Towards interpretable prediction of recurrence risk in breast cancer using pathology foundation models

Transcriptomic assays such as the PAM50-based ROR-P score guide recurrence risk stratification in non-metastatic, ER-positive, HER2-negative breast cancer but are not universally accessible. Histopathology is routinely available and may offer a scalable alternative. We introduce MAKO, a benchmarking framework evaluating 12 pathology foundation models and two non-pathology baselines for predicting ROR-P scores from H&E-stained whole-slide images using attention-based multiple instance learning. Foundation models, large neural networks pre-trained on millions of pathology images and adaptable to diverse downstream tasks, were trained and validated on the Carolina Breast Cancer Study and externally tested on TCGA BRCA. Several foundation models outperformed baseline models across classification, regression, and survival tasks. CONCH achieved the highest ROC AUC, while H-optimus-0 and Virchow2 showed the top correlation with continuous ROR-P scores. All pathology models stratified CBCS participants by recurrence similarly to transcriptomic ROR-P. Using the HIPPO interpretability method, we found that tumor regions were necessary and sufficient for high-risk predictions, and we identified candidate tissue biomarkers of recurrence. These results highlight the promise of interpretable, histology-based risk models in precision oncology.