Radiogenomic Analysis of a Peritumoral CT Image Feature and Its Prognostic Value in Early Stage NSCLC

Abstract

The prevalence of early stage non-small cell lung cancer (NSCLC) is expected to increase with the implementation of CT screening programs. Prognostic biomarkers are critically needed that can predict which patients are at a high risk of relapse and thus require additional systemic therapy. The purpose of this work is to identify the molecular basis and assess prognostic value of a novel peritumoral CT image feature in early stage NSCLC. We retrospectively analyzed seven independent NSCLC cohorts (n = 1069). First, a 3D quantitative pleural contact index (PCI) was defined on CT images as tumor-pleura contact area normalized by the total tumor surface area. Based on PCI, we dichotomized patients into two groups in a discovery cohort (n = 117) and tested on an external cohort (n = 88). Both cohorts consisted of stage I NSCLC patients treated with radiation therapy. Next, we analyzed another cohort of 89 NSCLC patients with both imaging and gene expression data to identify the molecular basis of PCI and build a gene expression-based surrogate (i.e., radiogenomic classifier). To further test its prognostic relevance, we identified four datasets totaling 775 stage I NSCLC patients with publically available gene expression data and linked survival information. PCI showed a high degree of reproducibility against variations in tumor contours with an intra-class correlation of 0.89. At a cutoff of 0.25, PCI significantly stratified patients for overall survival in both discovery (log-rank test P = 0.0076) and validation (log-rank test P = 0.0304) imaging cohorts. PCI also stratified patients for distant metastasis in the discovery cohort (log-rank test P = 0.0060). Gene set enrichment analysis showed that PCI was significantly associated with genes related to extracellular matrix organization/disassembly and collagen catabolic process (Spearmen test P < 0.05). The radiogenomic classifier stratified patients for overall survival in each of the four gene expression cohorts (log-rank test P range: <0.0001 to 0.019) and remained an independent predictor when adjusting for age, gender, and tumor stage (Wald test P = 0.0007). Pleural contact index can serve as a noninvasive prognostic marker and might be used to guide risk-adapted therapy in early stage NSCLC. We envision that the radiogenomic strategy can be used to identify biological meaningful and clinical relevant imaging biomarkers in other cancer types.