Zhou Juan, Wu Yinfei, Xie Mengqing, Fang Yujia, Zhao Jing, Lee Sung Yong, Im Yunjoo, Ye Lingyun, Su Chunxia
Department of Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China.
Division of Pulmonology, Allergy, and Critical Care Medicine, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.
Transl Lung Cancer Res. 2022 Apr;11(4):656-669. doi: 10.21037/tlcr-22-260.
The data about efficacy of immunotherapy for non-small cell lung cancer with brain metastases (BMs) from real-word settings are controversial. This real-word study is aimed to evaluate the clinical outcome of immune checkpoint inhibitor (ICI)-based treatment in lung adenocarcinoma patients with brain metastases (BMs) and explore potential risk factors, with a focus on the spatial distribution of BMs as previous studies suggested spatial heterogeneity on the brain immune microenvironment.
Advanced lung adenocarcinoma patients with non-oncogene-addicted, who received ICI monotherapy or plus chemotherapy, were enrolled. Efficacy was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Intergroup comparisons were performed using Pearson's χ or Fisher's exact tests for categorical variables. The progression-free survival (PFS) was estimated using Kaplan-Meier method and compared using log-rank test. Cox proportional hazards model was used for multivariate analyses. Peripheral blood was collected from 15 patients with BMs. Tumor-derived exosomes in plasma were isolated by size exclusion chromatography and the cDNA library preparations for miRNA were sequenced on an Illumina Hiseq platform. Differentially expressed genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed.
A total of 198 patients were enrolled and brain metastasis occurred in 20.7% patients (N=41). Compared with patients without BMs, those with BMs had a comparable objective response rate (ORR; 29.3% 43.9%; P=0.089), a lower disease control rate (DCR; 58.5% 78.3%; P=0.01), and a shorter PFS (3.6 8.6 months; P=0.069). For patients with BMs, factors, including the presence of neurological symptoms, the treatment of intracranial radiotherapy, and the combination of ICI with chemotherapy, had no impact on PFS, whereas cerebellum metastasis was significantly associated with shorter PFS (2.8 13.8 months, P=0.007). Six upregulated miRNAs were identified in patients with cerebellum metastases (N=8) compared with those without (N=7). The enrichment of differentially expression genes in the KEGG pathways indicated upregulated sulfur metabolism pathway in patients with cerebellum metastases.
For lung adenocarcinoma patients, those with BMs have inferior response to ICI-based treatment, but not significantly, and cerebellum metastasis is an independent risk factor with poor outcome for such patients, might attributing to the upregulated sulfur metabolism.
来自真实世界的关于免疫疗法治疗非小细胞肺癌脑转移（BMs）疗效的数据存在争议。这项真实世界研究旨在评估基于免疫检查点抑制剂（ICI）的治疗在肺腺癌脑转移（BMs）患者中的临床结局，并探索潜在风险因素，重点关注脑转移的空间分布，因为先前的研究表明脑免疫微环境存在空间异质性。
纳入接受ICI单药治疗或联合化疗的非致癌基因成瘾的晚期肺腺癌患者。疗效根据实体瘤疗效评价标准1.1版进行评估。分类变量的组间比较采用Pearson卡方检验或Fisher精确检验。采用Kaplan-Meier法估计无进展生存期（PFS），并采用对数秩检验进行比较。Cox比例风险模型用于多变量分析。从15例脑转移患者中采集外周血。通过尺寸排阻色谱法分离血浆中肿瘤来源的外泌体，并在Illumina Hiseq平台上对miRNA的cDNA文库制备进行测序。分析京都基因与基因组百科全书（KEGG）通路中差异表达的基因。
共纳入198例患者，20.7%的患者（N = 41）发生脑转移。与无脑转移的患者相比，有脑转移的患者客观缓解率（ORR）相当（29.3%对43.9%；P = 0.089），疾病控制率（DCR）较低（58.5%对78.3%；P = 0.01），PFS较短（3.6个月对8.6个月；P = 0.069）。对于有脑转移的患者，包括存在神经症状、颅内放疗治疗以及ICI与化疗联合使用等因素对PFS没有影响，而小脑转移与较短的PFS显著相关（2.8个月对13.8个月，P = 0.007）。与无脑转移的患者（N = 7）相比，在小脑转移患者（N = 8）中鉴定出6种上调的miRNA。KEGG通路中差异表达基因的富集表明小脑转移患者的硫代谢通路上调。
对于肺腺癌患者，有脑转移的患者对基于ICI的治疗反应较差，但差异不显著，小脑转移是此类患者预后不良的独立危险因素，可能归因于硫代谢上调。
