血清炎性标志物与一线免疫抑制剂治疗晚期非小细胞肺癌患者预后的关系

doi:10.11904/j.issn.1002-3070.2024.01.006

摘要/Abstract

摘要： 目的探讨基线水平中性粒细胞-淋巴细胞比值(NLR)、血小板计数-淋巴细胞比值(PLR)、单核细胞-淋巴细胞比值(MLR)、泛免疫炎症值(PIV)在应用PD-1抑制剂联合化疗的晚期非小细胞肺癌(Non-small cell lung cancer,NSCLC)中的预测价值,并建立预后相关的列线图模型。方法回顾性分析2019年1月—2021年1月于哈尔滨医科大学附属肿瘤医院一线应用PD-1抑制剂联合化疗的77例驱动基因阴性的晚期NSCLC患者的临床资料。采用单因素及多因素Cox回归分析确定无进展生存期(Progression-free survival,PFS)的独立预后因素;建立预后相关的列线图模型,并通过一致性指数等评估模型预测的准确性。结果多因素Cox回归分析表明,MLR、PIV、脑转移、胸膜转移是驱动基因阴性的晚期NSCLC患者PFS的独立影响因素(P＜0.05)。根据Cox回归结果构建的列线图预后模型预测能力较好(C-index值为0.786,95% CI:0.721~0.851)。ROC曲线表明MLR与PIV联合检测无进展生存期预后的效果(AUC=0.717,P=0.001)优于MLR(AUC=0.643)、PIV(AUC=0.640)。结论 MLR、PIV、脑转移、胸膜转移可预测一线应用化疗联合PD-1抑制剂治疗的驱动基因阴性的晚期NSCLC患者的预后,建立的列线图模型具有较高的准确度和临床实用性。MLR与PIV联合检测的预测效能可能优于MLR、PIV单独检测。

关键词: 非小细胞肺癌, 中性粒细胞-淋巴细胞比值, 血小板计数-淋巴细胞比值, 单核细胞-淋巴细胞比值, 泛免疫炎症值

Abstract: Objective The aim of this study was to explore the application of baseline neutrophil-lymphocyte ratio(NLR),platelet count-lymphocyte ratio(PLR),monocyte-lymphocyte ratio(MLR),and pan-immune inflammation value(PIV)in the use of PD-1 inhibitors combined with chemotherapy in advanced non-small cell lung cancer(NSCLC),and establish a prognosis-related nomogram model. Methods The clinical data of 77 patients with driver gene-negative advanced NSCLC who received first-line PD-1 inhibitor combined with chemotherapy at Harbin Medical University Cancer Hospital from January 2019 to January 2021 were retrospectively analyzed.Univariate and multivariate Cox regression analysis were used to determine the independent prognostic factors of progression-free survival(PFS);A prognostic-related nomogram model was established,and the accuracy of prediction model was evaluated through consistency index. Results Multivariate Cox regression analyses showed that MLR,PIV,brain metastasis,and pleural metastasis were independent factors affecting PFS in patients with driver gene-negative advanced NSCLC(P＜0.05).The nomogram prognostic model constructed based on the Cox regression results had a good predictive ability(C-index value was 0.786,95% CI:0.721-0.851).The ROC curve showed that the combined effect of MLR and PIV in detecting the prognosis of PFS(AUC=0.717,P=0.001)was better than that of MLR(AUC=0.643)and PIV(AUC=0.640). Conclusion MLR,PIV,brain metastasis,and pleural metastasis can predict the prognosis of driver gene-negative advanced NSCLC patients treated with first-line chemotherapy combined with PD-1 inhibitors.The established nomogram model has high accuracy and clinical practicability.The predictive performance of combined detection of MLR and PIV may be better than that of separate detection of MLR and PIV.

Key words: Non-small cell lung cancer, Neutrophil-lymphocyte ratio, Platelet count-lymphocyte ratio, Monocyte-lymphocyte ratio, Pan-immune inflammatory disease value

中图分类号:

R734.2

张萱, 李欣, 赵康. 血清炎性标志物与一线免疫抑制剂治疗晚期非小细胞肺癌患者预后的关系[J]. 实用肿瘤学杂志, 2024, 38(1): 37-44.

