Robust Multicenter CT Radiogenomics for Dual EGFR and KRAS Prediction in Lung Cancer with Stability-Aware Modeling and SHAP Interpretation

Abstract: Accurate identification of EGFR and KRAS mutations is essential for precision therapy in non-small cell lung cancer (NSCLC), but tissue genotyping is invasive and may not capture tumor heterogeneity. CT-based radiogenomics offers a noninvasive alternative, although generalization across centers remains challenging. We benchmarked handcrafted radiomics features (HRF), deep feature representations (DFR), and their fusion for three-class mutation prediction (wild-type, KRAS-mutant, and EGFR-mutant) with external testing. We curated 1,023 thoracic CT scans from 12 public datasets across more than 20 centers, including 136 patients with EGFR/KRAS labels. IBSI-compliant HRFs were extracted with standardized preprocessing, and DFRs were derived using PySERA. HRF-only, DFR-only, and fused HRF+DFR pipelines were evaluated using five-fold cross-validation and external testing. A semi-supervised pseudo-labeling strategy leveraged unlabeled CT scans, and SHAP supported interpretability. In external testing, HRF-based models generalized best, achieving AUC 0.77 +/- 0.07 and accuracy 0.77 +/- 0.00. DFR-based models showed a larger drop from cross-validation to external testing, with best external AUC around 0.57 +/- 0.05. Fusion improved robustness over DFR-only models but did not consistently outperform HRFs. SHAP identified morphology- and heterogeneity-related radiomic phenotypes as key predictors. Standardized handcrafted radiomics within a multicenter semi-supervised framework may provide a generalizable and interpretable approach for CT-based EGFR/KRAS stratification.