# Revisiting p53 Immunohistochemical Staining and Its Prognostic Implications in Advanced EGFR-Mutated Lung Adenocarcinoma

## TL;DR

This study finds that high p53 protein levels in lung cancer tumors may predict better survival, even when TP53 gene mutations are present.

## Contribution

The study reveals that p53 immunostaining, not just TP53 mutations, is a strong prognostic factor in EGFR-mutated lung cancer.

## Key findings

- Tumor p53 overexpression (≥50%) was strongly linked to better overall survival in patients.
- TP53 mutations were not associated with worse progression-free or overall survival.
- High p53 staining in L858R EGFR-mutated tumors correlated with significantly longer survival.

## Abstract

The areas under the receiver operating characteristic (ROC) curves with different cut-off values for p53 positivity ranged between 0.51 and 0.56. Under a cut-off value of 50% p53 immunostaining, the sensitivity and specificity of TP53 mutations were 66.7% and 45.5%, respectively, indicating an inconsistency between p53 immunostaining and TP53 mutations. Tumor p53 overexpression (≥50%) was identified as a strong prognostic factor after adjusting for other important clinical factors, such as EGFR mutation subtypes, baseline brain metastasis status, and smoking status. This study shows that p53 immunohistostaining could help spare patients from toxicity of novel combination therapy once validated and adds value to TP53 mutation analysis in the modern genomic era of EGFR-mutated lung adenocarcinoma.

Background/Objectives: TP53 mutations in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer could worsen prognosis. Therefore, we aimed to investigate the clinical significance of TP53 mutations and p53 expression in these patients. Methods: Patients with advanced/metastatic EGFR-mutated lung adenocarcinoma treated with first-line tyrosine kinase inhibitors were retrospectively enrolled. Sanger sequencing was performed to detect TP53 mutations and immunohistochemical staining was used to verify p53 protein expression levels. Kaplan-Meier and Cox proportional hazards analyses were used to estimate survival and hazard ratio (HR) with 95% confidence interval (CI). Results: The study involved 83 patients with adequate tumor samples for TP53/p53 analysis. Patients with tumor p53 immunostaining ≥50% showed significantly better overall survival (OS) (HR: 0.49 [95% CI: 0.30–0.81], p < 0.001), but TP53 mutations were not associated with inferior progression-free survival (PFS) or OS (missense vs. wild-type [PFS, HR: 0.68 (95% CI: 0.40–1.15), p = 0.151; OS, HR: 0.88 (95% CI: 0.56–1.42), p = 0.599]). Areas under the receiver operating characteristic curves of TP53 mutations with different cut-off values for p53 positivity were 0.51–0.56. The Kaplan-Meier survival analysis revealed significant survival benefits in patients with EGFR L858R substitution and tumor p53 immunostaining ≥50% (median PFS: 8.0 vs. 5.3; median OS: 20.4 vs. 15.3 months; log-rank p = 0.025 and 0.049, respectively). Conclusions: Tumor p53 immunostaining (≥50%) was associated with better OS, especially in patients with TP53 mutations or L858R. Prospective clinical trials are required to explore the prognostic significance of p53 expression in the genomic era of TP53 mutations.