Systematic Evaluation of Transfer Learning Strategies for Clinical Chemotherapy Response Prediction

Abstract Accurately predicting chemotherapy response remains a major challenge in precision oncology. Although machine-learning models based on tumour omics data have shown promise, the majority of existing studies are trained and evaluated on pre-clinical cell-line datasets, leaving their clinical applicability insufficiently characterised. In this study, we systematically evaluate a range of transfer-learning strategies for chemotherapy response prediction under realistic clinical constraints using patient data from The Cancer Genome Atlas (TCGA). Rather than proposing a new predictive model, we focus on assessing the effectiveness and limitations of commonly used approaches for transferring pre-clinical knowledge to clinical settings. These include cell-line-validated biomarkers, biologically informed feature representations, direct application of pre-clinical deep-learning models, model fine-tuning, and hybrid strategies that integrate pre-clinical predictions with clinical data. All methods are evaluated within a unified framework using consistent cohort construction, shared performance metrics, and bias-controlled validation procedures. Across multiple drugs and molecular data types, we find that most transfer strategies—including biomarker-based feature selection and direct pre-clinical model transfer—fail to produce robust or consistent improvements in clinical prediction performance. In contrast, conservative approaches based on fine-tuning pre-clinical models or incorporating pre-clinical predictions as features in clinical models yield more stable and reproducible gains. Further improvements are observed when basic pre-treatment clinical variables are integrated. Together, our results demonstrate the practical boundaries of pre-clinical to clinical transfer for drug response prediction and highlight hybrid and fine-tuning strategies as more reliable baselines for future translational modelling efforts. Competing Interest Statement The authors have declared no competing interest.