Background: Patients with early stage, non-small cell lung cancer (NSCLC) with solitary pulmonary lesions ≤4 cm typically have favorable outcomes. However, disease recurrence impacts up to 30% of patients, leading to either additional surgical or systemic interventions. New methods to risk stratify patients based on clinical and molecular parameters may improve our ability to select cases that would benefit from more frequent surveillance or enrollment in clinical trials evaluating systemic therapy.

Methods: We retrospectively analyzed data from 179 patients with early stage (T1a-2aN0M) NSCLC from a single institution. All patients had anatomic resection, negative margins, and systematic nodal sampling. Our de-identified dataset consisted of samples that were molecularly profiled using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage, whole exome-capture RNA-seq). For this study, we analyzed pathogenic mutations (single nucleotide variants and insertion/deletions) as well as RNA expression. Clinical and demographic data were abstracted from patient clinical documents. Bivariate Cox proportional Hazards models assessed the association of individual clinical, demographic, and molecular variables with recurrence-free survival, defined as the time from surgery until recurrence or death (surviving patients without recurrence were censored at their last follow-up).

Results: Our dataset included 166 stage IA1-3 patients and 13 stage IB patients, of which 36 patients experienced a recurrence or death event after surgery. Clinical and DNA-seq data was available for all patients, and RNA expression data was available for 172 patients. Across all patients, the most common somatically mutated genes were TP53 (33% of tumors) and KRAS (16% of tumors), consistent with previous studies. Increasing log10-RNA expression for NTRK1 (HR: 5.95; 95% CI, 1.16-30.4; p=0.027) and CD274 (PD-L1) (HR: 7.88; 95% CI, 1.61-38.6; p=0.013) and decreasing log10-RNA expression for EGFR (HR: 0.24; 95% CI, 0.05-1.21; p=0.071) and ERBB2 (Her2) (HR: 0.20; 95% CI, 0.04-0.97; p=0.042) were associated with increased risk of recurrence/death.

Conclusions: Increased expression of NTRK1 and CD274 (PD-L1) and decreased expression of EGFR and ERBB2 (Her2) were associated with a significantly increased risk for disease recurrence following surgery; this may have mechanistic implications for heightened tumor aggressiveness and/or metastatic potential. Future work will expand our cohort and validate our findings in a broader set of early-stage NSCLC patients, with the ultimate goal of better identifying patients at a high risk of recurrence who would benefit from increased surveillance or systemic therapy.

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