Molecular, histopathological, and clinical risk factors for overall metastatic disease and brain metastases in surgically resected stage I-III lung cancer.

Lung cancer remains a major cause of cancer-related mortality, including among patients diagnosed with potentially curable disease. Current decisions regarding perioperative treatment and follow-up rely on a limited number of established prognostic factors. Further knowledge is needed regarding the clinical, histopathological, and molecular factors associated with subsequent metastatic disease, particularly brain metastasis (BM), which is associated with poor prognosis. We investigated these factors in a large cohort of patients with surgically resected stage I-III lung cancer followed for more than five years. BM was associated with higher pathological tumour and lymph-node stage and younger age at surgery. Lung adenocarcinoma was associated with a higher risk of BM than lung squamous cell carcinoma. Several molecular alterations were associated with metastatic disease or BM, including KRAS mutations in lung adenocarcinoma and NFE2L2 mutations in lung squamous cell carcinoma. Additional associations involving specific EGFR and KRAS mutation subtypes and rarer alterations were observed, but were based on small numbers of cases and should be considered exploratory. Several of the associated genes are involved in the RAS/MAPK, PI3K/AKT/mTOR, or NRF2-related pathways. However, pathway activation and causality could not be established in this observational study. These findings support further investigation of clinical, histopathological, and molecular factors associated with metastatic progression after surgical resection. Validation in larger, independent, stage-stratified and contemporary cohorts with comprehensive treatment data is required before the identified molecular alterations can be considered for clinical risk stratification or surveillance.