AUTHOR=Liu Xiaocui , Mei Fengjun , Fang Mei , Jia Yaqiong , Zhou Yazhu , Li Chenxi , Tian Panpan , Lu Chufan , Li Guangrui 

TITLE=Cerebrospinal fluid ctDNA testing shows an advantage over plasma ctDNA testing in advanced non-small cell lung cancer patients with brain metastases

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1322635

DOI=10.3389/fonc.2023.1322635

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Brain metastases (BM), including brain parenchyma metastases (BPM) and leptomeningeal metastases (LM), are devastating metastatic complications in advanced cancer patients. Next-generation sequencing (NGS) is emerging as a new promising tool for profiling cancer mutation, which could facilitate the diagnosis of cancer. This retrospective study aimed to investigate the molecular genetic characteristics of non-small cell lung cancer (NSCLC) patients with BPM and LM using NGS.</p></sec><sec><title>Methods</title><p>Cerebrospinal fluid (CSF) samples and paired plasma samples were collected from 37 patients of NSCLC-BM. We profiled genetic mutation characteristics using NGS from NSCLC-BM by comparing CSF circulating tumour DNA (ctDNA) with plasma ctDNA and primary tumour tissues.</p></sec><sec><title>Results</title><p>Among the 37 patients with NSCLC-BM, 28 patients had LM with or without BPM, while 9 patients only had BPM. Driver and drug-resistant mutations in primary tumours with LM included: <italic>EGFR</italic> L858R (10, 35.7%), <italic>EGFR</italic> 19del (6, 21.4%), <italic>EGFR</italic> L858R+<italic>MET</italic> (1, 3.6%), <italic>EGFR</italic> L858R+S768I (1, 3.6%), <italic>ALK</italic> (2, 7.1%), <italic>ROS1</italic> (1, 3.6%), negative (5, 17.9%), and unknown (2, 7.1%). In patients with NSCLC-LM, the detection rate and abundance of ctDNA in the CSF were significantly higher than those in paired plasma. The main driver mutations of NSCLC-LM remained highly consistent with those of the primary tumours, along with other unique mutations. Circulating tumour DNA was negative in the CSF samples of BPM patients. Patients with BMP had a higher ratio of <italic>EGFR</italic> 19del than L858R mutation (55.6% vs 11.1.%), whereas NSCLC patients with LM had a higher ratio of <italic>EGFR</italic> L858R than 19del mutation (50.0% vs 25.0%). Most patients with positive plasma ctDNA results were male (<italic>p</italic> = 0.058) and in an unstable state (<italic>p</italic> = 0.003).</p></sec><sec><title>Conclusion</title><p>Our study indicated that the CSF ctDNA detected by NGS may reflect the molecular characteristics and heterogeneity of NSCLC-LM. Timely screening of patients with NSCLC for CSF ctDNA, especially for patients with positive plasma ctDNA, may facilitate the early detection of LM. Furthermore, patients with the <italic>EGFR</italic> 19del may have a higher risk of developing BPM.</p></sec>