Leptomeningeal metastases (LM) are more common in non-small cell lung cancer (NSCLC) with EGFR mutations. The diagnosis is difficult by traditional imaging only, and leads to poor understanding of resistance mechanisms of LM.
We compared the CellSearch Assay™, the Thinprep cytologic test (TCT), and brain magnetic resonance imaging (MRI) in 21 NSCLC patients with suspected LM. Next-Generation sequencing that included 416 cancer-associated genes was also performed on cerebrospinal fluid circulating tumor cells (CSFCTCs) of 19 patients.
Twenty-one patients were diagnosed with LM, and CSFCTCs were captured by CellSearch in 20 patients (median, 969 CSFCTCs/7.5 mL; range, 27–14,888). CellSearch had a sensitivity of 95.2% for LM diagnosis, which was higher than that of TCT (12/21, 57.1%), MRI (10/21, 47.6%), and MRI plus TCT (19/21, 90.5%), respectively. CTCs were found only in 5 of 14 patients (median, 2 CTCs/7.5 mL; range, 2–4), which was a much lower ratio than CSFCTCs. Genetic profiles of CSFCTCs were highly concordant with molecular mutations identified in the primary tumor (17/19, 89.5%). The resistance gene EGFR T790M was detected in 7 of 9 patients with extracranial lesions, but was only detected in 1 of 14 CSFCTCs samples. Other potential resistant mutations such as MET amplification and ERBB2 mutation were also identified in CSFCTCs.Table:
|Patient No.||Primary gene profile||Targeted therapy before LM||Rebiopsy gene profile||CSFCTCs gene profile (NGS)|
|1||EGFR L858R (lung)||Erlotinib||EGFR L858R (lung, ARMS); MET(IHC):80% (3+)||EGFR L858R|
|2b||EGFR del19 (lymph node)||Icotinib||UA||EGFR del19; EGFR T790M|
|3||EML4-ALK (lung)||Crizotinib||EML4-ALK (pleural effusion)||EML4-ALK; MET amplification|
|4||EGFR 20INS (lung)||None||UA||EGFR 20INS|
|5||EGFR del19 (pleura)||Gefitinib||EGFR del19 and T790M (lung)||EGFR del19; EGFR amplification|
|6||EGFR L858R (lung)||Erlotinib||EGFR L858R and T790M (lung)||EGFR L858R|
|7||EGFR, ALK (WT)||None||Snapshot, MET, KIT (WT)||Common driver gene (WT)|
|9||EGFR del19 (pleura)||Gefitinib||EGFR del19 and T790M (liver);MET: 100% (3+) (liver)||EGFR del19; ERBB2 exon8 T328fs; ROS1 exon7 W215X|
|10||EGFR L858R (lung)||Gefitini, erlotinib||EGFR del19 and T790M (lung)||EGFR del19|
|11||EGFR L858R (lung)||Gefitini, erlotinib||UA||EGFR L858R|
|12||EGFR L858R (lung)||Gefitinib||EGFR L858R and T790M (plasma)||Common driver gene (WT)|
|14||EGFR del19 (lung)||Erlotinib, afatinib||UA||EGFR del19; MET amplification|
|15||EGFR del19 (lung)||Icotinib||UA||EGFR del19|
|16||EGFR L858R (lung)||None||EGFR L858R (lymph node)||EGFR and ALK (WT); RET exon4 V253E|
|17||EGFR L861Q (lymph node)||Erlotinib||UA||EGFR L861Q; EGFR del19|
|18c||EGFR L858R (lung)||Gefitinib||EGFR L858R and T790M (lung)||EGFR L858R; PIK3CA exon2 N107S; MET exon11 F839L|
|19||EGFR L858R (lung)||Gefitinib||EGFR L858R and T790M (lung)||EGFR L858R|
|21||EGFR L858R (lung)||Gefitinib||UA||EGFR L858R|
CellSearch could be a more sensitive method for detecting tumor cells in CSF, and potentially provides earlier diagnosis of LM. More importantly, CSFCTCs could be an important and new way of “liquid biopsy” for genetic profiles of metastatic tumor cells in LM patients of NSCLC.
Clinical trial identification
Legal entity responsible for the study
Geneseeq Biotechnology, Inc., Nanjing, China
All authors have declared no conflicts of interest.