Enabling DCIS subtyping: leveraging foundation models for robust grading and molecular biomarker scoring.

Ductal Carcinoma In Situ (DCIS) is a non-obligate precursor of invasive breast cancer. Due to a lack of reliable prognostic markers, nearly all women with DCIS undergo intensive treatment-often unnecessarily. The LORD trial addresses this by offering active surveillance to women with screen-detected, ER-positive, HER2-negative, grade 1 or 2 DCIS, aiming to reduce overtreatment. To support this, we developed a deep learning pipeline based on foundation models to predict grade, ER, and HER2 status directly from H&E-stained digitized pathology slides. Models were trained and tested on a Dutch multicenter dataset (n = 887) and externally validated on a UK dataset (n = 259). On the Dutch data, the models achieved mean AUROCs of 0.90 (ER), 0.84 (HER2), and 0.86 (grade); external validation yielded 0.80, 0.74, and 0.75, respectively. Using these outputs, we stratified patients according to active surveillance criteria, reaching balanced accuracies of 0.81 (Dutch) and 0.64 (UK), with corresponding NPVs of 0.86 and 0.76. Our models generalize across cohorts and reliably predict key biomarkers, supporting the identification of DCIS patients eligible for less aggressive management.