Impact of Baseline β-Catenin Comutations on Prognosis in EGFR-Mutant Lung Cancer

PURPOSE Epidermal growth factor receptor (EGFR) mutations are a main actionable driver in non–small cell lung cancer (NSCLC). However, the clinical significance of catenin beta-1 (CTNNB1) comutations remains unclear. This study evaluated outcomes of patients with EGFR/CTNNB1 comutated NSCLC in a dual-center cohort. METHODS A retrospective analysis of 1,804 patients with NSCLC undergoing next-generation sequencing (NGS) in 2019-2024 at University Hospital Würzburg (single-center cohort, including 15 patients with EGFR/CTNNB1 comutations) was complemented with patients with EGFR/CTNNB1 comutated NSCLC receiving first-line osimertinib at the Thoraxklinik Heidelberg (n = 11) to extend and validate initial findings. We assessed clinical outcomes after first-line osimertinib therapy in 90 EGFR-mutated patients with CTNNB1 wild-type (wt) status and 23 with CTNNB1 comutation. RESULTS CTNNB1 mutations were identified in 2.0% (36/1,804) of all patients with NSCLC from the single-center cohort, with 41.7% of these also harboring EGFR mutations. Among EGFR-mutant tumors, 7.7% (15/195) exhibited concurrent CTNNB1 mutations. In the dual-center cohort, the objective response rate with first-line osimertinib was 74.4% in CTNNB1-wt (n = 90) and 65.0% in CTNNB1-mutant patients (n = 23; P = .38). Notably, CTNNB1 mutations were associated with significantly longer progression-free survival (PFS; hazard ratio [HR], 0.32; P < .001) and overall survival (OS; HR, 0.33; P = .003). Multivariate analysis confirmed CTNNB1 comutation as an independent prognostic factor for improved PFS (HR, 0.31 [95% CI, 0.14 to 0.69]; P = .004) and OS (HR, 0.26 [95% CI, 0.10 to 0.65]; P = .004). Additionally, CTNNB1 mutations correlated with lower PD-L1 expression ( P = .001) and TP53-wt status ( P < .001). CONCLUSION CTNNB1 comutations are associated with lower PD-L1 expression and TP53-wt status, correlating with improved outcomes in patients with EGFR-mutant NSCLC undergoing osimertinib therapy. These results suggest that CTNNB1 comutations may serve as a favorable prognostic biomarker in patients with EGFR-mutant NSCLC. Additional prospective studies are warranted to validate these results.