Abstract：
BACKGROUND: Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.
METHODS: Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).
RESULTS: The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL\'s potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.
CONCLUSIONS: These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.
METHODS: Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).
RESULTS: The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL\'s potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.
CONCLUSIONS: These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.
摘要：
背景：核因子κB受体激活剂配体（RANKL）可以通过改变肿瘤微环境和免疫细胞反应，直接促进肿瘤生长并间接支持肿瘤免疫逃避。本研究旨在评估可溶性RANKL在接受程序性细胞死亡1（PD1）/程序性死亡配体1（PDL1）检查点抑制剂治疗的晚期非小细胞肺癌（NSCLC）患者中的预后意义。
方法：在接受PD1/PDL1检查点抑制剂单药治疗的100例没有骨转移的晚期NSCLC患者中测定血浆RANKL水平。要建立最佳截止值，我们在四个不同患者组的R.生存曲线中使用了CutoffFinder包，根据其RANKL和PDL1水平（高或低），使用Kaplan-Meier方法生成，并与对数秩检验进行比较。Cox回归模型计算了总生存期(OS)和无进展生存期(PFS)的HR和95%CI。
结果：最佳RANKL截止值为280.4pg/mL，将患者分为RANKL水平高或低的组。在24个月时，RANKL浓度增加和生存率降低之间观察到显着关联。仅在表达高水平PDL1的亚组中（p=0.002）。此外,低RANKL水平与PDL1表达升高与PFS改善相关(中位数22个月,95%CI6.70至50vs中位数4个月，95%CI3.0至7.30，p=0.009）和OS（中位数26个月，95%CI20未达到vs中位数7个月，95%CI6至13，p=0.003），表明RANKL可能是这些患者不良预后的指标。多因素分析确定RANKL是PFS和OS的独立阴性预后因素，与其他临床病理特征无关。
结论：这些结果突出了RANKL在PDL1高表达患者中的预后和预测价值。
方法：在接受PD1/PDL1检查点抑制剂单药治疗的100例没有骨转移的晚期NSCLC患者中测定血浆RANKL水平。要建立最佳截止值，我们在四个不同患者组的R.生存曲线中使用了CutoffFinder包，根据其RANKL和PDL1水平（高或低），使用Kaplan-Meier方法生成，并与对数秩检验进行比较。Cox回归模型计算了总生存期(OS)和无进展生存期(PFS)的HR和95%CI。
结果：最佳RANKL截止值为280.4pg/mL，将患者分为RANKL水平高或低的组。在24个月时，RANKL浓度增加和生存率降低之间观察到显着关联。仅在表达高水平PDL1的亚组中（p=0.002）。此外,低RANKL水平与PDL1表达升高与PFS改善相关(中位数22个月,95%CI6.70至50vs中位数4个月，95%CI3.0至7.30，p=0.009）和OS（中位数26个月，95%CI20未达到vs中位数7个月，95%CI6至13，p=0.003），表明RANKL可能是这些患者不良预后的指标。多因素分析确定RANKL是PFS和OS的独立阴性预后因素，与其他临床病理特征无关。
结论：这些结果突出了RANKL在PDL1高表达患者中的预后和预测价值。
