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

Abstract

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.

Keywords: brain metastasis; epidermal growth factor receptor; mutation; non-small cell lung cancer; tyrosine kinase inhibitors.

Figure 1

Uncommon mutations in the epidermal growth factor receptor (EGFR) gene from cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients with non-small cell lung cancer (NSCLC). BPM, brain parenchymal metastases; LM, leptomeningeal metastases; TKI, tyrosine kinase inhibitor.

Figure 2

Case 01 was a male of 34 years of age, with lung adenocarcinoma and with a history of smoking, but quitted 10 years ago. (A) T2 FLAIR enhanced magnetic resonance imaging (MRI) showed abnormal high signal in the medulla, oblongata, pon, and ventral and dorsal midbrain, suggesting leptomeningeal metastases (LMs). (B) T2 FLAIR enhanced MRI during afatinib treatment showed that the abnormal high signal in the medulla, oblongata, and ventral and dorsal midbrain was lower than before treatment. (C) Carcinoembryonic antigen (CEA) levels before and after afatinib treatment.

Figure 3

Case 05 was a male of 71 years of age, with lung adenocarcinoma but without smoking history. (A) Cerebellar vermis, bilateral cerebral hemispheres, and pia meninges shoed abnormal enhancement on magnetic resonance imaging. Leptomeningeal metastasis (LM) was considered. (B) Chest computed tomography revealing the primary lung lesion. (C) Carcinoembryonic antigen (CEA) levels before and after osimertinib treatment.

Figure 4

Case 12 was a female of 57 years of age, with lung adenocarcinoma but without smoking history. (A) In September 2018, the right cerebellopontine angle area, the edge of the tetras, and the lateral edge of the right arm were abnormally enhanced on magnetic resonance imaging. (B) In December, the enhancement intensity was decreased on the right side, and her condition was improved. (C) Carcinoembryonic antigen (CEA) levels before and after afatinib treatment.

Figure 5

Case 17 was a female of 65 years of age, with lung adenocarcinoma but without smoking history. (A) Magnetic resonance imaging (MRI) of the brain. (B) Carcinoembryonic antigen (CEA) levels before and after afatinib treatment.