Cerebrospinal Fluid Circulating Tumor DNA Genotyping and Survival Analysis in Lung Adenocarcinoma With Leptomeningeal Metastases

Abstract

Purpose The prognosis of patients with leptomeningeal metastasis (LM) remains poor. Circulating tumor DNA (ctDNA) has been proven more abundantly present in the cerebrospinal fluid (CSF), hence, its clinical implication as a biomarker need to be further verified. Methods We conducted a retrospective study of 35 lung adenocarcinoma (LUAD) patients with LM, and all patients collected matched CSF and plasma samples. All paired samples underwent next-generation sequencing (NGS) of 139 lung cancer-associated genes. The clinical characteristics and genetic profiling of LM were analyzed association with survival prognosis. Results LM showed genetic heterogeneity, which CSF had higher detection rate of ctDNA (P = 0.003), more median mutations count (P < 0.0001), higher frequencies of driver mutations (P < 0.01), more copy number variations (CNVs) alterations (P < 0.001) than plasma. The mutation frequency of EGFR, TP53, CDKN2A, MYC and CDKN2B genes were easier to be detected in CSF than in LUAD tissue (P < 0.05), this may reveal the underlying mechanism of LM metastasis. CSF ctDNA is helpful to analyze the mechanism of EGFR-TKIs resistance. In cohort 1, who receive 1/2 EGFR-TKIs before the diagnosis of LM, TP53 and CDKN2A were the most common EGFR-independent resistant mutations. In cohort 2, who progressed after osimertinib and developed LM, 7 patients (43.75%) had EGFR CNV detected in CSF but not plasma. Furthermore, patient characteristics and various genes were included for interactive survival analysis. Patients with EGFR gene mutation in lung tissue (P = 0.042) had higher median OS and CSF ctDNA mutation with TERT (P = 0.013) indicated lower median OS. Lastly, we reported a LM case whose CSF ctDNA dynamic changes were well correlated with his clinical treatment. Conclusions CSF ctDNA could provide a more comprehensive genetic landscape of LM, which indicated the potential metastasis-related and EGFR-TKIs resistance mechanisms of LM patients. Besides, genotyping of CSF combined with clinical outcomes can predict the prognosis of LUAD patients with LM.