Zeuschner Philip, Hölters Sebastian, Stöckle Michael, Seliger Barbara, Mueller Anja, Bachmann Hagen S, Grünwald Viktor, Christoph Daniel C, Stenzl Arnulf, Grimm Marc-Oliver, Brüning Fabian, Goebell Peter J, Augustin Marinela, Roos Frederik, Harde Johanna, Benz-Rüd Iris, Staehler Michael, Junker Kerstin
Department of Urology and Pediatric Urology, Saarland University, Kirrberger Street, 66421 Homburg/Saar, Germany.
Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Universitätsplatz 10, 06108 Halle (Saale), Germany.
Cancers (Basel). 2021 May 25;13(11):2594. doi: 10.3390/cancers13112594.
There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.
转移性肾细胞癌（mRCC）治疗中对预测性生物标志物存在未满足的需求。IV期MARC - 2试验在主要为透明细胞mRCC且从依维莫司二线治疗中获益的患者中寻找预测性血液生物标志物。采用探索性方法，通过蛋白质组学、酶联免疫吸附测定（ELISA）和多态性分析评估潜在生物标志物。基线时血管生成相关蛋白血小板反应蛋白-2（TSP-2）水平较低（≤665十亿分之一，ppb）可识别出中位无进展生存期（PFS）较长的治疗反应者（基线≤665 ppb：6.9个月对1.8个月，P = 0.005）。治疗开始后两周，反应者血清中的乳酸脱氢酶（LDH）水平较高（>27.14 nmol/L），这与较长的中位PFS（3.8个月对2.2个月，P = 0.013）和改善的总生存期（OS；31.0个月对14.0个月，P < 0.001）相关。与包括国际转移性肾细胞癌联合数据库（IMDC）评分在内的基线患者参数相比，基线TSP-2水平与PFS的关系更强（风险比[HR] 0.36，P = 0.008）。治疗开始后两周血清LDH水平升高是OS的最佳预测指标（HR 0.21，P < 0.001）。雷帕霉素靶蛋白（mTOR）多态性似乎与治疗反应相关，但不显著。因此，我们确定TSP-2和LDH是透明细胞mRCC患者在一种血管内皮生长因子（VEGF）靶向治疗失败后对依维莫司治疗反应有前景的预测性生物标志物。
