Mutation Profile of ResectedEGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing

Abstract

Background The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co‐mutations in resected epidermal growth factor receptor (EGFR)‐mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. Materials and Methods Mutation profiling of 416 cancer‐relevant genes was conducted for 139 resected stage I–IIIa lung ADCs with EGFR mutations using targeted next‐generation sequencing. Co‐mutation profiles were systematically analyzed. Results Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first‐generation TKIs. Ninety‐one percent of patients harbored at least one co‐mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II–III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty‐four percent of patients with EGFR TKI‐sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. Conclusion Operable lung ADCs with EGFR TKI‐sensitizing mutations are associated with a high proportion of co‐mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. Implications for Practice The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next‐generation sequencing of 416 cancer‐relevant genes in 139 resected lung cancers revealed the co‐mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI‐resistant mutations in 34.71% of patients with a drug‐sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non–Small-Cell Lung Cancer: A Clash of the Generations

“…20 Recent data have indicated that approximately one third of EGFR mutationpositive tumors will carry genetic alterations involving EGFR downstream effectors or bypass pathways such as PIK3CA, BRCA1, and NOTCH that could lead to the development of TKI-resistant subclones. 21 Accordingly, a rationale exists for the development of treatment strategies that will target multiple intracellular signaling pathways in EGFR mutation-positive NSCLC.…”

Immune landscape and a promising immune prognostic model associated with TP53 in early‐stage lung adenocarcinoma

“…[24][25][26] TP53, the encoding gene of p53 protein, is the most commonly mutated gene in multiple cancers and is subsistent in approximately 37%-50% LUAD cases. [27][28][29] Mutant p53 potentially triggers chromosomal/genomic instability and further results in a high TMB, which is frequently related to more aggressive malignancy and unsatisfactory prognosis in LUAD. [30][31][32] Nevertheless, several studies have highlighted that TP53-mutated LUAD is characterized with higher PD-L1 expression by malignant cells, boosted T-cell infiltration and tumor immunogenicity, leading to an increased response to ICIs.…”

“…The products of p53 target genes are proved to participate in a sequence of crucial biological pathways, including cell proliferation and apoptosis, DNA damage repair, anti‐oxidant function, metabolism and angiogenesis as well as immunoreaction, thus making contributions to the tumor‐suppression effect of p53 24‐26 . TP53, the encoding gene of p53 protein, is the most commonly mutated gene in multiple cancers and is subsistent in approximately 37%‐50% LUAD cases 27‐29 . Mutant p53 potentially triggers chromosomal/genomic instability and further results in a high TMB, which is frequently related to more aggressive malignancy and unsatisfactory prognosis in LUAD 30‐32 .…”

An enzymatic on/off switch‐mediated assay for KRAS hotspot point mutation detection of circulating tumor DNA

“…SnaPShot and next‐generation sequencing, the sensitivity of SnaPshot for KRAS mutation detection was about 10%, but this method is also laborious and time‐consuming 16,17 . Next‐generation sequencing is relatively expensive, time‐consuming, and complicated data interpreting 18,19 . Choong et al detected the KRAS mutations using the isothermal‐based optical sensor for companion diagnostics, 20 a rapid, specific, and sensitive method, but the preparation process is relatively complex and the result is not easy to interpret.…”

“…16,17 Next-generation sequencing is relatively expensive, time-consuming, and complicated data interpreting. 18,19 Choong et al detected the KRAS mutations using the isothermal-based optical sensor for companion diagnostics, 20 a rapid, specific, and sensitive method, but the preparation process is relatively complex and the result is not easy to interpret. Therefore, a high-throughput, economical, sensitive, and easy data analysis assay is urgently needed.…”