TP53 co-mutations increase risk of recurrence in EGFR-mutated stage I lung adenocarcinoma

Introduction: Adjuvant osimertinib was shown to improve survival outcomes in resected, EGFR mutated, stage IB-IIIA NSCLC. However, the prognostic implications of co-occurring mutations in resected, stage I tumours are unclear. Due to the poor prognosis of EGFR/TP53 co-mutations in patients with advanced NSCLC, we focused on this event in a cohort of patients with untreated, resected-stage I-LUAD. Methods: Patients who underwent radical surgical treatment for stage I LUAD in two high volume centers with available postoperative molecular testing were collected. Survival curves were estimated using the Kaplan-Meier product-limit method and were compared using the log-rank test; multivariable Cox regression analyses were used to assess the association between clinical and biological variables and RFS, and results were reported in the form of hazard ratios and their 95 % confidence intervals. We then leveraged publicly available datasets (OncoSG, MSK-LUAD604) to further test the hypothesis in external cohorts. Results: A total of 370 patients were included from two high volume centers of which 97 had an EGFR mutation. In the McGill/IRE cohort, patients with EGFR+TP53 co-mutation had a significantly worse RFS when compared to patients with EGFR-mutated LUAD (p = 0.001). In the multivariable analysis, EGFR+TP53 co-mutations (HR 5.32) were significantly associated with worse RFS. In the MSKCC cohort, EGFR+TP53 co-mutations were associated with shorter RFS and similar OS. Conclusion: Our results suggest that, among patients with EGFR-mutated, resected-stage I-LUAD, the presence of a TP53 co-mutation is associated with worse RFS. These findings corroborate the aggressive biology associated with these molecular findings in patients with metastatic, EGFR-mutated LUAD.