Rare Epidermal Growth Factor Receptor Gene Alterations in Non-Small Cell Lung Cancer Patients, Tyrosine Kinase Inhibitor Response and Outcome Analysis

Abstract Background The predictive value of rare epidermal growth factor receptor gene (EGFR) mutations for non-small cell lung carcinoma (NSCLC) patients remain elusive. We evaluated the distribution, clinicopathological association, tyrosine kinase inhibitor (TKI) response, and outcome of NSCLC patients carrying uncommon EGFR aberrations in comparison to classical EGFR mutations. Methods Treatment naive, advanced NSCLC cases tested by Next-Generation sequencing (NGS) method between 2015 and 2020 were included. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed. Results A total of 237 tumor samples were sequenced. Among the sixty-nine (29%) EGFR mutated cases, 41 (59.4%) harbored classical mutation (37.7% Del19, 21.7% p.L858R). Non-classical aberrations included missense mutations in exon 18/20/21 (15.9%), EGFR amplification (8.7%), exon 20 insertions (7.2%), EGFR Variant III (4.3%), exon 18 indel (2.9%), exon 21 missense (2.9%) and exon 19 missense mutation (1.4%). These occurred as complex mutations in 16% of cases. Oral TKI was administered in 66.7% cases. The patients harboring non-classical variants had a lower ORR and DCR (23.1% and 61.5%) than those carrying a common mutation (57.6% and 84.8%). Collectively, compared to the patients with common EGFR mutations, the uncommon group showed early disease progression and had shorter overall survival. Conclusion NGS testing has the capacity to reveal a diverse spectrum of uncommon EGFR variants. Our study can contribute to the database of uncommon EGFR mutations with a positive influence on evidence-based care of advanced lung cancer patients with EGFR mutations.