Abstract 4391: Real world data and multi-genomic analysis of non-common mutations in the EGFR mutation-positive non-small cell lung cancer
Authors: Kim Seoree , Sung Yeoun Eun , Kim Joo Ri , Jung Chan Kwon , Kim Jeong-Oh , Shin Jeong-yeon , Lee Guk Jin , Chun Sang hoon , Lee Young Ho , Kang Jin Hyoung 
Published: April 2023

Abstract
Introduction: There are similar and different properties between the epidermal growth factor receptor mutations (mEGFR), which are classified into common, uncommon, and compound mutation subtypes depending on their location and pattern on the EGFR gene. We investigated the RWD and RNA expression profile of non-common mutations (uncommon and compound mutations) in the mEGFR+ NSCLC patients.
Method: We analyzed the NGS data extracted from the Foundation Medicine (FMI) SRC. And, we collected the medical information for stage I-IIIA mEGFR+ NSCLC patients receiving curative surgical resection. In Böehringer Ingelheim (BI) open data access (ODA), we analyzed treatment results in stage IV mEGFR+ NSCLC patients treated with EGFR TKI. We explored the RNA expression profile by High-Plex Digital Spatial Profiling. A total of 18,676 DEG libraries were constructed, and 419 significance genes with &gt; 2-fold changes, 3-log 2 normalized read counts, and p-value = 0.05 (up and down) were identified.
Result: In FMI-SRC cohort, 10,059 mEGFR+ cases of total 78,656 cases consist of common, 6,994 (69.5%), uncommon, 1,966 (19.6%), and compound, 1,099 (10.9%). In hospital cohort, 941 mEGFR+ cases consist of common, 860 (91.4%), uncommon, 60 (7.4%), and compound, 21 (2.2%). Median relapse-free survival (mRFS) in non-common mutations (31.4M and 33.7M) was shorter than common mutations (40.1M, p=0.877). CNS recurrence in the non-common mutations (40.0% and 35.3%) tended to be higher than that of common mutations (27.4%, p=0.361). In BI-ODA, median time on treatment (mTOT) in 163 uncommon mutations (10.0M) and 139 compound mutations (11.5M) were shorter than historical data of common mutations (17.3M). Spatial RNA-seq data of the ratio of deconvolution individual cells showed that genes involved in inflammatory and immune response were relatively lower in non-common mutations. Gene ontology string analysis revealed RNA expression of genes in compound mutations was functionally associated with chemokine production (23.4%), electron transfer activity (14.9%) and T cell selection (8.5%), and, in uncommon mutations, was associated with regulation of oligopeptide transport (26.1%), hypermethylation of CpG island (21.7%), and CD4+ CD25+ regulatory T cell lineage commitment (13.0%), compared to common mutations. Based on the GSEA, relatively highly clustered genes in compound mutations were the protein modification process, G-protein coupled receptor, regulation of cytosolic calcium ion concentration, and IL-5 production pathways, and lower ES levels in oxidative phosphorylation and RNA processing pathways, when compared to common mutations.
Conclusion: Taken together, our results suggest that uncommon and compound mEGFR subtypes exhibiting shorter mRFS and mTOT, and distinguishing RNA expression profile of functional signaling pathways be not same disease entity as common mEGFR subtype
Citation Format: Seoree Kim, Yeoun Eun Sung, Joo Ri Kim, Chan Kwon Jung, Jeong-Oh Kim, Jeong-yeon Shin, Guk Jin Lee, Sang hoon Chun, Young Ho Lee, Jin Hyoung Kang. Real world data and multi-genomic analysis of non-common mutations in the EGFR mutation-positive non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4391.