| Summary: | This study aimed to investigate if combining clinical characteristics with pre-therapeutic <sup>18</sup> F-fluorodeoxyglucose (<sup>18</sup> F-FDG) positron emission tomography (PET) radiomics could predict the presence of molecular alteration(s) in key molecular targets in lung adenocarcinoma. This non-interventional monocentric study included patients with newly diagnosed lung adenocarcinoma referred for baseline PET who had tumour molecular analyses. The data were randomly split into training and test datasets. LASSO regression with 100-fold cross-validation was performed, including sex, age, smoking history, AJCC cancer stage and 31 PET variables. In total, 109 patients were analysed, and it was found that 63 (57.8%) patients had at least one molecular alteration. Using the training dataset (<i>n</i> = 87), the model included 10 variables, namely age, sex, smoking history, AJCC stage, excessKustosis_<sub>HISTO</sub>, sphericity_<sub>SHAPE</sub>, variance_<sub>GLCM</sub>, correlation_<sub>GLCM</sub>, LZE_<sub>GLZLM</sub>, and GLNU_<sub>GLZLM</sub>. The ROC analysis for molecular alteration prediction using this model found an AUC equal to 0.866 (<i>p</i> < 0.0001). A cut-off value set to 0.48 led to a sensitivity of 90.6% and a positive likelihood ratio (LR+) value equal to 2.4. After application of this cut-off value in the unseen test dataset of patients (<i>n</i> = 22), the test presented a sensitivity equal to 90.0% and an LR+ value of 1.35. A clinico-metabolic <sup>18</sup> F-FDG PET phenotype allows the detection of key molecular target alterations with high sensitivity and negative predictive value. Hence, it opens the way to the selection of patients for molecular analysis.
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