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Background:  The significance of uncommon  epidermal growth factor receptor  ( EGFR ) mutations in patients with non-small cell lung cancer (NSCLC) and brain metastasis (BM) remains unclear. Cerebrospinal fluid (CSF) liquid biopsy is a novel tool for assessing  EGFR  mutations in BM. This study aimed to evaluate the  EGFR  mutations in patients with NSCLC and newly diagnosed BM and to examine the effect of EGFR tyrosine kinase inhibitors (TKI) on BM harboring CSF-tested uncommon  EGFR  mutations.   Methods:  This was a prospective study of 21 patients with NSCLC and BM diagnosed between 04/2018 and 01/2019. CSF was obtained to detect the BM  EGFR  mutations by next-generation sequencing. BM characteristics at magnetic resonance imaging (MRI) and EGFR-TKI response were examined.   Results:  Of 21 patients with NSCLC, 10 (47.6%) had leptomeningeal metastasis (LM), while 11 (52.4%) had brain parenchymal metastasis (BPM); 13 (61.9%) had confirmed  EGFR  mutation-positive primary tumors. The uncommon mutation rate in CSF ctDNA was 33.3% (7/21). Among those with  EGFR  mutation-positive primary tumors, the rate of uncommon  EGFR  mutations in CSF was 53.8% (7/13). Uncommon  EGFR  mutations were more common in patients with LM than in patients with PBM (6/11, 54.5% vs. 1/10, 10%), and included G719A, L861Q, L703P, and G575R. TKI was effective for four patients with BMs harboring uncommon  EGFR  mutations.   Conclusion:  In patients with NSCLC and LM, the rate of uncommon  EGFR  mutation was high. The BMs with uncommon  EGFR  mutations seem to respond to EGFR-TKI treatment. CSF liquid biopsy could reveal the  EGFR  genetic profile of the BM and help guide treatment using small-molecule TKI.

Tyrosine Kinase Inhibitors Could Be Effective Against Non-small Cell Lung Cancer Brain Metastases Harboring Uncommon EGFR Mutations