Abstract Probability of malignancy (POM) for Breast Imaging Reporting and Data System (BI-RADS) category 4 designated breast lesions ranges from 2% – 95% and contributes to a high unnecessary biopsy rate. This is as most clinicians often stick to the biopsy option to rule in or out breast cancer early; withholding biopsy could be risky, and biopsies of BI-RADS 4 lesions serve as a quality metric and performance standard. At 21.1%, biopsy-proven positive predictive value (PPV3) rates for BI-RADS 4 have not improved for decades, translating to high false-positive rates of mammography. Unnecessary biopsies are a big issue in the management of BI-RADS 4 lesions with negative implications including increased medical costs, healthcare wastes, unnecessary psychological burdens to the patients, and potential complications and risks. Objectives 1. Optimize the precision breast cancer risk assessment tool, iBRISK, that utilizes artificial intelligence (AI) technologies, including natural language processing (NLP), image processing, and deep learning, with clinical risk factors and imaging features. 2. Develop a user-friendly web interface for iBRISK to facilitate clinicians or insurers in estimating cancer risk and making informed biopsy decisions for BI-RADS 4 lesions. Methods Our intelligent-augmented breast cancer risk calculator (iBRISK) model was trained on multimodal data collected from 10,778 patients, including demographic factors, historical and clinical characteristics, mammographic features, and pathologic signatures. We validated iBRISK using 4,200 patients from multiple leading hospitals, including Houston Methodist Neal Cancer Center, the University of Texas MD Anderson Cancer Center, and the University of Texas Health San Antonio MD Anderson Mays Cancer Center. The iBRISK was connected to a backend server which is linked to a frontend web user interface using technologies like Hypertext Preprocessor (PHP) for the backend application running on an APACHE HTTP server and React-JavaScript for the front-end web application that communicates with the backend using Representational State Transfer Application Programming Interface (RESTful API) and JavaScript Object Notation (JSON) format. The communication was secured using Secure Sockets Layer (SSL) encryption. Results The iBRISK model demonstrated high sensitivity in malignancy prediction and achieved an accuracy of 89.5%, area under the receiver operating characteristic curve of 0.93 (95% CI: 0.92-0.95), sensitivity of 100%, and specificity of 81%. Only 0.16% of lesions determined to have low POM by the model were malignant. Our multi-center study shows that iBRISK achieves at least 50% reduction in unnecessary biopsies of BI-RADS 4 cases. Data elements for the required 20 features are entered into the interface using a variety of imputation methods including direct text, dropdown menus and radio button selections. The user-friendly web interface provides risk scores (0 – 1), risk levels (low, medium, and high), and associated biopsy recommendations. Conclusion The user-friendly iBRISK web interface is proposed as an adjunct to the BI-RADS system, enhancing the precision of BI-RADS 4 lesion cancer risk stratification. It is expected to reduce unnecessary biopsies, lower health costs, and enhance the quality of health care. This approach aims to tackle a critical issue in breast cancer diagnosis by leveraging advanced AI technologies and big data and providing clinicians with a tool to make more informed and precise biopsy decisions for BI-RADS 4 lesions. Citation Format: Chika Ezeana, Xiaohui Yu, Zhihao Wan, Tiancheng He, Tejal Patel, Virginia Kaklamani, Maryam Elmi, Erika Brigmon, Pamela Otto, Kenneth Kist, Lin Wang, Joe Ensor, Heather Speck, Ya-Chen Shih, Bumyang Kim, I-Wen Pan, David Spak, Wei Yang, Jenny Chang, Stephen Wong. An on-line deep learning decision support tool, iBRISK, aimed at improving breast cancer risk estimation and reducing unnecessary biopsies for BI-RADS 4 patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-06.