Introduction: molecular alterations in cancer-related genes are common in lung adenocarcinoma (ADK). Our previous studies have shown that mutations in EGFR/KRAS can be found in the non-tumoral lung epithelium (MUTNTL), regardless of the mutational status of the primary tumor. Short-term follow-up data suggested an impact on prognosis. The objective of our study was to evaluate the impact of MUTNTL on overall survival (OS) in patients who have undergone surgery for ADK. Secondary objectives: analyze differences in progression pattern and progression-free survival PFS

Methods:  78 patients from 2 cohorts were included: C1 (Chalela R et al, J Clin Med 2019) and C2 (Chalela R et al, Pathol Oncol Res 2021). The mutation profile was evaluated using CastPCR in histologically normal lung tissue, and confirmation was performed with digital PCR. In all cases, a 60-month follow-up was performed after surgery 

Results: MUTNTL was identified in 13 cases (16.7%). The results of OS showed a statistically significant association between the presence of MUTNTL, both for the crude analysis (HR=0.28, CI95%: [0.11;0.70], p=0.007) and in the multivariate analysis (HR=0.15, CI95%: [0.04;0.50], p=0.002). Worse PFS was found, but without achieving statistical significance (Univariate, HR=0.45, CI95%: [0.19;1.04], p=0.061. Multivariate HR=0.42, p=0.089). In both groups, the progression was almost exclusively by distant metastasis and not local (0% local progression in the MUTNTL group vs 6%)

Conclusion: molecular alterations in EGFR or KRAS in non-tumoral tissues are associated with higher overall mortality in patients with localized lung adenocarcinoma who are eligible for surgical treatment