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Context.--Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression. Thereby, eligibility relies on an accurate diagnosis of HER2-low status defined by immunohistochemistry IHC 1+/2+ with no gene amplification. Objective.--To assess pathologists' accuracy and training efficacy in the diagnosis of HER2-low. Design.--Agreement rates of HER2-low scoring in breast cancer tissue were assessed between expert consensus and real-world pathologists (n = 77 from 14 countries) before and after a specific 4-hour training for HER2-low detection. Two assays were evaluated, the Ventana Pathway 4B5 CDx and the Dako HercepTest (polyclonal). Concordance of the pathologists with consensus score and efficacy of training were measured by Cohen k, overall rater agreement, and receiver operating characteristic (ROC) curve statistics. Results.--In the Ventana 4B5 HER2-low category, baseline agreement rates were >80% but Conclusions.--The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified. doi: 10.5858/arpa.2024-0052OA, During the past 20 years, diagnosis of human epidermal growth factor receptor 2 (HER2) status has been essential in determining eligibility of breast cancer patients for HER2-targeted therapies. (1,2) Although [...]