Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway.
J Pathol Clin Res. 2018 Apr;4(2):114-123. doi: 10.1002/cjp2.96. Epub 2018 Mar 5.
Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, and anti-angiogenic treatment is currently first line therapy for metastatic ccRCC (mccRCC). Response rates and duration of response show considerable variation, and adverse events have a major influence on patient quality of life. The need for predictive biomarkers to select responders to receptor tyrosine kinase inhibitors upfront is urgent. We investigated the predictive value of immunohistochemical biomarkers associated with angiogenesis and systemic inflammation in mccRCC. Forty-six patients with metastatic or non-resectable ccRCC treated with sunitinib were included. Metastatic and/or primary tumour tissue was stained by immunohistochemistry for selected markers related to angiogenesis [vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR2), platelet-derived growth factor receptor β (PDGFRβ), and heat shock protein 27 (HSP27)] and immune responses [Interleukin 6 receptor α (IL6Rα), interleukin-6 (IL6), and jagged1 (JAG1)]. The predictive potential of the candidate markers was assessed by correlations with response rates (RECIST). In addition, progression free survival (PFS) and overall survival (OS) were analysed. Low tumour cell expression of IL6Rα was significantly associated with improved response to sunitinib (Fisher's exact test, p = 0.03), but not with PFS or OS. Median/high expression of IL6Rα showed significant association with median/high expression of VEGF-A and HSP27. Furthermore, low expression of IL6 was significantly associated with improved PFS, but not OS or response rates. High expression of IL6 was significantly associated with high expression of JAG1, VEGF-A, VEGFR2, and PDGFRβ. Loss of tumour cell expression of IL6Rα in mccRCC patients treated with sunitinib predicts improved treatment response, and might represent a candidate predictive marker.
透明细胞肾细胞癌 (ccRCC) 是最常见的肾细胞癌类型，抗血管生成治疗目前是转移性 ccRCC（mccRCC）的一线治疗方法。反应率和反应持续时间存在显著差异，不良事件对患者的生活质量有重大影响。目前迫切需要预测生物标志物来选择对受体酪氨酸激酶抑制剂有反应的患者。我们研究了与 mccRCC 血管生成和全身炎症相关的免疫组织化学生物标志物的预测价值。纳入了 46 名接受舒尼替尼治疗的转移性或不可切除的 ccRCC 患者。通过免疫组织化学染色对选定的与血管生成相关的标志物[血管内皮生长因子 A (VEGF-A)、血管内皮生长因子受体 2 (VEGFR2)、血小板衍生生长因子受体 β (PDGFRβ)和热休克蛋白 27 (HSP27)]和免疫反应[白细胞介素 6 受体 α (IL6Rα)、白细胞介素 6 (IL6)和锯齿 1 (JAG1)]进行了转移性和/或原发性肿瘤组织染色。通过与反应率 (RECIST) 的相关性评估候选标志物的预测潜力。此外，还分析了无进展生存期 (PFS) 和总生存期 (OS)。肿瘤细胞 IL6Rα 低表达与舒尼替尼的反应改善显著相关（Fisher 确切检验，p=0.03），但与 PFS 或 OS 无关。IL6Rα 中/高表达与 VEGF-A 和 HSP27 中/高表达显著相关。此外，IL6 低表达与 PFS 改善显著相关，但与 OS 或反应率无关。IL6 高表达与 JAG1、VEGF-A、VEGFR2 和 PDGFRβ 高表达显著相关。接受舒尼替尼治疗的 mccRCC 患者肿瘤细胞 IL6Rα 表达缺失预测治疗反应改善，可能是候选预测标志物。
