A Case Report of Concurrent Epidermal Growth Factor Receptor (EGFR) Exon 18 (G719A) and Exon 21 (L833_V834delinsFL) Mutations and Treatment Challenges

Molecular profiling of lung tumors is crucial for guiding targeted therapeutic strategies and identifying potential resistance mechanisms to specific therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). During this profiling, mutations with uncertain treatment implications can be identified. This case study represents a 69-year-old female with a co-occurring EGFR mutation profile that presents a unique therapeutic challenge. Tumor DNA was used for next-generation sequencing (NGS) of a custom 275 cancer-related QIAseq Human Comprehensive Cancer Panel (Qiagen). Next-generation RNA sequencing was performed using the Illumina TruSight panel. FISH analysis and PD-L1 22C3 immunohistochemical testing were also performed. Microscopic analysis revealed an invasive adenocarcinoma with papillary, acinar, and focal micropapillary features with a 6 mm invasive component. The final pathology stage was determined to be pT1aN0M0. NGS for DNA variant detection identified two mutations in EGFR, an EGFR G719A and EGFR L833_V834delinsFL with a variant allele frequency (VAF) of 22.2% and 21.1%, respectively. Targeted NGS RNA fusion analysis was also performed, which came back negative. PD-L1 22C3 immunohistochemical testing showed only 1% of the tumor cells expression. FISH analysis revealed one copy of MET and D7Z1 in 27% of cells, indicating an aneuploid neoplastic clone with monosomy 7. EGFR TKIs are universally accepted as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with a sensitizing EGFR mutation. While mutations such as G719A are sensitive to all generations of EGFR-TKI, the effects are unknown for rare compound mutations in EGFR, such as EGFR L833_V834delinsFL. There are no reports in the literature with any mention of an algorithm of treatment for such a case. The patient had two metachronous lung primary cancers resected in 2022 and 2024. Due to the complete surgical resection, the sensitivity of this mutation of TKIs could not be established. This unique mutation profile still remains of paramount importance to understand if the patient relapses or presents with a new tumor with the same genetic profile.