Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Thoracic Medical Oncology, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Zhejiang, China.
Cancer Med. 2024 Sep;13(17):e70223. doi: 10.1002/cam4.70223.
The 9th edition of the TNM Classification for lung cancer delineates M1c into two subcategories: M1c1 (Multiple extrathoracic lesions within a single organ system) and M1c2 (Multiple extrathoracic lesions involving multiple organ systems). Existing research indicates that patients with lung cancer in stage M1c1 exhibit superior overall survival compared to those in stage M1c2. The primary frontline therapy for patients with advanced non-small cell lung cancer (NSCLC), lacking driver gene mutations, involves the use of immune checkpoint inhibitors (ICIs) combined with chemotherapy. Nevertheless, a dearth of evidence exists regarding potential survival disparities between NSCLC patients with M1c1 and M1c2 undergoing first-line immune-chemotherapy, and reliable biomarkers for predicting treatment outcomes are elusive. Serum metabolic profiles may elucidate distinct prognostic mechanisms, necessitating the identification of divergent metabolites in M1c1 and M1c2 undergoing combination therapy. This study seeks to scrutinize survival discrepancies between various metastatic patterns (M1c1 and M1c2) and pinpoint metabolites associated with treatment outcomes in NSCLC patients undergoing first-line ICIs combined with chemotherapy.
In this study, 33 NSCLC patients lacking driver gene mutations diagnosed with M1c1, and 22 similarly diagnosed with M1c2 according to the 9th edition of TNM Classification, were enrolled. These patients received first-line PD-1 inhibitor plus chemotherapy. The relationship between metastatic patterns and progression-free survival (PFS) in patients undergoing combination therapy was analyzed using univariate and multivariate Cox regression models. Serum samples were obtained from all patients before treatment initiation for untargeted metabolomics analysis, aiming to identify differential metabolites.
In the univariate analysis of PFS, NSCLC patients in M1c1 receiving first-line PD-1 inhibitor plus chemotherapy exhibited an extended PFS (HR = 0.49, 95% CI, 0.27-0.88, p = 0.017). In multivariate PFS analyses, these M1c1 patients receiving first-line PD-1 inhibitor plus chemotherapy also demonstrated prolonged PFS (HR = 0.45, 95% CI, 0.22-0.92, p = 0.028). The serum metabolic profiles of M1c1 and M1c2 undergoing first-line PD-1 inhibitors plus chemotherapy displayed notable distinctions. In comparison to M1c1 patients, M1c2 patients exhibited alterations in various pathways pretreatment, including platelet activation, linoleic acid metabolism, and the VEGF signaling pathway. Diminished levels of lipid-associated metabolites (diacylglycerol, sphingomyelin) were correlated with adverse outcomes.
NSCLC patients in M1c1, devoid of driver gene mutations, receiving first-line PD-1 inhibitors combined with chemotherapy, experienced superior outcomes compared to M1c2 patients. Moreover, metabolomic profiles strongly correlated with the prognosis of these patients, and M1c2 patients with unfavorable outcomes manifested distinct changes in metabolic pathways before treatment. These changes predominantly involved alterations in lipid metabolism, such as decreased diacylglycerol and sphingomyelin, which may impact tumor migration and invasion.
肺癌的第 9 版 TNM 分类将 M1c 分为两个亚类：M1c1（单一器官系统内的多个远处转移灶）和 M1c2（涉及多个器官系统的多个远处转移灶）。现有研究表明，M1c1 期肺癌患者的总生存期优于 M1c2 期患者。对于缺乏驱动基因突变的晚期非小细胞肺癌（NSCLC）患者，一线治疗主要采用免疫检查点抑制剂（ICI）联合化疗。然而，对于 M1c1 和 M1c2 期接受一线免疫化疗的 NSCLC 患者之间潜在的生存差异，以及预测治疗结果的可靠生物标志物，目前证据不足。血清代谢谱可能阐明不同的预后机制，因此需要确定在接受联合治疗的 M1c1 和 M1c2 中存在差异的代谢物。本研究旨在探讨不同转移模式（M1c1 和 M1c2）之间的生存差异，并确定与 NSCLC 患者一线接受 ICI 联合化疗治疗结果相关的代谢物。
本研究纳入了 33 例缺乏驱动基因突变且根据第 9 版 TNM 分类诊断为 M1c1 的 NSCLC 患者，以及 22 例同样诊断为 M1c2 的患者。这些患者接受了一线 PD-1 抑制剂联合化疗。使用单变量和多变量 Cox 回归模型分析了联合治疗患者的转移模式与无进展生存期（PFS）之间的关系。所有患者在治疗前均采集血清样本进行非靶向代谢组学分析，以鉴定差异代谢物。
在 PFS 的单变量分析中，M1c1 期接受一线 PD-1 抑制剂联合化疗的 NSCLC 患者 PFS 延长（HR=0.49，95%CI，0.27-0.88，p=0.017）。在多变量 PFS 分析中，这些接受一线 PD-1 抑制剂联合化疗的 M1c1 患者的 PFS 也延长（HR=0.45，95%CI，0.22-0.92，p=0.028）。接受一线 PD-1 抑制剂联合化疗的 M1c1 和 M1c2 的血清代谢谱存在明显差异。与 M1c1 患者相比，M1c2 患者在血小板激活、亚油酸代谢和 VEGF 信号通路等各种途径预处理时发生了改变。脂质相关代谢物（二酰基甘油、鞘磷脂）水平降低与不良结局相关。
缺乏驱动基因突变且接受一线 PD-1 抑制剂联合化疗的 M1c1 期 NSCLC 患者的结局优于 M1c2 期患者。此外，代谢组学图谱与这些患者的预后密切相关，而预后不良的 M1c2 患者在治疗前表现出代谢途径的明显改变。这些改变主要涉及脂代谢的改变，如二酰基甘油和鞘磷脂的减少，这可能影响肿瘤的迁移和侵袭。
