Applying next-generation sequencing to predict short progression-free survival in patients with advanced EGFR-mutant lung adenocarcinoma receiving epidermal growth factor receptor tyrosine kinase inhibitors

<jats:p>For patients with advanced <jats:italic toggle="yes">EGFR</jats:italic>-mutant lung adenocarcinoma, progression-free survival (PFS) is significantly improved by epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) medications. However, a subset of patients still experiences early disease progression. In this study, we aimed to identify potential risk factors associated with shorter PFS through next-generation sequencing (NGS) analysis. This retrospective study included patients with advanced <jats:italic toggle="yes">EGFR</jats:italic>-mutant lung adenocarcinoma who received first-line EGFR-TKI treatment with upfront NGS. The genetic alterations included two types, mutations and copy number variations. Alterations involving <jats:italic toggle="yes">EGFR</jats:italic> downstream signaling pathways were classified as ‘<jats:italic toggle="yes">PIK3CA-AKT/RAS-RAF</jats:italic> alterations’. Clinical and histopathological data were also collected and analyzed. We studied a total of 82 advanced lung cancer patients with sensitive <jats:italic toggle="yes">EGFR</jats:italic> mutations. Multivariable analyses showed associations with a shorter PFS for the following factors: P<jats:italic toggle="yes">IK3CA-AKT/RAS-RAF</jats:italic> alterations [hazard ratio (HR) 3.197, <jats:italic toggle="yes">P</jats:italic> = 0.006], age ≤50 (HR 3.034, <jats:italic toggle="yes">P</jats:italic> = 0.010), and PD-L1 ≥50% (HR 2.256, <jats:italic toggle="yes">P</jats:italic> = 0.035). Based on the above risk factors, patients were classified into no-risk and ≥1 risk groups. In the no-risk group, third-generation EGFR-TKIs showed a numerically longer PFS compared to first/second-generation EGFR-TKIs (not reached vs. 20.0 months, <jats:italic toggle="yes">P</jats:italic> = 0.084). However, in patients with ≥1 risk factor, third-generation EGFR-TKIs showed no PFS advantages (6.6 vs. 6.2 months, <jats:italic toggle="yes">P</jats:italic> = 0.831). In conclusion, besides clinicopathological factors, NGS provides additional insights to predict shorter PFS after EGFR-TKI treatment. We identified three risk factors: (1) <jats:italic toggle="yes">PIK3CA-AKT/RAS-RAF</jats:italic> alterations, (2) age ≤50, and (3) PD-L1 ≥50%. Patients with these factors had poor PFS regardless of EGFR-TKI generation.</jats:p>