Department of Nuclear Medicine, Jiangxi Province Key Laboratory of Laboratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.
Biological Resource Center, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China; Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang 330006, China.
Pharmacol Res. 2021 Aug;170:105734. doi: 10.1016/j.phrs.2021.105734. Epub 2021 Jun 19.
OBJECTIVE: Cancer elicited inflammation is the main environmental cause leading to carcinogenesis and metastasis of non-small cell lung cancer (NSCLC). Roles of the inflammatory biomarker in predicting the clinical efficacy of tyrosine kinase inhibitor (TKI) and prognosis of naive patients with advanced NSCLC need to be determined, and the best inflammatory predicted biomarker remains unknown. METHODS: A total of 178 eligible advanced NSCLC patients (124 and 54 cases within discovery and validation cohorts, respectively) who received first-line EGFR-TKI between July of 2014 and October of 2020 were enrolled in the present study. We detected circulating immune cell counting, albumin (Alb), pre-albumin (pAlb), ALP, AST, LDH, GGT, HDL-c, and fibrinogen (Fib) concentrations, and calculated 22 inflammatory ratios and scores. Logistic regression and Cox proportional hazards models were used to assess the impact of these ratios and scores on objective response and disease control rate (ORR and DCR) as well as progression-free survival (PFS) in these patients. RESULTS: Twenty-five percentage and 24.07% of NSCLC patients were observed objective response to the treatment of first-line EGFR-TKI in discovery and validation cohort, respectively. Univariate and multivariate Cox regression showed that high PLR, NPS, SII, SIS, mSIS, GLR and FPR as well as low PNI were significantly associated with poor PFS in discovery cohort. However, only high SII and FPR were found to be associated with unsatisfactory outcome in validation cohort. Time-dependent areas under ROC of FPR were 0.702 (0.517-0.888) in discovery cohort, and 0.767 (0.613-0.921) in validation cohort, which were extremely higher than the other biomarkers. The patients with FPR-SII combined score 2 harbored worse prognosis compared to the combined score 0 in discovery (p = 0.003, adjusted HR = 2.888, 95%CI = 1.500-5.560) and validation cohort (p = 0.001, adjusted HR = 3.769, 95%CI = 1.676-8.478) as well as overall population (p < 0.001, adjusted HR = 3.109, 95%CI = 1.878-5.147), and its time-dependent AUCs were 0.747 (0.594-0.900) and 0.815 (0.688-0.942) in the two cohorts, respectively, which were significantly higher than the single biomarker in the two cohorts. The patients with high FPR and FPR-SII score harbored worse DCR than the low patients in the two cohorts and overall population, respectively. Moreover, the similar poor survival was observed in advanced high-FPR NSCLC patients with different treatment options, however, the survival of low-FPR patients with treatment of single TKI, radiotherapy or chemotherapy or radio-chemotherapy combined TKI was good compared to the high-FPR patients with radio-chemotherapy combined TKI, and the survival differences were observed between TKI (p < 0.001) or radiotherapy combined TKI (p = 0.014) treated low-FPR patients and the high FPR patients. Additionally, FPR-SII combined score could monitor the progression of the disease in real-time, and the median month of the positive score appearance was significantly earlier than CT/MRI detection (p < 0.001 for 3 months vs. 13 months). CONCLUSIONS: High-grade cancer elicited inflammation could attenuates response and outcome in tyrosine kinase inhibitor naive patients with advanced NSCLC. FPR-SII combined score was the best inflammatory biomarker to monitor and predict the progression of advanced NSCLC patients with treatment of TKI.
目的：癌症引发的炎症是导致非小细胞肺癌（NSCLC）发生和转移的主要环境因素。炎症生物标志物在预测酪氨酸激酶抑制剂（TKI）的临床疗效和预测晚期 NSCLC 初治患者的预后方面的作用需要确定，而最佳的炎症预测生物标志物仍不清楚。
方法：本研究共纳入了 178 名接受一线 EGFR-TKI 治疗的晚期 NSCLC 患者（分别为 124 名和 54 名在发现和验证队列中的患者），这些患者在 2014 年 7 月至 2020 年 10 月期间接受了治疗。我们检测了循环免疫细胞计数、白蛋白（Alb）、前白蛋白（pAlb）、碱性磷酸酶（ALP）、天门冬氨酸氨基转移酶（AST）、乳酸脱氢酶（LDH）、γ-谷氨酰转肽酶（GGT）、高密度脂蛋白胆固醇（HDL-c）和纤维蛋白原（Fib）浓度，并计算了 22 个炎症比值和评分。使用逻辑回归和 Cox 比例风险模型评估这些比值和评分对这些患者的客观缓解率（ORR 和 DCR）和无进展生存期（PFS）的影响。
结果：在发现和验证队列中，分别有 25%和 24.07%的 NSCLC 患者对一线 EGFR-TKI 治疗有客观缓解。单因素和多因素 Cox 回归显示，高 PLR、NPS、SII、SIS、mSIS、GLR 和 FPR 以及低 PNI 与发现队列的不良 PFS显著相关。然而，只有高 SII 和 FPR 与验证队列的不良结果相关。FPR 的时间依赖性 ROC 曲线下面积在发现队列中为 0.702（0.517-0.888），在验证队列中为 0.767（0.613-0.921），均显著高于其他生物标志物。FPR-SII 联合评分 2 的患者与评分 0 的患者相比，在发现（p=0.003，调整后的 HR=2.888，95%CI=1.500-5.560）和验证队列（p=0.001，调整后的 HR=3.769，95%CI=1.676-8.478）以及总体人群（p<0.001，调整后的 HR=3.109，95%CI=1.878-5.147）中预后更差，其时间依赖性 AUC 在两个队列中分别为 0.747（0.594-0.900）和 0.815（0.688-0.942），均显著高于两个队列中的单个生物标志物。高 FPR 和 FPR-SII 评分的患者与低评分患者相比，在两个队列和总体人群中的 DCR 更差。此外，在不同治疗方案的晚期高 FPR NSCLC 患者中观察到类似的不良生存情况，然而，与高 FPR 患者联合 TKI 放疗或化疗或放化疗联合 TKI 治疗相比，低 FPR 患者单独接受 TKI、放疗或化疗或放化疗联合 TKI 治疗的生存情况较好，并且在 TKI（p<0.001）或放疗联合 TKI（p=0.014）治疗的低 FPR 患者与高 FPR 患者之间观察到生存差异。此外，FPR-SII 联合评分可以实时监测疾病的进展，阳性评分出现的中位时间明显早于 CT/MRI 检测（p<0.001，3 个月 vs. 13 个月）。
结论：高级别癌症引发的炎症可降低晚期 NSCLC 初治患者对 TKI 的反应和疗效。FPR-SII 联合评分是监测和预测接受 TKI 治疗的晚期 NSCLC 患者疾病进展的最佳炎症生物标志物。
Cochrane Database Syst Rev. 2016-5-25
Zhongguo Fei Ai Za Zhi. 2019-2-20
Int J Oncol. 2024-7
Zotero 插件