PET/CT Radiogenomic Mutation Prediction in Non-Small Cell Lung Cancer Using Multi-Label Learning

Lung cancer results in roughly 1.8 million fatalities annually worldwide, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Despite advancements in treatment, survival stratification remains challenging due to intratumoral heterogeneity inadequately captured by conventional descriptors. Standard radiomic and deep learning techniques regard imaging features as independent quantities, overlooking structured interactions between tumor characteristics. We evaluate whether structured proxy features can enhance multimodal NSCLC survival prediction by augmenting pretreatment computed tomography (CT) representations, radiomics, and clinical variables with six simulation-derived features designed to capture interactions between heterogeneity and morphology. A radiomic-parameterized cellular automaton generates growth-rate and necrosis-ratio proxy features from baseline CT by using entropy and sphericity to compute low-dimensional proxy parameters. The imaging backbone is a Transformer-based Masked Autoencoder (TMAE), which was chosen after a systematic evaluation with alternative encoders within the same pipeline and provides attention-based visualizations that highlight tumor regions receiving higher model attention. On the public Lung1 cohort (n = 390), the primary four-modality fusion attained a C-index of 0.641 (iAUC 0.731, log-rank p < 0.001). The primary result compares favorably with prior multimodal results on Lung1 (C-index 0.631; iAUC 0.592 [15]) under a comparable evaluation protocol, while a separate exploratory coefficient-optimization analysis achieved a best observed C-index of 0.662 (iAUC 0.748). These results indicate that, in addition to conventional radiomic, deep, and clinical representations within the Lung1 benchmark, simulation-derived proxy features may provide complementary predictive information within this fixed Lung1 benchmark.

Accurate prediction of overall survival (OS) from positron emission tomography/computed tomography (PET/CT) can support personalized treatment and follow-up strategies in oncology. However, the impact of temporal modeling on imaging-based survival prediction remains insufficiently explored. We investigate how different temporal formulations influence survival prediction by developing two complementary approaches: Attention-guided Time-Conditioned Survival (ATCS) and Multi-Time Survival (MTS). We retrospectively analyzed pre-treatment PET/CT images from 848 patients with non-small cell lung cancer (NSCLC), including 556 for model development and 292 for held-out testing. A previously proposed Time-Conditioned Survival (TCS) model was used as a baseline. Models were trained using 5-fold cross-validation and evaluated on the test set using time-dependent area under the curve (AUC) at 6-month intervals from 0.5 to 5 years. Both ATCS and MTS outperformed the baseline TCS model, achieving mean AUCs of 0.794 and 0.793, respectively, compared to 0.767. ATCS performed better at earlier time points (0.5-3 years), whereas MTS performed better at later intervals (3.5-5 years). Combining tumor-specific and tissue-wise PET/CT features improved performance over either input alone. Finer temporal discretization improved short-term prediction, while coarser intervals provided more stable long-term estimates. These findings demonstrate that temporal modeling and input design influence PET/CT-based survival prediction. The proposed approaches enable time-specific survival estimation from pre-treatment imaging and may support improved risk stratification and clinical decision-making.

Resistance to first-line osimertinib in EGFR-mutant non-small-cell lung cancer (NSCLC) is the canonical example of predictable clonal evolution under therapeutic pressure, yet no public benchmark exists for training or evaluating computational models on the corresponding longitudinal patient trajectories. We introduce OncoTraj, a public benchmark of 813 EGFR-mutant NSCLC patients receiving first-line osimertinib, harmonized from three real-world clinical-genomic sources: MSK-CHORD (672 patients), AACR Project GENIE BPC NSCLC (34 patients), and the FLAURA molecular-resistance supplement (107 patients). OncoTraj defines three locked tasks: (A) binary classification of progression by a fixed 12-month landmark, (B) regression of time-to-first-progression in days, and (C) six-class classification of the dominant resistance mechanism. We release the harmonized dataset, patient-level train/validation/test splits with an audited no-leakage guarantee, an open-source evaluation harness, and six reference baselines spanning a majority-class predictor, logistic regression, random forest, XGBoost, an LSTM, and a multi-task transformer. With v1's single-timepoint snapshot features, no task clears chance on clean within-source evaluation: the uniformity of this ceiling across every model class localizes the limit to the input modality (single-snapshot tissue NGS rather than serial ctDNA), not the algorithm. The benchmark does recover a reproducible literature-consistent association: TP53 co-mutation raises the 12-month progression rate from 29% to 59% cohort-wide. OncoTraj establishes a reproducible, leakage-audited baseline and converts the modality limit into concrete design requirements for a serial-ctDNA-enriched v2.