Unique genomic profiles obtained from cerebrospinal fluid cell-free DNA of non-small cell lung cancer patients with leptomeningeal metastases

Abstract

Background: Leptomeningeal metastases (LM), associated with poor prognosis, are frequent complications of advanced non-small cell lung cancer (NSCLC) patients, especially in patients with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the mutational landscape of LM has not been comprehensively investigated in large cohorts and the underlining biology of LM remains elusive. Some studies have explored the potential of cerebrospinal fluid (CSF) in reflecting the molecular profile of LM but with limited number of patients enrolled. Methods: In this study, we performed capture-based targeted sequencing using a panel consisting of 168 lung cancer-related genes on matched CSF and plasma samples from 72 advanced NSCLC patients with confirmed LM to interrogate the potential of CSF as a source of liquid biopsy. Results: We revealed a rate of detection of 81.5% and 62.5% for CSF and plasma, respectively (p = 0.008). The maximum allelic fraction (MaxAF) was also significantly higher in CSF (43.6% vs. 4.6%) (p < 0.001). CSF, harboring a unique genomic profile by having a significant number of CSF-specific mutations, primarily copy number variations, is superior to plasma in reflecting the mutational profile of LM. Further pathway enrichment analysis revealed that most of CSF-specific mutations participated in pathways relevant to the tumorigenesis and the development of metastases. Moreover, our data also revealed that TP53 loss of heterozygosity (LOH) predominantly existed in CSF (p < 0.001). Conclusions: Collectively, we demonstrated that CSF provides a more comprehensive profile of LM than plasma in a large cohort, thus can be used as an alternative source of liquid biopsy for LM patients.

Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases

“…In particular, LMs have been found to be enriched in EGFR, MET proto-oncogene, receptor tyrosine kinase (MET), and tumor protein p53 (TP53) mutations, whereas they rarely harbor KRAS alterations compared to other solid metastases from NSCLC. [20][21][22] Tailoring therapy to molecular alterations found in the CSF has been reported to be feasible while providing clinical benefit in subsets of patients. 22 In this context, the use of CSF as liquid biopsy specimens may facilitate translational research programs and help to personalize subsequent treatment.…”

Leptomeningeal metastases from non-small cell lung cancer: state of the art and recent advances

“…Zheng et al [68] have reported that next-generation sequencing of paired plasma and CSF samples of 11 patients with LM from ALK rearranged NSCLC identified driver mutations in 81.8% of CSF and 45.5% only of plasma. Similarly, Ying et al [69] have compared CSF and plasma samples of 92 patients with LM from EGFR mutated NSCLC reporting a high mutation rate in CSF (81.5%) with an overall amount of 197 mutations, whereas plasma displayed a lower mutation rate (62.5%) and amount of mutations (68%). Furthermore, a significant discordance of mutation profiles between CSF and plasma has been reported: a further analysis of EGFR showed an activating mutation in 51.4% of CSF and 38.9% of plasma samples with a concordance of 47.7%.…”

“…Overall, CSF liquid biopsy appears to be more sensitive than plasma in detecting druggable mutations in LM. Moreover, CSF has a significant number of specific mutations, such as TP53 LOH, MET amplification, CDKN2A, NTRK1 and CDK4 mutations, that contribute to the tumorigenesis and development of LM from NSCLC [69,75] .…”

Current and future trends in non–small cell lung cancer biomarker testing: The American experience

“…CSF produced by the choroid plexus circulates from the intracerebral ventricles to the spinal subarachnoid space and has been shown to be a viable option for tumor molecular profiling in patients with primary and metastatic brain tumors. [33][34][35][36][37][38] In patients with NSCLC with leptomeningeal disease, circulating tumor cells have been reported to be more likely to be detected in the CSF than in the peripheral blood with a highly concordant molecular profile to that of the primary tumor, making liquid biopsy using CSF preferable to plasma. 35 Other studies have demonstrated that ctDNA derived from CSF supernatant fluid is more representative than not only plasma but also the cellular component of CSF, which is likely contaminated with benign hematopoietic elements.…”

“…31,37,39,40 Brain metastases often demonstrate different molecular profiles from those of the primary tumor and the therapeutic approach for these patients should aim at targeting the central nervous system-specific genomic alterations. 37,38,41 Profiling CSF supernatant fluid in these patients would provide a highly enriched source of ctDNA compared with targeting the plasma ctDNA and typically requires a small volume (approximately 5-10 mL) of fluid. 35,37,39 Several targeted therapeutic agents have shown clinical activity in patients with NSCLC with brain metastases and CSF ctDNA may be a potential source for monitoring actionable mutations and resistance mutations in these patients.…”