ZHANG Xuan, LI Xin, ZHAO Kang. Relationship between serum inflammatory markers and prognosis of advanced non-small cell lung cancer patients treated with first-line immunosuppressants[J]. Journal of Practical Oncology, 2024, 38(1): 37-44.

参考文献

1 赫捷,魏文强.《2021年中国肿瘤登记年报》[M].北京:人民卫生出版社,2023.
2 Topalian SL,Hodi FS,Brahmer JR,et al.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer[J].N Engl J Med,2012,366(26):2443-2454.
3 Yarchoan M,Hopkins A,Jaffee EM.Tumor mutational burden and response rate to PD-1 inhibition[J].N Engl J Med,2017,377(25):2500-2501.
4 Asaoka Y,Ijichi H,Koike K.PD-1 Blockade in tumors with mismatch-repair deficiency[J].N Engl J Med,2015,373(20):1979.
5 Lemery S,Keegan P,Pazdur R.First FDA approval agnostic of cancer site - when a biomarker defines the indication[J].N Engl J Med,2017,377(15):1409-1412.
6 Singh N,Baby D,Rajguru JP,et al.Inflammation and cancer[J].Ann Afr Med,2019,18(3):121-126.
7 Coffelt SB,de Visser KE.Cancer:inflammation lights the way to metastasis[J].Nature,2014,507(7490):48-49.
8 Lu X,Wan J,Shi H.Platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios are associated with the efficacy of immunotherapy in stage III/IV non-small cell lung cancer[J].Oncol Lett,2022,24(2):266.
9 Ren F,Zhao T,Liu B,et al.Neutrophil-lymphocyte ratio(NLR)predicted prognosis for advanced non-small-cell lung cancer(NSCLC)patients who received immune checkpoint blockade(ICB)[J].Onco Targets Ther,2019,12:4235-4244.
10 Mantovani A,Allavena P,Sica A,et al.Cancer-related inflammation[J].Nature,2008,454(7203):436-440.
11 Russo A,Russano M,Franchina T,et al.Neutrophil-to-Lymphocyte Ratio(NLR),Platelet-to-Lymphocyte Ratio(PLR),and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer(NSCLC):A large retrospective multicenter study[J].Adv Ther,2020,37(3):1145-1155.
12 Liu J,Li S,Zhang S,et al.Systemic immune-inflammation index,neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab[J].J Clin Lab Anal,2019,33(8):e22964.
13 Zheng L,Xiong A,Wang S,et al.Decreased monocyte-to-lymphocyte ratio was associated with satisfied outcomes of first-line PD-1 inhibitors plus chemotherapy in stage ⅢB~Ⅳ non-small cell lung cancer[J].Front Immunol,2023,14:1094378.
14 Watanabe K,Noma D,Masuda H,et al.Preoperative inflammation-based scores predict early recurrence after lung cancer resection[J].J Thorac Dis,2021,13:2812-2823.
15 Unal D,Eroglu C,Kurtul N,et al.Are neutrophil/lymphocyte and platelet/lymphocyte rates in patients with non-small cell lung cancer associated with treatment response and prognosis[J].Asian Pac J Cancer Prev,2013,14:5237-5242.
16 Yao M,Liu Y,Jin H,et al.Prognostic value of preoperative inflammatory markers in Chinese patients with breast cancer[J].Onco Targets Ther,2014,7:1743-1752.
17 Lee M,Kim SW,Nam EJ,et al.The impact of pretreatment thrombocytosis and persistent thrombocytosis after adjuvant chemotherapy in patients with advanced epithelial ovarian cancer[J].Gynecol Oncol,2011,122:238-241.
18 Russo A,Franchina T,Ricciardi GRR,et al.Baseline neutrophilia,derived neutrophil-to-lymphocyte ratio(dNLR),platelet-to-lymphocyte ratio(PLR),and outcome in non small cell lung cancer(NSCLC)treated with Nivolumab or Docetaxel[J].J Cell Physiol,2018,233(10):6337-6343.
19 Chanmee T,Ontong P,Konno K,et al.Tumor-associated macrophages as major players in the tumor microenvironment[J].Cancers(Basel),2014,6(3):1670-1690.
