Role of TP53 Mutations and EGFR Amplification in Risk Stratification of Early-Stage EGFR-Mutated Non-Small Cell Lung Cancer With Immunohistochemistry as a Surrogate Marker.

Abstract

Background: Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related mortality, with recurrence risks posing significant challenges in early-stage disease management. While epidermal growth factor receptor (EGFR) mutations are common, the role of concurrent genetic alterations remains underexplored, and findings have often been inconsistent, particularly in early-stage tumors.

Methods: We retrospectively analyzed 424 EGFR-mutated NSCLC patients diagnosed from 2017 to 2022. Next-generation sequencing (NGS) was used to identify genetic alterations, and immunohistochemistry (IHC) was employed to correlate TP53 mutations and EGFR amplification with protein expression. Survival outcomes were assessed using Kaplan-Meier and Cox regression analyses, while predictive cutoffs were determined with receiver operating characteristic (ROC) curve analysis.

Results: TP53 mutations and EGFR amplification were more prevalent in Stages 2-4 compared to Stage 1 (p < 0.001 and 0.005, respectively). In Stage 1, TP53 mutations, particularly exon 4 and frameshift/nonsense types, were associated with worse overall survival (OS) and disease-free survival (DFS). EGFR amplification was linked to shorter DFS in Stage 1 (p = 0.006). Both alterations correlated with aggressive pathological features, including advanced N stage, lymphovascular invasion, and high histological grade. IHC cutoffs of 15% for TP53 and H-score ≥ 180 for EGFR amplification demonstrated high predictive accuracy (AUC = 0.981 and 0.936, respectively).

Conclusion: Specific subtypes of TP53 mutations and EGFR amplification are important prognostic markers in early-stage NSCLC. IHC offers a practical surrogate for genetic testing, aiding in risk stratification and guiding adjuvant therapy decisions for high-risk patients. Larger validation studies are warranted.