AUTHOR=Yang Hainan , Wen Lei , Zhao Chao , Li Xuefei , Shan Changguo , Liu Da , Hong Weiping , Zhou Zhaoming , Zhou Cheng , Cai Linbo , Zhou Caicun 

TITLE=EGFR amplification is a putative resistance mechanism for NSCLC–LM patients with TKI therapy and is associated with poor outcome

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.902664

DOI=10.3389/fonc.2022.902664

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Leptomeningeal metastases (LM) have become increasingly common in non-small cell lung cancer (NSCLC) patients who harbor epidermal growth factor receptor (<italic>EGFR</italic>) mutation treated with <italic>EGFR</italic>-TKI and are correlated with inferior prognosis. Evidence in prior research demonstrated that <italic>EGFR</italic> amplification was more likely presented in advanced clinical stages and was associated with worse survival. However, whether <italic>EGFR</italic> amplification is a prognostic marker in NSCLC–LM is still inconclusive.</p></sec><sec><title>Methods</title><p>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 <italic>EGFR</italic> amplification.</p></sec><sec><title>Results</title><p>This study enrolled 53 NSCLC–LM patients, all of whom had <italic>EGFR</italic> mutations. <italic>TP53</italic> and <italic>EGFR</italic> 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 <italic>EGFR</italic> amplification was much higher at the time of leptomeningeal progression than at initial diagnosis (<italic>p</italic> &lt; 0.01). Karnoskfy performance status was poorer (<italic>p</italic> = 0.021), and CSF pressure was higher (<italic>p</italic> = 0.0067) in patients with <italic>EGFR</italic> amplification than those without. A multivariable Cox proportional hazard regression model showed that <italic>EGFR</italic> amplification was an independent prognostic factor for poorer OS (8.3 <italic>vs</italic>. 15 months; <italic>p</italic> = 0.017). The median OS was shorter in NSCLC–LM patients with mutated <italic>TP53</italic> than those with wild-type <italic>TP53</italic>, but the difference was not statistically significant (10 <italic>vs</italic>. 17.3 months, <italic>p</italic> = 0.184).</p></sec><sec><title>Conclusions</title><p><italic>EGFR</italic> gene amplification could be a potential resistance mechanism to <italic>EGFR</italic>-TKI failure in NSCLC–LM and is associated with inferior clinical outcomes.</p></sec>