20 Sanchez LR,Borriello L,Entenberg D,et al.The emerging roles of macrophages in cancer metastasis and response to chemotherapy[J].J Leukoc Biol,2019,106(2):259-274.
21 Lewis CE,Harney AS,Pollard JW.The Multifaceted role of perivascular macrophages in tumors[J].Cancer Cell,2016,30(2):365.
22 Riabov V,Gudima A,Wang N,et al.Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis[J].Front Physiol,2014,5:75.
23 Schmidt H,Bastholt L,Geertsen P,et al.Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma:a prognostic model[J].Br J Cancer,2005,93(3):273-278.
24 Lee YY,Choi CH,Sung CO,et al.Prognostic value of pre-treatment circulating monocyte count in patients with cervical cancer:comparison with SCC-Ag level[J].Gynecol Oncol,2012,124(1):92-97.
25 Sekine K,Kanda S,Goto Y,et al.Change in the lymphocyte-to-monocyte ratio is an early surrogate marker of the efficacy of nivolumab monotherapy in advanced non-small-cell lung cancer[J].Lung Cancer,2018,124:179-188.
26 Zeng R,Liu F,Fang C,et al.PIV and PILE score at baseline predict clinical outcome of anti-PD-1/PD-L1 inhibitor combined with chemotherapy in extensive-stage small cell lung cancer patients[J].Front Immunol,2021,12:724443.
27 Fucà G,Guarini V,Antoniotti C,et al.The pan-immune-inflammation value is a new prognostic biomarker in metastatic colorectal cancer:results from a pooled-analysis of the valentino and TRIBE first-line trials[J].Br J Cancer,2020,123(3):403-409.
28 Corti F,Lonardi S,Intini R,et al.The pan-immune-inflammation value in microsatellite instability-high metastatic colorectal cancer patients treated with immune checkpoint inhibitors[J].Eur J Cancer,2021,150:155-167.
29 Sato S,Shimizu T,Ishizuka M,et al.The preoperative pan-immune-inflammation value is a novel prognostic predictor for with stage I-III colorectal cancer patients undergoing surgery[J].Surg Today,2022,52(8):1160-1169.
30 Ligorio F,Fucà G,Zattarin E,et al.The pan-immune-inflammation-value predicts the survival of patients with human epidermal growth factor receptor 2(HER2)-positive advanced breast cancer treated with first-line taxane-trastuzumab-pertuzumab[J].Cancers(Basel),2021,13(8):1964.
31 Şahin AB,Cubukcu E,Ocak B,et al.Low pan-immune-inflammation-value predicts better chemotherapy response and survival in breast cancer patients treated with neoadjuvant chemotherapy[J].Sci Rep,2021,11(1):14662.
32 Demir H,Demirci A,Eren SK,et al.A new prognostic index in young breast cancer patients[J].J Coll Physicians Surg Pak,2022,32(1):86-91.
33 Yoshifumi B,Shigeki N,Tasuku T.Pan-immune-inflammation value and prognosis in patients with esophageal cancer[J].Ann Surg,2022,3(1):e113.
34 Chen X,Hong X,Chen G,et al.The pan-immune-inflammation value predicts the survival of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer treated with first-line ALK inhibitor[J].Transl Oncol,2022,17:101338.
35 Gambichler T,Said S,Abu Rached N,et al.Pan-immune-inflammation value independently predicts disease recurrence in patients with merkel cell carcinoma[J].J Cancer Res Clin Oncol,2022,148(11):3183-3189.
36 Fucà G,Beninato T,Bini M,et al.The pan-immune-inflammation value in patients with metastatic melanoma receiving first-line therapy[J].Target Oncol,2021,16(4):529-536.
37 Pérez-Martelo M,González-García A,Vidal-Ínsua Y,et al.Clinical significance of baseline Pan-Immune-Inflammation Value and its dynamics in metastatic colorectal cancer patients under first-line chemotherapy[J].Sci Rep,2022,12(1):6893.

