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

ABSTRACT

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 31 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.