The objective of this systematic review was to analyze the current state of the art of imaging-derived biomarkers predictive of genetic alterations and immunotherapy targets in lung cancer. We included original research studies reporting the development and validation of imaging feature-based models. The overall quality, the standard of reporting and the advancements towards clinical practice were assessed. Eighteen out of the 24 selected articles were classified as “high-quality” studies according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The 18 “high-quality papers” adhered to Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) with a mean of 62.9%. The majority of “high-quality” studies (16/18) were classified as phase II. The most commonly used imaging predictors were radiomic features, followed by visual qualitative computed tomography (CT) features, convolutional neural network-based approaches and positron emission tomography (PET) parameters, all used alone or combined with clinicopathologic features. The majority (14/18) were focused on the prediction of epidermal growth factor receptor (EGFR) mutation. Thirty-five imaging-based models were built to predict the EGFR status. The model’s performances ranged from weak (n
= 5) to acceptable (n
= 11), to excellent (n
= 18) and outstanding (n
= 1) in the validation set. Positive outcomes were also reported for the prediction of ALK rearrangement, ALK/ROS1/RET fusions and programmed cell death ligand 1 (PD-L1) expression. Despite the promising results in terms of predictive performance, image-based models, suffering from methodological bias, require further validation before replacing traditional molecular pathology testing.
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