[1]	苗玲, 赵之寒, 王敏. 非小细胞肺癌患者肿瘤组织PA28γ、miR-7-5p的表达水平及临床意义[J]. 实用肿瘤学杂志, 2023, 37(4): 344-350.
[2]	曹莹月, 庞露薏, 张键, 金时. 癌相关成纤维细胞在非小细胞肺癌进展中的作用[J]. 实用肿瘤学杂志, 2023, 37(4): 383-388.
[3]	陈琪, 何明旭, 贾科良, 苗健龙, 韩丽萍. TP53-EGFR共突变对非小细胞肺癌预后及治疗的研究进展[J]. 实用肿瘤学杂志, 2023, 37(3): 262-266.
[4]	龙朝恋, 李琨, 刘子臣, 张娜娜, 车南颖. 非小细胞肺癌程序性死亡配体-1表达与临床病理特征和常见驱动基因变异的相关性研究[J]. 实用肿瘤学杂志, 2023, 37(2): 117-122.
[5]	徐子涵, 于国华, 聂玉辉, 孙蒙蒙, 丰慧, 刘淑真. 外周血标志物对晚期非小细胞肺癌免疫相关不良反应的预测作用及与生存结局的相关性分析[J]. 实用肿瘤学杂志, 2022, 36(6): 544-550.
[6]	朱开彬, 贺长军, 陈澜涛, 孔祥龙, 赵苏, 徐世东. TAM通过PLGF/Flt-1和TGF-β1通路促进非小细胞肺癌生长和肿瘤血管异生的研究[J]. 实用肿瘤学杂志, 2022, 36(5): 391-397.
[7]	刘倩倩, 尚利华. 晚期非小细胞肺癌免疫治疗相关不良反应与疗效的相关性研究进展[J]. 实用肿瘤学杂志, 2022, 36(5): 463-467.
[8]	董琳, 刘欣, 鲁海玲. 晚期非小细胞肺癌抗血管生成治疗联合免疫检查点抑制剂的研究进展[J]. 实用肿瘤学杂志, 2022, 36(4): 351-355.
[9]	张浩, 杨新官, 何涌. 肌少症与晚期非小细胞肺癌临床病理特征及预后的相关性分析[J]. 实用肿瘤学杂志, 2022, 36(3): 214-219.
[10]	张梦茹, 曹德东, 戈伟. 恩度静脉持续泵入与滴注联合含铂双药方案化疗治疗晚期非小细胞肺癌的疗效与安全性比较[J]. 实用肿瘤学杂志, 2022, 36(1): 20-25.
[11]	罗雯, 贾莉, 张佳文, 王冬杰, 孔英君. circRNA MYO1C对肺癌细胞自噬和肿瘤干细胞分化的影响[J]. 实用肿瘤学杂志, 2021, 35(6): 500-505.
[12]	汪叶, 尚乃舰. 影像组学在非小细胞肺癌诊疗中的应用进展[J]. 实用肿瘤学杂志, 2021, 35(5): 485-488.
[13]	王俊美, 潘慧卿, 李婧铱, 贾迪, 赵炜明, 吕昌莲. MT2-MMP在Ⅱ期肺腺癌中的表达及临床意义[J]. 实用肿瘤学杂志, 2021, 35(3): 243-247.
[14]	尹蕾, 杨旭东, 杨悦, 牛星鉴, 周晓平, 姬宏飞, 王一然. 中性粒细胞与淋巴细胞比值在非小细胞肺癌患者预后评估中的临床意义及相关机制研究[J]. 实用肿瘤学杂志, 2021, 35(2): 117-124.
[15]	董程(综述),段勇(审校). Dickkopf家族蛋白在非小细胞肺癌中的作用机制和治疗应用的研究进展[J]. 实用肿瘤学杂志, 2021, 35(1): 64-68.