Multimodal Gene Expression Deep Learning for Predicting Sentinel Lymph Node Macro-metastasis in Early Breast Cancer: Development and Validation in the SCAN-B Cohort

Abstract Background: This study evaluates DL using GEX and preoperatively available clinical data (PreopClinic) to predict SLNM, and explores their potential for guiding axillary surgery and prognostic assessment. Methods: We retrospectively included 6,836 clinically node-negative T1-T2 patients with invasive breast cancer who underwent primary surgery from the SCAN-B. Three DL models—a multilayer perceptron, a pathway-informed sparse neural network, and a transformer—were developed using the development set (n=4,625) and evaluated against XGBoost in the independent test set (n=2,211). Results: The Transformer outperformed other methods for GEX modeling and minimized prior gene selection. In the independent test set, the combined Pre-opClinic+GEX model significantly improved SLNM prediction compared to Pre-opClinic alone (ROC AUC 0.693 vs 0.596, P < 0.001) and identified low-risk patients who might avoid unnecessary SLNB (reduction rate 27.2% at 92.1% sen-sitivity). However, the combined model did not significantly outperform GEX alone. While GEX provided the dominant predictive signal, PreopClinic contributed complementary information with modest numerical gains in clinical utility. Across-subtype training outperformed within-subtype training, particularly in TNBC, where the combined model achieved AUC 0.734 (95% CI: 0.644-0.837). The derived SLNM predictor also provided prognostic information beyond the estab-lished prognostic factors. Although the models were developed primarily using surgical specimen–derived GEX, paired biopsy and surgical-specimen analyses (n=116) demonstrated substantial concordance of transcriptomic patterns and nodal predictions. Conclusion: These findings highlight the Transformer’s robustness against noise and effectiveness in capturing informative transcriptomic features for SLNM pre-diction. The agreement observed between paired biopsy and surgical specimens supports the feasibility of future biopsy-based preoperative applications.