Pericardial Fat and Primary Tumor Radiomics for Predicting Occult N2 Disease and Survival in Clinical Stage I Non-Small Cell Lung Cancer: Multicenter Study and Biologic Correlation.

Abstract

<b>BACKGROUND</b>. Occult N2 disease significantly affects clinical stage I non-small cell lung cancer (NSCLC) prognosis. Pericardial fat characteristics also have prognostic associations. <b>OBJECTIVE</b>. The purpose of this study was to develop and test a model incorporating pericardial fat and tumor radiomic features on CT for detecting occult N2 disease in clinical stage I NSCLC, explore the model's prognostic role, and investigate its biologic basis through radiogenomics analyses. <b>METHODS</b>. This retrospective study included patients who underwent clinical stage I NSCLC resection at three hospitals (center 1 [January 2016 to December 2022], stratified randomly by a 6:2:2 ratio into training, tuning, and internal test sets; centers 2 and 3 [January 2019 to December 2023], serving as external test sets). Pericardial fat and primary tumors were segmented on preoperative CT to extract radiomic features and generate tumor and fat radiomics scores (rad-scores), respectively. Multivariable analysis was performed to create a hybrid model for predicting occult N2 disease at surgery. Performance was evaluated in external test sets. Associations with recurrence-free survival (RFS) and overall survival (OS) were evaluated using log-rank tests in the internal test set; follow-up data were unavailable in the external test sets. Biologic mechanisms were explored through RNA and gene expression analysis in a separate set of patients with NSCLC obtained from a public radiogenomics database. <b>RESULTS</b>. From the three centers, 1662 patients (mean age, 58.6 years; 663 men, 999 women) were included. After multivariable analysis, the hybrid model included nodule density, fat rad-score, and tumor rad-score. The model had AUC, accuracy, sensitivity, and specificity for occult N2 disease of 0.921, 89.7%, 59.3%, and 93.1% and 0.913, 91.8%, 56.2%, and 95.5% in external test sets 1 and 2, respectively. In the internal test set, high-risk compared with low-risk patients showed worse RFS (<i>p</i> < .001) and OS (<i>p</i> < .001). In 122 patients in radiogenomics analysis, high-risk status was associated with activation of molecular pathways and increased activated dendritic cell and mast cell infiltration. <b>CONCLUSION</b>. A model incorporating tumor and pericardial fat radiomics showed good performance in predicting occult N2 disease as well as associations with survival and with RNA and gene expression. <b>CLINICAL IMPACT</b>. The model could help guide NSCLC management.