同源物。对16例标本进行VHL基因突变分析。5例患者对替西罗莫司有客观反应(1例PR/4例MRS)。磷酸化S6的表达(P=0.02)和PACT的阳性表达(P=0.07)与替西罗莫司的疗效呈正相关。没有磷酸化S6或PACT高表达的患者出现客观的肿瘤反应。碳酸氢酶IX、磷酸酶和张力蛋白同源基因的表达或VHL状态与替西罗莫司的疗效无关。结论：磷酸化S6和PAKT的表达是预测替西罗莫司疗效的有希望的生物标志物，值得在雷帕霉素抑制剂靶点的哺乳动物患者选择模型中进一步探索。
Purpose: Similar to other molecularly targeted agents, temsirolimus, an inhibitor of mammalian target of rapamycin, has shown promising activity in advanced renal cell carcinoma. However, only a subset of patients appears to derive significant tumor responses. In an effort to identify potential predictors of response to temsirolimus, tumor samples from a subset of patients within a randomized phase 11 trial of temsirolimus in advanced renal cell carcinoma were studied. Patients and Methods: Paraffin-embedded tissue sections from patients who had received temsirolimus were immunostained with antibodies to carbonic anhydrase IX, phosphoS6, phospho-Akt (pAkt), and phosphotase and tensin homologue. Expression levels were correlated with objective response (partial response [PR], minor response [MR]) and clinical benefit (PR, MR, SD >= 4 cycles) to temsirolimus. In addition, von Hippel-Lindau (VHL) mutational analysis was performed and correlated with response. Results: Tissue specimens were obtained from 20 patients who were evaluable for both tumor response and staining for phospho-S6 and carbonic anhydrase IX. In addition, 19 specimens were evaluable for pAkt, and 18 for phosphotase and tensin homologue. VHL mutational analysis was performed on 16 samples. Five patients achieved an objective response (1 PR/4 MRs) to temsirolimus. There was a positive association of phospho-S6 expression (P =.02) and a trend toward positive expression of pAkt (P =.07) with response to temsirolimus. No patient without high expression of either phospho-S6 or pAkt experienced an objective tumor response. There was no correlation of carbonic anhydrase IX and phosphotase and tensin homologue expression or VHL status with response to temsirolimus. Conclusion: These results suggest that phospho-S6 and pAkt expression are promising predictive biomarkers for response to temsirolimus that are worthy of further exploration for use in patient selection models for mammalian target of rapamycin inhibitors.