Development and validation of an AI-enabled digital breast cancer assay to predict early-stage breast cancer recurrence within 6 years

Background: Breast cancer (BC) grading plays a critical role in patient management despite the considerable inter- and intra-observer variability, highlighting the need for decision support tools to improve reproducibility and prognostic accuracy for use in clinical practice. The objective was to evaluate the ability of a digital artificial intelligence (AI) assay (PDxBr) to enrich BC grading and improve risk categorization for predicting recurrence. Methods: In our population-based longitudinal clinical development and validation study, we enrolled 2075 patients from Mount Sinai Hospital with infiltrating ductal carcinoma of the breast. With 3:1 balanced training and validation cohorts, patients were retrospectively followed for a median of 6 years. The main outcome was to validate an automated BC phenotyping system combined with clinical features to produce a binomial risk score predicting BC recurrence at diagnosis. Results: The PDxBr training model (n = 1559 patients) had a C-index of 0.78 (95% CI, 0.76–0.81) versus clinical 0.71 (95% CI, 0.67–0.74) and image feature models 0.72 (95% CI, 0.70–0.74). A risk score of 58 (scale 0–100) stratified patients as low or high risk, hazard ratio (HR) 5.5 (95% CI 4.19–7.2, p < 0.001), with a sensitivity 0.71, specificity 0.77, NPV 0.95, and PPV 0.32 for predicting BC recurrence within 6 years. In the validation cohort (n = 516), the C-index was 0.75 (95% CI, 0.72–0.79) versus clinical 0.71 (95% CI 0.66–0.75) versus image feature models 0.67 (95% CI, 0.63–071). The validation cohort had an HR of 4.4 (95% CI 2.7–7.1, p < 0.001), sensitivity of 0.60, specificity 0.77, NPV 0.94, and PPV 0.24 for predicting BC recurrence within 6 years. PDxBr also improved Oncotype Recurrence Score (RS) performance: RS 31 cutoff, C-index of 0.36 (95% CI 0.26–0.45), sensitivity 37%, specificity 48%, HR 0.48, p = 0.04 versus Oncotype RS plus AI-grade C-index 0.72 (95% CI 0.67–0.79), sensitivity 78%, specificity 49%, HR 4.6, p < 0.001 versus Oncotype RS plus PDxBr, C-index 0.76 (95% CI 0.70–0.82), sensitivity 67%, specificity 80%, HR 6.1, p < 0.001. Conclusions: PDxBr is a digital BC test combining automated AI-BC prognostic grade with clinical–pathologic features to predict the risk of early-stage BC recurrence. With future validation studies, we anticipate the PDxBr model will enrich current gene expression assays and enhance treatment decision-making.