Zhao Jun, Zhong Jia, Chen Yujie, Chen Zipei, Yin Huan, He Yuange, Chen Rongrong, Guo Renhua
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department I of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
CAMS Key Laboratory of Translational Research on Lung Cancer, State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center.
Ther Adv Med Oncol. 2024 Sep 24;16:17588359241275421. doi: 10.1177/17588359241275421. eCollection 2024.
Metastasis is the primary cause of lung cancer-related death. Primary cancer cells invade through the lymphatic or blood vessels to distant sites. Recently, it was proposed that lymphatic metastasis was more a hallmark of tumor aggressiveness or metastatic potential than a gateway to metastases. Therefore, the underlying molecular mechanism of metastasis is not entirely clear.
This study aimed to explore the genetic mechanisms underlying liver metastases from lung cancer and to evaluate the efficacy of different therapies in these patients.
We retrospectively analyzed the mutation spectrum of different biopsy samples including primary lung tumors, liver, lymph node metastasis, and circulating tumor DNA (ctDNA) from 1090 non-small-cell lung cancer (NSCLC) patients with liver metastasis between the years 2017 and 2022.
Demographic and disease characteristics were summarized using descriptive parameters. Time to treatment discontinuation was used to analyze the clinical outcome.
More liquid biopsies were performed than tissue biopsies, especially in the treated advanced NSCLC patients. Liver metastasis before treatment was associated with poor response to immune checkpoint inhibitors and targeted therapy. Liver and lymph node metastasis had higher levels of single nucleotide variants and copy number variants than primary lung tumors. In paired lung and liver, lymph nodes, and simultaneous ctDNA, we found actionable mutations were always shared, while metastasis samples had multiple private mutations. Serial ctDNA analysis identifies potential resistant mutations and describes the evolution of tumor cells.
Liver and lymph node metastasis in NSCLC showed shared actionable mutations. Of note, the discrepancy of private mutations in liver and lymph node metastases indicated that liver metastases are mainly seeded by the primary tumor rather than the earlier colonized lymph node metastases.
转移是肺癌相关死亡的主要原因。原发性癌细胞通过淋巴管或血管侵入远处部位。最近，有人提出淋巴转移更多是肿瘤侵袭性或转移潜能的标志，而非转移的途径。因此，转移的潜在分子机制尚不完全清楚。
本研究旨在探讨肺癌肝转移的遗传机制，并评估这些患者不同治疗方法的疗效。
我们回顾性分析了2017年至2022年间1090例非小细胞肺癌（NSCLC）肝转移患者的不同活检样本的突变谱，包括原发性肺肿瘤、肝脏、淋巴结转移灶和循环肿瘤DNA（ctDNA）。
使用描述性参数总结人口统计学和疾病特征。采用治疗中断时间分析临床结局。
液体活检的实施次数多于组织活检，尤其是在接受治疗的晚期NSCLC患者中。治疗前发生肝转移与对免疫检查点抑制剂和靶向治疗的反应不佳相关。肝脏和淋巴结转移灶的单核苷酸变异和拷贝数变异水平高于原发性肺肿瘤。在配对的肺、肝脏、淋巴结和同步ctDNA中，我们发现可操作的突变总是共享的，而转移样本有多个私有突变。连续ctDNA分析可识别潜在的耐药突变并描述肿瘤细胞的演变。
NSCLC的肝脏和淋巴结转移显示出共享的可操作突变。值得注意的是，肝脏和淋巴结转移中私有突变的差异表明，肝转移主要由原发性肿瘤播散，而非早期定植的淋巴结转移。
