A machine learning framework for supervised treatment response prediction from tumor transcriptomics: A large-scale pan-cancer study

Abstract

Precision oncology aims to guide treatment decisions using biomarkers. While DNA-based panels are increasingly applied, RNA transcriptomics remain underused due to limited datasets and the absence of robust models. We assembled the largest transcriptomic resource for drug response prediction to date, spanning 91 cohorts, 5,675 patients, nine cancer types, and six frontline therapies: anti-PD-1/PD-L1 immune-checkpoint inhibitors, trastuzumab, bevacizumab, BRAF inhibitors, paclitaxel, and FAC/FEC (Fluorouracil-Adriamycin-Cyclophosphamide/Fluorouracil-Epirubicin-Cyclophosphamide) chemotherapy. We developed EXPRESSO (EXpression-Profile-RESponSe-Optimizer), a supervised machine-learning framework that predicts treatment response from pre-treatment transcriptomes by integrating drug targets and context-specific biomarkers. EXPRESSO achieves mean ROC-AUCs of 0.62-0.73 and median odds ratios of 2.4-4.6 across therapies, outperforming 20 published transcriptomic signatures and other machine learning methods. Prospective validation on 22 independent cohorts confirms that performance generalizes beyond cross-validation. The EXPRESSO signature additionally stratifies progression-free survival in immune checkpoint blockade-treated cohorts, demonstrating prognostic value beyond binary response prediction. Robustness analysis reveals that predictive performance plateaued for some therapies with increasing training cohorts but continued to improve for others. These findings suggest inherent limits of supervised brute-force learning for certain treatments, but additional data and deeper mechanistic modeling may further enhance transcriptomics-based predictors. SIGNIFICANCEEXPRESSO forms the next step in studying the feasibility of harnessing bulk transcriptomic data to inform therapeutic decision-making, advancing the role of transcriptomics from exploratory biomarker discovery to actionable predictive modeling.