Genomic assays such as Oncotype DX have transformed adjuvant treatment selection for hormone receptor-positive, HER2-negative, early breast cancer but remain inaccessible to many patients because of high cost and logistical barriers. We aimed to develop and validate an artificial intelligence (AI) model that estimates Oncotype DX 21-gene recurrence scores directly from routine histopathology slides and clinicopathological variables.

In this multicentre, model development and validation study, a multimodal deep-learning model was trained on digital whole-slide images and clinical features using a foundation model pre-trained on 171 189 histopathology slides for predicting Oncotype DX recurrence score. We included slides from patients with hormone receptor-positive, HER2-negative, invasive breast cancers and without scanning artifacts and with at least 100 tissue tiles (1·6 mm ² ). The model was fine-tuned and validated on the TAILORx randomised trial (8284 patients after quality control). Prognostic and predictive performance was assessed in the TAILORx-test set and externally validated in six independent cohorts (Carmel, Haemek, and Sheba medical centres [Israel], the University of Chicago Medical Center [USA], the Australian Breast Cancer Tissue Bank [Australia], and the Cancer Genome Atlas Breast Invasive Carcinoma project [USA]).

In the TAILORx-test set (n=2407), the AI model classified 1097 (45·6%) patients as low risk, 1021 (42·4%) as intermediate risk, and 289 (12·0%) as high risk. For identifying high genomic-risk disease (recurrence score ≥26), the area under the curve (AUC) was 0·898 (95% CI 0·879–0·913). AI-based risk stratification was prognostic for recurrence-free interval (hazard ratio 2·61 [95% CI 1·68–4·04]), distant recurrence-free interval (2·88 [1·73–4·79]), and disease-free survival (1·32 [0·92–1·89]). Chemotherapy benefit was evident in premenopausal patients classified by AI as being at high risk (0·63 [0·46–0·86]) but absent in postmenopausal patients classified by AI as being at low risk (0·94 [0·78–1·12]). 151 (31·3%) clinically high-risk postmenopausal women (by MINDACT criteria) were reclassified as low AI risk with no chemotherapy benefit. Analysis on external cohorts (5497 patients) showed that the model is transferable to new data with high generalisability (recurrence score ≥26 AUC ranging from 0·858 to 0·903).

These findings show that AI applied to routine histopathology can serve as a practical and scalable tool for guiding chemotherapy decisions in hormone receptor-positive, HER2-negative, early breast cancer. This approach has the potential to reduce unnecessary chemotherapy and broaden access to precision oncology, particularly in resource-limited settings where genomic testing remains unavailable or unaffordable.

Israel Innovation Authority (Kamin), Zimin Institute for Artificial Intelligence Solutions in Healthcare, Israel Precision Medicine Partnership program, and Israel Cancer Research Fund.