Abstract
The OncotypeDX 21-gene assay guides adjuvant chemotherapy decisions in early-stage, hormone receptor–positive, HER2-negative breast cancer, but cost and turnaround time limit access. This study presents a deep learning-based approach for predicting OncotypeDX recurrence scores directly from hematoxylin and eosin-stained whole slide images. Our approach leverages a deep learning foundation model pre-trained on 171,189 slides via self-supervised learning, which is fine-tuned for our task. The model was developed and validated using five independent cohorts, out of which three are external. On the two external cohorts that include OncotypeDX scores, the model achieved an AUC of 0.836 and 0.817, and identified 22% and 16.3% of the patients as low-risk with sensitivity of 0.97 and 0.97 and negative predictive value of 0.97 and 0.96, showing strong generalizability despite variations in staining protocols and imaging devices. Kaplan-Meier analysis demonstrated that patients classified as low-risk by the model had a significantly better prognosis than those classified as high-risk, with a hazard ratio of 4.1 (P < 0.001) and 2.0 (P < 0.01) on the two external cohorts that include patient outcomes. This artificial intelligence-driven solution offers a rapid, cost-effective, and scalable alternative to genomic testing, with the potential to enhance personalized treatment planning, especially in resource-constrained settings.
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Acknowledgements
This research was supported by the Israel Innovation Authority—Kamin 69997 (R.K. and G.S.), the Zimin Institute for Artificial Intelligence Solutions in Healthcare grant (R.K. and G.S.), and the Israel Precision Medicine Partnership program (IPMP) grant 3864/21 (R.K. and G.S.). We would like to thank Karin Stoliar for helping with the data acquisition and quality assurance, Hen Davidov for supporting the deep learning experiments, and Liat Dizengoff for managing the Helsinki approvals in Carmel Medical Center.
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Howard reported receiving personal fees from Novartis AG and Leica Biosystems outside the submitted work. Alexander T. Pearson reports personal fees from the Prelude Therapeutics Advisory Board, Elevar Advisory Board, AbbVie consulting, Ayala Advisory Board, ThermoFisher Advisory Board, Break Through Cancer Scientific Advisory Board, Merck research funds, Kura Oncology research funds, and EMD Serono research funds. The other authors do not have a competing interest.
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Cohen, S., Shamai, G., Sabo, E. et al. Prediction of OncotypeDX recurrence score using hematoxylin and eosin-stained whole slide images. npj Breast Cancer (2026). https://doi.org/10.1038/s41523-026-00937-w
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DOI: https://doi.org/10.1038/s41523-026-00937-w
