PET/CT-Based Radiogenomics Supports KEAP1/NFE2L2 Pathway Targeting for Non–Small Cell Lung Cancer Treated with Curative Radiotherapy

In lung cancer patients, radiotherapy is associated with a increased risk of local relapse (LR) when compared with surgery but with a preferable toxicity profile. The KEAP1/NFE2L2 mutational status (Mut_KEAP1/NFE2L2) is significantly correlated with LR in patients treated with radiotherapy but is rarely available. Prediction of Mut_KEAP1/NFE2L2 with noninvasive modalities could help to further personalize each therapeutic strategy. Methods: Based on a public cohort of 770 patients, model RNA (M-RNA) was first developed using continuous gene expression levels to predict Mut_KEAP1/NFE2L2, resulting in a binary output. The model PET/CT (M-PET/CT) was then built to predict M-RNA binary output using PET/CT-extracted radiomics features. M-PET/CT was validated on an external cohort of 151 patients treated with curative volumetric modulated arc radiotherapy. Each model was built, internally validated, and evaluated on a separate cohort using a multilayer perceptron network approach. Results: The M-RNA resulted in a C statistic of 0.82 in the testing cohort. With a training cohort of 101 patients, the retained M-PET/CT resulted in an area under the curve of 0.90 (P < 0.001). With a probability threshold of 20% applied to the testing cohort, M-PET/CT achieved a C statistic of 0.7. The same radiomics model was validated on the volumetric modulated arc radiotherapy cohort as patients were significantly stratified on the basis of their risk of LR with a hazard ratio of 2.61 (P = 0.02). Conclusion: Our approach enables the prediction of Mut_KEAP1/NFE2L2 using PET/CT-extracted radiomics features and efficiently classifies patients at risk of LR in an external cohort treated with radiotherapy.