Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
Department of Pathology, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
Br J Cancer. 2014 May 27;110(11):2700-7. doi: 10.1038/bjc.2014.225. Epub 2014 May 1.
Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients.
Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out.
The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05).
Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
舒尼替尼是转移性肾细胞癌患者广泛使用的治疗药物。即便如此，仍有一部分患者表现出毒性而无临床获益。在本研究中，我们分析了参与血管生成的关键分子靶标（血管内皮生长因子 A（VEGF-A）、VEGF 受体 2（KDR）、磷酸化（p）KDR 和微血管密度（MVD）），以测试它们在接受舒尼替尼治疗的肾细胞癌患者中作为临床获益预测生物标志物的潜在价值。
通过免疫组织化学检测 48 例肾细胞癌患者（包括 23 例转移性病例接受舒尼替尼治疗）中 VEGF-A、KDR 和 pKDR-Y1775 的表达以及 CD31，用于 MVD 的可视化。为每个生物标志物定义了阈值，并进行了无进展生存期（PFS）和总生存期（OS）的单变量和多变量分析。
VEGF-A 的组织评分平均值为 121.6（范围，10-300）；KDR 为 258.5（范围，150-300）；pKDR-Y1775 为 10.8（范围，0-65），CD31 阳性结构的平均 MVD 可视化值为 49（范围，10-126）。在接受舒尼替尼治疗的患者中，pKDR-Y1775 观察到 PFS（P=0.01）和 OS（P=0.007）的统计学差异。重要的是，在多变量 Cox 分析中，pKDR-Y1775 对 PFS（P=0.01；HR：5.35，95%CI，1.49-19.13）和 OS（P=0.02；HR：5.13，95%CI，1.25-21.05）仍然具有显著意义。
我们的研究结果表明，肿瘤基质中磷酸化（即激活）KDR 的表达可作为肾细胞癌一线舒尼替尼治疗患者临床结局的预测生物标志物。
