Molecular characteristics and prognostic factors of leptomeningeal metastasis in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer with leptomeningeal metastasis (NSCLC-LM) is emerging as a new management challenge for oncologists and is associated with poor prognosis. This study aimed to investigate the molecular characteristics and prognostic factors of NSCLC-LM. METHODS: This retrospective study included 97 patients with NSCLC-LM between January 2015 and October 2021. Progression-free survival (PFS) and overall survival (OS) were evaluated. Gene mutations were detected by next-generation sequencing (NGS). RESULTS: The median PFS and OS were 8.4 (95 % confidence interval [CI]: 4.839-11.901) and 14.0 (95 % CI: 9.254-18.746) months, respectively. Sixty-seven patients harboured epidermal growth factor receptor-mutated (EGFRm): L858R (34), 19del (29), T790M (13), and G719C with L861Q (1). Other mutations included ALK (5), ROS1 (3), KRAS (1), TP53 (14), MET amplification (6). The detection rate and types of circulating tumour DNA (ctDNA) in the cerebrospinal fluid (CSF) samples were higher than the paired plasma samples. Patients with EGFR mutations had a longer median OS than those without mutations (19.0 vs. 13.0 months, P = 0.015). Patients with gene mutations had shorter median OS than those without mutations, such as ALK (11.8 vs. 19.9 months, P = 0.014), ROS1 (12.7 vs. 19.8 months, P = 0.014), KRAS (4.0 vs. 19.0 months, P = 0.005), TP53 (15.0 vs. 19.0 months, P = 0.014), and MET amplification (6.0 vs. 19.0 months, P = 0.003). Multivariate analysis indicated that MET amplification was an independent predictor of poor survival. Along with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3, LM accompanied with brain parenchymal metastasis (BPM), extracranial disease, and seizures were independent predictors of poor survival, whereas intrathecal chemotherapy, and third-generation EGFR-TKIs were independent predictors of favorable survival. CONCLUSIONS: CSF ctDNA detected using NGS had a high sensitivity for NSCLC-LM, showing high potential in detecting driver and drug-resistant gene mutations. Genomic profiles, combined with clinically relevant prognostic factors, will guide individualised treatments and improve the outcomes of NSCLC-LM patients.

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

Background: 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. Methods: 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. Results: 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: EGFR L858R (10, 35.7%), EGFR 19del (6, 21.4%), EGFR L858R+MET (1, 3.6%), EGFR L858R+S768I (1, 3.6%), ALK (2, 7.1%), ROS1 (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 EGFR 19del than L858R mutation (55.6% vs 11.1.%), whereas NSCLC patients with LM had a higher ratio of EGFR L858R than 19del mutation (50.0% vs 25.0%). Most patients with positive plasma ctDNA results were male (p = 0.058) and in an unstable state (p = 0.003). Conclusion: 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 EGFR 19del may have a higher risk of developing BPM.