Abstract 5754: The molecular characteristics of EGFR co-mutations in lung adenocarcinoma

Abstract Background: With the development of sensitive next-generation sequencing (NGS) techniques that go beyond the genotyping of specific mutations, detection rates for uncommon mutations have risen clinically. Given this rise in mutation identification, discoveries regarding isolation or coexistent mutations with the EGFR mutation (termed a “complex” mutation) are in “uncharted territory” in terms of their biological impacts on oncogenic pathways and their sensitivity or resistance, to EGFR TKIs. Methods: Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: A cohort of 262 Chinese lung adenocarcinoma patients were recruited. The most common mutated gene was EGFR (63%, 165/262), and followed by TP53 gene (59.2%, 155/262). Beyond single genetic lesions, we found that enriched co-mutations in lung adenocarcinoma were significantly different for TP53 (p < 0.001) and RTK-RAS (p = 0.0012) signaling pathways between the EGFR-positive and EGFR-negative groups. In all EGFR co-mutated patients, the frequency of co-mutation for EGFR/TP53 and the classical EGFR mutation was 106 (64.2%) and 144 (87.3%), respectively. EGFR-only mutations occurred in 50 (30.3%) patients, while co-mutation of EGFR and at least one tumor suppressor gene (TSG) occurred in 84 (50.9%) patients. Patients with EGFR-only mutation had a lower tumor mutational burden (p = 0.026) as compared to patients with only a TSG mutation. Patients with co-mutations of EGFR and at least one TSG also displayed a lower tumor mutational burden, although only a slight difference (p = 0.062) was determined. Conclusions: Profiles of EGFR co-mutational TSGs should be regarded as a unique subgroup for predictive insights in treatments for patients with co-occurrence of somatic EGFR and TSG mutations. To improve predictions related to drug sensitivity in targeted therapies for oncogenes with diverse mutations, our future studies will include publications dedicated to this topic. Citation Format: Yanhong Shang, Hao Zhang, Aiming Zang, Shaohua Yuan, Xiaofang Li, Wenpan Zhang, Ran Huo, Guotao Fang, Zhengyue Dou, Weiwei Liu, Xiao Han, Qi Zhao, Chenglin Xi. The molecular characteristics of EGFR co-mutations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5754.