Clinical utility of receptor status prediction in breast cancer and misdiagnosis identification using deep learning on hematoxylin and eosin-stained slides

Molecular profiling of estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (also known as Her2) is essential for breast cancer diagnosis and treatment planning. Nevertheless, current methods rely on the qualitative interpretation of immunohistochemistry and fluorescence in situ hybridization (FISH), which can be costly, time-consuming, and inconsistent. Here we explore the clinical utility of predicting receptor status from digitized hematoxylin and eosin-stained (H&E) slides using machine learning trained and evaluated on a multi-institutional dataset. We developed a deep learning system to predict ER, PR, and ERBB2 statuses from digitized H&E slides and evaluated its utility in three clinical applications: identifying hormone receptor-positive patients, serving as a second-read tool for quality assurance, and addressing intratumor heterogeneity. For development and validation, we collected 19,845 slides from 7,950 patients across six independent cohorts representative of diverse clinical settings. Here we show that the system identifies 30.5% of patients as hormone receptor-positive, achieving a specificity of 0.9982 and a positive predictive value of 0.9992, demonstrating its ability to determine eligibility for hormone therapy without immunohistochemistry. By restaining and reassessing samples flagged as potential false negatives, we discover 31 cases of misdiagnosed ER, PR, and ERBB2 statuses. These findings demonstrate the utility of the system in diverse clinical settings and its potential to improve breast cancer diagnosis. Given the substantial focus of current guidelines on reducing false negative diagnoses, this study supports the integration of H&E-based machine learning tools into workflows for quality assurance. Breast cancer diagnosis involves identifying three important proteins: estrogen receptor (ER), progesterone receptor (PR), and ERBB2. Profiling these proteins helps oncologists determine which treatments are most likely to benefit patients. However, current testing methods can be expensive, time-consuming, and sometimes inaccurate. This study introduces and validates an artificial intelligence system that predicts the presence of these proteins using routine tissue slides. The system is tested on data from multiple medical centers and accurately identifies patients with ER and PR proteins who could benefit from hormone therapy. It also detects cases where the original diagnosis was incorrect. This tool may improve diagnostic accuracy, reduce errors, and enhance the efficiency of breast cancer care by integrating artificial intelligence into clinical workflows. Shamai et al. develop and validate a deep learning system for predicting receptor status from H&E images in breast cancer. The system accurately identifies hormone receptor-positive patients and detects false negative diagnoses, supporting its integration into clinical workflows to improve diagnostic accuracy, patient care, and quality assurance.