HER2-low breast cancer in routine practice: a nationwide study of diagnostic variability across pathology laboratories.

Patients with HER2-low breast cancer (BC) may be eligible for trastuzumab-deruxtecan (T-DXd) treatment. However, studies have shown that different HER2 antibodies vary in their sensitivity for low HER2 expression, potentially impacting HER2-low BC diagnosis and patient selection for T-DXd. We investigated the frequency of HER2-low BC in relation to the HER2-antibody used across Dutch pathology laboratories. Patients with primary BC without neoadjuvant treatment, diagnosed between 2013 and 2024, were included. HER2-low frequencies from 34 laboratories were obtained from the Dutch Nationwide Pathology Databank (Palga). Additional information (e.g., type of HER2 antibody, staining protocol) was obtained through a questionnaire. A total of 88,713 patients were included, representing 103,505 tumors, of which 94,934 had a conclusive HER2 status. Among non-amplified cases, HER2-low frequencies varied widely across laboratories (33.4%-94.5%), with a gradual increase since 2022. The most commonly used antibody clones were 4B5 (n = 21), DG44 (n = 7), A0485 (n = 4), and SP3 (n = 2). HER2-low proportions were highest with A0485 (71.5%), followed by DG44 (66.7%), SP3 (60.1%), and 4B5 (59.1% with Ultraview, 57.0% with Optiview). Substantial inter-laboratory variation was observed even within the same antibody group (4B5/Ultraview: 40.5%-80.4%; 4B5/Optiview: 37.3%-68.4%; DG44: 40.6%-95.4%; A0485: 62.3%-94.7%; SP3: 31.6%-78.6%). Our data showed a notable variation in HER2-low BC frequency across Dutch pathology laboratories, even among those using the same antibody and detection system. These differences may influence patient eligibility for T-DXd.