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

Abstract

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

SEC61G assists EGFR -amplified glioblastoma to evade immune elimination

“…It has been shown that EGFR amplification in GBM or lung cancer renders tumor insensitive to EGFR-TKIs ( 3 , 17 ), but the underlying mechanism remains largely unclear. Extensive analysis of cancer genomics indicated that amplification of oncogenes or deletion of tumor suppressors often encompasses the neighboring genes, which cooperatively contribute to tumorigenesis ( 13 – 15 ).…”

“…The reasons that lead to resistance to EGFR-TKIs in GBM are largely unknown, which may include intertumoral heterogeneity, redundancy in signaling pathways, and insufficient brain penetration of the inhibitors due to the BBB ( 3 ). It has been shown that amplification of EGFR renders tumor insensitive to EGFR-TKIs ( 17 ). Our study demonstrates that SEC61G is coamplified with EGFR in GBM and promotes immune evasion, which reveals a mechanism underlying the inefficiency of EGFR-TKIs in EGFR -amplified tumors.…”

The association of EGFR amplification with aberrant exon 20 insertion report using the cobas EGFR Mutation Test v2

“…Our study also showed that EGFR amplification was significantly associated with high-grade histology, tumor necrosis, and high tumor content (See S3 Table in S1 File ). EGFR amplification has been reported as a putative resistance mechanism to EGFR-TKIs in patients with leptomeningeal metastases [ 39 ]. However, one study demonstrated that EGFR sensitizing mutations and amplification were associated with better overall survival and progression-free survival in Hispanic patients treated with erlotinib [ 40 ].…”

Búsqueda de biomarcadores pronósticos y terapéuticos en el carcinoma pulmonar de células escamosas. Correlación clínico-patológica

“…El estado funcional de Karnofsky fue peor (p = 0,02) y la presión del LCR fue mayor (p = 0,006) en los pacientes con amplificación de EGFR que en los que no la tenían. El análisis multivariante mostró que la mediana de SG fue significativamente más corta en pacientes con amplificación de EGFR que en aquellos que no la tenían, convirtiéndose en un factor pronóstico independiente para una SG (8,3 frente a 15 meses; p = 0,017) (182). Estos hallazgos apoyan nuestra teoría de que la amplificación del gen EGFR en pacientes con CPCE confiere un peor pronóstico y afecta negativamente la supervivencia de estos pacientes.…”