Abstract Background: Trastuzumab deruxtecan has substantially changed the treatment of HER2-low breast cancer, emphasizing the need for accurate differentiation between HER2 immunohistochemistry (IHC) scores of 0 and 1+. However, the current accuracy of HER2 IHC 0 and 1+ scoring in real-world is inadequate. Artificial intelligence (AI) has emerged as a potential solution to improve interpretation accuracy. We developed an AI algorithm based on whole slide images (WSI) to quantitatively assess HER2 expression and its role in interpreting HER2 IHC scores of 0 and 1+. Methods: Our three-phase AI analysis framework involved segmenting tumor areas (excluding ductal carcinoma in situ), detecting and classifying tumor cells based on membrane staining patterns, and grading HER2 IHC scores according to the 2018 ASCO/CAP HER2 guideline. The AI tool was trained using 6012 patches annotated by experienced pathologists. Performance evaluation was conducted using a test dataset comprising 265 slides. A total of 141 HER2 IHC slides (27 IHC 0 and 114 IHC 1+) from patients diagnosed with invasive breast cancer at Fudan University Shanghai Cancer Center in 2021 were included. Two pretrained expert pathologists independently rescored the HER2 slides, followed by analysis using the AI tool. All inconsistent cases were also reviewed by a third senior pathologist. Interobserver agreement between the pathologists and concordance between the pathologists and the AI interpretation results were assessed. We also explored potential ranges where HER2 interpretation by pathologists exhibited inconsistency or inaccuracy. Results: The HER2 AI algorithm showed high performance in interpreting all levels of HER2 expression, with an overall kappa value of 0.85. For HER2 IHC 0 and 1+ cases, the AI model demonstrated high sensitivities (0.839 and 0.914) and specificities (0.983 and 0.890) (Table 1). After the rescoring process, 51 cases were reclassified as IHC 0 and 90 cases as IHC 1+. The overall agreement rate between the historical and re-scoring results was 73.05% (103/141). The agreement rate between the AI and re-scoring results was 91.49% (129/141) (Table 2), indicating comparable interpretation capabilities between the AI model and well-trained pathologists. The interobserver agreement between the two pathologists was 83.69% (118/141), with agreement rates of 88.23% (45/51) for IHC 0 and 81.11% (73/90) for IHC 1+. Analyzing the inconsistent cases (n=12) between IHC 0 and IHC 1+, we examined the percentage of weak and incomplete expression provided by the AI. In 9 out of 12 cases, the AI provided the same results as the third senior pathologist, suggesting that AI could assist in interpretation within this range. We identified a range of 2.83% to 24.98% as a "grey-zone," where even well-trained pathologists provided inconsistent results. Conclusion: Our study demonstrates the excellent performance of an AI-based tool for scoring HER2 IHC 0 and 1+. The AI model exhibits comparable capabilities to well-trained pathologists in interpreting HER2 expression. Additionally, we identified a "grey-zone" among pathologists, highlighting the limitations of manual subjective interpretation. AI assistance within this zone may help mitigate subjective variations. Table 1. Correlation between pathologist read and AI read of HER2 immunohistochemistry. Table 2. Correlation between pathologist rescoring and AI read of HER2 immunohistochemistry. Citation Format: Ming Li, Hong Lv, Yizhi Zhao, Chenglu Zhu, Hansheng Li, Mingzhen Lin, Wen-Tao Yang. The Advantage of Artificial-Intelligence in HER2 IHC 0 and 1+ Scoring in Breast Cancer [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 PO4-26-09.