Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma.
Analyses of potential predictive markers and survival data for a response to sunitinib in patients with metastatic renal cell carcinoma.
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DOI：
10.1371/journal.pone.0076386
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fuessel S
中科院分区：
文献类型：
--
作者：
Dornbusch J;Zacharis A;Meinhardt M;Erdmann K;Wolff I;Froehner M;Wirth MP;Zastrow S;Fuessel S
转移性透明细胞肾细胞癌（ccRCC）患者经常接受酪氨酸激酶抑制剂（TKI）治疗，如舒尼替尼。它主要通过靶向VEGF和PDGF的受体来抑制血管生成途径。在ccRCC中，血管生成的特征在于von Hippel-Lindau基因（VHL）的失活，这反过来导致HIF 1 α靶基因（如CA 9和VEGF）的诱导。此外，ccRCC的血管生成表型还通过内皮标志物（CD 31、CD 34）或其他肿瘤促进因子如Ki 67或存活素来反映。来自42名接受舒尼替尼治疗的转移性ccRCC患者的原发性肿瘤标本的组织微阵列针对与血管生成相关的选定标志物进行了化学染色。根据舒尼替尼治疗3、6、9个月后和末次报告后（12-54个月）根据RECIST标准评价的客观缓解率，评估这些标志物的预后和预测潜力。此外，对来自20名ccRCC患者的冷冻保存的肿瘤组织的DNA进行VHL拷贝数和突变分析。HIF-1α、CA 9、Ki 67、CD 31、pVEGFR 1、VEGFR 1和-2、pPDGFRα和-β的免疫染色与舒尼替尼治疗6个月和9个月后的反应以及治疗期间的最后报告显著相关。此外，HIF-1α、CA 9、CD 34、VEGFR 1和-3和PDGRFα与无进展生存期（PFS）和总生存期（OS）显著相关。在多变量考克斯比例风险回归分析中，高CA 9膜染色和9个月后的反应是更长OS的独立预后因素。经常观察到的VHL基因拷贝数丢失和突变导致VHL、HIF-1α、CA 9和VEGF的表达改变。转移性ccRCC患者原发肿瘤中HIF-1α、CA 9、Ki 67、CD 31、pVEGFR 1、VEGFR 1和-2、pPDGFRα和-β的免疫表达可能支持舒尼替尼治疗的良好反应的预测。
Patients with metastatic clear cell renal cell carcinoma (ccRCC) are frequently treated with tyrosine kinase inhibitors (TKI) such as sunitinib. It inhibits angiogenic pathways by mainly targeting the receptors of VEGF and PDGF. In ccRCC, angiogenesis is characterized by the inactivation of the von Hippel-Lindau gene (VHL) which in turn leads to the induction of HIF1α target genes such as CA9 and VEGF. Furthermore, the angiogenic phenotype of ccRCC is also reflected by endothelial markers (CD31, CD34) or other tumor-promoting factors like Ki67 or survivin. Tissue microarrays from primary tumor specimens of 42 patients with metastatic ccRCC under sunitinib therapy were immunohistochemically stained for selected markers related to angiogenesis. The prognostic and predictive potential of theses markers was assessed on the basis of the objective response rate which was evaluated according to the RECIST criteria after 3, 6, 9 months and after last report (12–54 months) of sunitinib treatment. Additionally, VHL copy number and mutation analyses were performed on DNA from cryo-preserved tumor tissues of 20 ccRCC patients. Immunostaining of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β was significantly associated with the sunitinib response after 6 and 9 months as well as last report under therapy. Furthermore, HIF-1α, CA9, CD34, VEGFR1 and -3 and PDGRFα showed significant associations with progression-free survival (PFS) and overall survival (OS). In multivariate Cox proportional hazards regression analyses high CA9 membrane staining and a response after 9 months were independent prognostic factors for longer OS. Frequently observed copy number loss and mutation of VHL gene lead to altered expression of VHL, HIF-1α, CA9, and VEGF. Immunoexpression of HIF-1α, CA9, Ki67, CD31, pVEGFR1, VEGFR1 and -2, pPDGFRα and -β in the primary tumors of metastatic ccRCC patients might support the prediction of a good response to sunitinib treatment.
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作者：
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影响因子：
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作者：
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通讯作者：
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