Cancer Res Treat.  2024 Jan;56(1):104-114. 10.4143/crt.2023.728.

Clinical Impact of Genomic and Pathway Alterations in Stage I EGFR-Mutant Lung Adenocarcinoma

• Lee JS
• Kim EK
• Kim KA
• Shim HS

• KMID: 2550327
• DOI: http://doi.org/10.4143/crt.2023.728

Abstract

Purpose
We investigated the clinical impact of genomic and pathway alterations in stage I epidermal growth factor receptor (EGFR)–mutant lung adenocarcinomas, which have a high recurrence rate despite complete surgical resection.
Materials and Methods
Out of the initial cohort of 257 patients with completely resected stage I EGFR-mutant lung adenocarcinoma, tumor samples from 105 patients were subjected to analysis using large-panel next-generation sequencing. We analyzed 11 canonical oncogenic pathways and determined the number of pathway alterations (NPA). Survival analyses were performed based on co-occurring alterations and NPA in three patient groups: all patients, patients with International Association for the Study of Lung Cancer (IASLC) pathology grade 2, and patients with recurrent tumors treated with EGFR–tyrosine kinase inhibitor (TKI).
Results
In the univariate analysis, pathological stage, IASLC grade, TP53 mutation, NPA, phosphoinositide 3-kinase pathway, p53 pathway, and cell cycle pathway exhibited significant associations with worse recurrence-free survival (RFS). Moreover, RPS6KB1 or EGFR amplifications were linked to a poorer RFS. Multivariate analysis revealed that pathologic stage, IASLC grade, and cell cycle pathway alteration were independent poor prognostic factors for RFS (p=0.002, p < 0.001, and p=0.006, respectively). In the grade 2 subgroup, higher NPA was independently associated with worse RFS (p=0.003). Additionally, in patients with recurrence treated with EGFR-TKIs, co-occurring TP53 mutations were linked to shorter progression-free survival (p=0.025).
Conclusion
Genomic and pathway alterations, particularly cell cycle alterations, high NPA, and TP53 mutations, were associated with worse clinical outcomes in stage I EGFR-mutant lung adenocarcinoma. These findings may have implications for risk stratification and the development of new therapeutic strategies in early-stage EGFR-mutant lung cancer patients.

Keyword

Adenocarcinoma of lung; mutation; Early stage; Recurrence; Genomics

Figure

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  Fig. 1. Genomic landscape of stage I EGFR-mutant lung adenocarcinoma according to recurrence status. EGFR, epidermal growth factor receptor; NR, not recurred; PY, pack-years; R, recurred.

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  Fig. 2. List of altered genes and distribution of pathway alterations.

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  Fig. 3. Survival curves based on IASLC grades and genomic alterations. (A) RFS of all patients based on IASLC grades. (B) RFS for all patients based on cell cycle pathway alterations. (C) RFS for patients with IASLC grade 2 EGFR-mutant lung adenocarcinoma based on NPA. (D) PFS for patients treated with EGFR-TKI after recurrence based on TP53 mutations. EGFR, epidermal growth factor receptor; IASLC, International Association for the Study of Lung Cancer; NPA, number of pathway alterations; PFS, progression-free survival; RFS, recurrence-free survival; TKI, tyrosine kinase inhibitor.

Reference

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