Identifying and Characterising Response in Clinical Trials: Development and Validation of a Machine Learning Approach in Colorectal Cancer

Cancer treatment planning requires decisions across multiple clinical dimensions at once. Clinicians must determine whether a patient should receive targeted molecular therapy, radiation therapy, and whether they are likely to survive beyond six months. Existing pathway-informed deep learning models have been developed and tested in isolation, making fair comparison across architectures impossible. We present the first unified benchmark for pathway-guided therapy response modeling, evaluating three biologically informed architectures, BINN, GraphPath, and PATH, across five cancer cohorts drawn from The Cancer Genome Atlas, representing 2,622 patients encoded using Reactome pathway activity scores. Each model is trained jointly on all three clinical outcomes under identical data and evaluation conditions, the first study to treat pathway-structured deep learning as a combined therapy and survival prediction problem. Our results show that no single architecture wins across all tasks: PATH performs best for targeted molecular therapy prediction overall, BINN is most reliable for survival prediction, and no model produces useful predictions for radiation therapy, as the key drivers of that decision are clinical variables not captured in gene expression data. Most strikingly, GraphPath achieves an AUROC of 0.92 on prostate targeted molecular therapy prediction, the highest score in the entire benchmark, demonstrating that lateral co-regulation structure produces exceptional discriminative power when matched to a cohort with a narrow targetable driver programme, even under conditions of extreme class imbalance at only 11% positive prevalence.

Precision oncology is currently limited by the small-N, large-P paradox, where high-dimensional genomic data is abundant but pharmacological response samples are sparse. While deep learning achieves predictive accuracy, it frequently fails to provide the mechanistic clarity required for clinical adoption. We present the Contextual Invertible World Model (CIWM), a Neuro-Symbolic Agentic Framework that bridges this gap by integrating a quantitative machine learning emulator with a Large Language Model reasoning layer. Utilising a stringently curated, high-fidelity data engineering pipeline on the Sanger GDSC dataset ($N=83$), we isolate true biological signals from in vitro artifacts to establish a rigorous baseline predictive correlation for complex transcriptomics ($r=0.268$). Through Inverse Reasoning, we perform in silico CRISPR perturbations across the colorectal landscape. The framework autonomously overturns classical mechanistic assumptions, identifying a hierarchical dominance of mutant KRAS over the APC/Wnt-axis in driving 5-fluorouracil resistance ($Δ=-0.0469$) via a "KRAS Shield" mapped to MAPK/PI3K networks. Furthermore, the agentic layer identified a "PIK3CA Paradox", revealing that repairing PIK3CA inadvertently increases chemoresistance ($Δ=+0.0085$) by triggering a compensatory feedback loop that hyperactivates the dominant MAPK survival pathway.

Prediction of pathological complete response before neoadjuvant chemotherapy may facilitate more tailored therapeutic planning for breast cancer patients. This work proposes a deep-learning model for pretreatment data only, combining apparent diffusion coefficient maps, dynamic contrast-enhanced magnetic resonance imaging, and clinical variables. The study uses the public ACRIN 6698/I-SPY2 multicenter dataset. The architecture employs EfficientNet-B0 pretrained encoders for image feature extraction and late fusion with clinical information. Multiple clinical variables were evaluated, including age, race, histological type, HR/HER2 subtype, SBR grade, and maximum diameter. Only HR/HER2 subtype improved the average area under the receiver operating characteristic curve (AUC) and was retained in the final model. Using stratified five-fold cross-validation, standalone apparent diffusion coefficient maps achieved a mean AUC of 0.79, whereas dynamic contrast-enhanced magnetic resonance imaging achieved 0.74. Adding HR/HER2 subtype improved performance to 0.83 and 0.81, respectively. The final configuration, using both imaging modalities and HR/HER2 subtype, achieved an AUC of 0.86. These results support pretreatment multimodal learning for response prediction, although external validation is required before clinical use.