amplification is a putative resistance mechanism for NSCLC-LM patients with TKI therapy and is associated with poor outcome.

Background: Leptomeningeal metastases (LM) have become increasingly common in non-small cell lung cancer (NSCLC) patients who harbor epidermal growth factor receptor () mutation treated with -TKI and are correlated with inferior prognosis. Evidence in prior research demonstrated that amplification was more likely presented in advanced clinical stages and was associated with worse survival. However, whether amplification is a prognostic marker in NSCLC-LM is still inconclusive.

Methods: This study enrolled patients diagnosed with NSCLC-LM from June 2019 to September 2021 and who had received previous EGFR-TKI at Guangdong Sanjiu Brain Hospital. Cerebrospinal fluid (CSF) samples were collected and subjected to targeted next-generation sequencing of 168 cancer-related genes. Clinical characteristics and overall survival (OS) were compared in patients with and without amplification.

Results: This study enrolled 53 NSCLC-LM patients, all of whom had mutations. and amplifications are the two most frequent mutations in the study cohort, presenting at 72% (38 of 53) and 40% (21 of 53), respectively. The rate of amplification was much higher at the time of leptomeningeal progression than at initial diagnosis ( < 0.01). Karnoskfy performance status was poorer ( = 0.021), and CSF pressure was higher ( = 0.0067) in patients with amplification than those without. A multivariable Cox proportional hazard regression model showed that amplification was an independent prognostic factor for poorer OS (8.3 . 15 months; = 0.017). The median OS was shorter in NSCLC-LM patients with mutated than those with wild-type , but the difference was not statistically significant (10 . 17.3 months, = 0.184).

Conclusions: gene amplification could be a potential resistance mechanism to -TKI failure in NSCLC-LM and is associated with inferior clinical outcomes.