Chromosomal Instability Identifies High‐Risk Patients With Early‐Stage Non‐Small Cell Lung Cancer

ABSTRACT Background Patients with stage I–III non‐small cell lung cancer (NSCLC) can have very different outcomes, even when they have the same anatomic stage. This suggests that tumor biology plays an important role in prognosis. Fraction genome altered (FGA) is a measure of chromosomal instability that can be calculated from routine targeted next‐generation sequencing (NGS) already used in clinical care. We evaluated whether FGA is associated with survival in early‐stage NSCLC and whether it adds information beyond standard clinical factors and tumor mutation burden (TMB). Methods We studied 7722 patients with NSCLC who underwent clinical‐grade targeted NGS with available copy‐number data. FGA was calculated from copy‐number profiles and analyzed by quartiles and as high (top quartile) versus low (lower three quartiles). Overall survival (OS) was evaluated using Kaplan–Meier analysis and Cox regression models adjusted for age, sex, smoking history, histology, disease stage, sequencing panel, and TMB. Results Higher FGA was associated with worse OS in stage I–III NSCLC. Five‐year OS declined from 65.6% in the lowest FGA quartile to 39.6% in the highest. Patients with high FGA had significantly poorer survival compared with those with low FGA ( p < 0.001). After adjustment for clinical factors, high FGA remained independently associated with mortality, whereas TMB did not. Conclusions Chromosomal instability measured by FGA is associated with survival in stage I–III NSCLC and provides useful prognostic information beyond standard clinical features and TMB. FGA may help identify early‐stage patients at higher risk who could benefit from closer follow‐up or clinical trials.