Deep Learning-Based Screening for POLE mutations on Histopathology Slides in Endometrial Cancer

Abstract POLE sequencing for somatic mutations ( POLE mut) guides adjuvant therapy in endometrial cancer (EC), but cost and infrastructural considerations lead to limited uptake. Omission of POLE testing leads to unnecessary exposure to radiotherapy and/or chemotherapy. We developed POLARIX, a multiple instance deep learning model with attention pooling, which predicts POLE mutation status from routine hematoxylin and eosin whole-slide images (WSIs). Trained on 2,238 cases from eleven EC cohorts, POLARIX showed clinical-grade discrimination across three external cohorts (Pooled: AUC=0.95, 95% CI: 0.91–0.98; n =68/481 POLE mut/ POLE wt). Attention maps highlight POLE morphologies. Clinical applicability is demonstrated using predefined thresholds based on three resource scenarios. The most sensitive threshold (“Low”) yields a test reduction of 77% (73%-81%) (sensitivity: 93% (85%-99%), specificity: 89% (87%-92%)). POLARIX is an interpretable and cost-efficient approach to reduce POLE testing in women with endometrial cancer, broadening access to precision oncology.