Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial.
Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial.
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DOI：
10.1002/stem.156
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发表时间：
2009-09
期刊：
影响因子：
5.2
通讯作者：
Blau, C. Anthony
中科院分区：
文献类型：
--
作者：
Miller, Chris P.;Lowe, Kimberly A.;Valliant-Saunders, Karine;Kaiser, Joringel F.;Mattern, Dominik;Urban, Nicole;Henke, Michael;Blau, C. Anthony
关键词：
尽管癌症中普遍存在贫血，但重组促红细胞生成素(EPO)的使用量有所下降，因为最近的第三阶段试验显示，在随机服用EPO的受试者中，癌症进展更快，生存时间更短。由于EPO受体(EPOR)、JAK2和Hsp70是红系细胞中EPO信号的典型介体，我们推测EPO在肿瘤中高水平表达这些效应物的患者中可能尤其有害。由于免疫组织化学对低水平EPOR蛋白的检测不敏感，我们建立了检测福尔马林固定石蜡包埋肿瘤(FFPE)中EPOR、JAK2和Hsp70mRNA水平的方法。我们测试了来自Enhance的23例乳癌和136例头颈癌，这是一项III期试验，包括351名患者，在肿瘤完全切除、部分切除或不切除后，随机接受EPO与安慰剂配合放射治疗。EPOR、JAK2和Hsp70的mRNA水平在乳腺癌中分别为30倍、12倍和13倍，在头颈部癌中分别为30倍、40倍和30倍。在EPOR、JAK2或Hsp70表达高于或低于中位数水平的头颈部癌症患者中，局部区域无进展生存率(LPFS)没有差异，但在未切除肿瘤患者(n=28)中，EPOR高于中位数、JAK2高于中位数和Hsp70mRNA低于中位数的患者的局部区域无进展生存期(LPFS)均与显著较差相关。我们的结果为利用其他三期临床试验中的存档肿瘤探索促红细胞生成素、癌症进展和生存率之间的关系提供了一个框架。
Despite the prevalence of anemia in cancer, recombinant erythropoietin (Epo) has declined in use because of recent Phase III trials showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Since Epo receptor (EpoR), Jak2, and Hsp70 are well-characterized mediators of Epo signaling in erythroid cells, we hypothesized that Epo might be especially harmful in patients whose tumors express high levels of these effectors. Because of the insensitivity of immunohistochemistry for detecting low level EpoR protein, we developed assays to measure levels of EpoR, Jak2 and Hsp70 mRNA in formalin-fixed paraffin-embedded (FFPE) tumors. We tested 23 archival breast tumors as well as 136 archival head and neck cancers from ENHANCE, a Phase III trial of 351 patients randomized to Epo versus placebo concomitant with radio-therapy following complete resection, partial resection, or no resection of tumor. EpoR, Jak2, and Hsp70 mRNA levels varied >30-fold, >12-fold, and >13-fold across the breast cancers, and >30-fold, >40-fold, and >30-fold across the head and neck cancers, respectively. Locoregional progression-free survival (LPFS) did not differ among patients whose head and neck cancers expressed above- versus below-median levels of EpoR, Jak2 or Hsp70, except in the subgroup of patients with unresected tumors (n = 28), where above-median EpoR, above-median Jak2, and below-median Hsp70 mRNA levels were all associated with significantly poorer LPFS. Our results provide a framework for exploring the relationship between Epo, cancer progression, and survival using archival tumors from other Phase III clinical trials.
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影响因子：
45.3
作者：
Leyland-Jones, B;Semiglazov, V;Vercammen, E
通讯作者：
Vercammen, E
影响因子：
168.9
作者：
Henke, M;Laszig, R;Frommhold, H
通讯作者：
Frommhold, H
DOI：
10.1196/annals.1391.018
发表时间：
2007-01-01
期刊：
STRESS RESPONSES IN BIOLOGY AND MEDICINE
影响因子：
--
作者：
Morano, Kevin A.
通讯作者：
Morano, Kevin A.
影响因子：
11.5
作者：
Arcasoy, Murat O.
通讯作者：
Arcasoy, Murat O.
影响因子：
5
作者：
Antonov, J;Goldstein, DR;Jaggi, R
通讯作者：
Jaggi, R