Defining the biological basis of radiomic phenotypes in lung cancer

Medical imaging can visualize characteristics of human cancer noninvasively. Radiomics is an emerging field that translates these medical images into quantitative data to enable phenotypic profiling of tumors. While radiomics has been associated with several clinical endpoints, the complex relationships of radiomics, clinical factors, and tumor biology are largely unknown. To this end, we analyzed two independent cohorts of respectively 262 North American and 89 European patients with lung cancer, and consistently identified previously undescribed associations between radiomic imaging features, molecular pathways, and clinical factors. In particular, we found a relationship between imaging features, immune response, inflammation, and survival, which was further validated by immunohistochemical staining. Moreover, a number of imaging features showed predictive value for specific pathways; for example, intra-tumor heterogeneity features predicted activity of RNA polymerase transcription (AUC = 0.62, p=0.03) and intensity dispersion was predictive of the autodegration pathway of a ubiquitin ligase (AUC = 0.69, p<10(-4)). Finally, we observed that prognostic biomarkers performed highest when combining radiomic, genetic, and clinical information (CI = 0.73, p<10(-9)) indicating complementary value of these data. In conclusion, we demonstrate that radiomic approaches permit noninvasive assessment of both molecular and clinical characteristics of tumors, and therefore have the potential to advance clinical decision -making by systematically analyzing standard-of-care medical images.