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Background Studies in EGFR+ non‐small cell lung cancer (NSCLC) patients with leptomeningeal metastasis (LM) comparing survival rates and gene mutation detection with matched cerebrospinal fluid (CSF) and plasma are relatively scarce. We evaluated gene mutations, treatment strategies, and clinical outcomes in EGFR+ NSCLC patients with LM. Methods We retrospectively reviewed gene mutation status in the CSF and plasma of 32 EGFR+ NSCLC patients with LM for prognostic significance. Results The rate of LM disease control was significantly higher in patients that switched EGFR‐tyrosine kinase inhibitor (TKI) treatments, initiated EGFR‐TKIs, or received high‐dose EGFR‐TKI treatment than those who continued their current EGFR‐TKI treatment, received chemotherapy, or were not administered antitumor treatment (24/24, 100.0% vs. 1/8, 12.5%; P = 0.000). Overall survival was 27.0 months (95% confidence interval [CI] 19.0–37.5), median survival after LM was 7.0 months (95% CI 5.0–11.0), and median survival before LM was 17.0 months (95% CI 12–25.5). Median survival after LM was significantly shorter in patients with “worse” status (n = 7) than in those with “improved/stable” status (n = 25; 4.2 [95% CI 2.2–6.1] vs. 33.7 [95% CI 25.5–41.8] months, HR 10.114, 95% CI 0.29–1.37; P = 0.008). Conclusions EGFR‐TKIs should be the priority course of treatment in EGFR+ NSCLC patients after a diagnosis of LM. Liquid biopsy in both plasma and CSF, as well as dynamic detection, play important roles in the direction of treatment for such patients.