Approximately a half of breast tumors traditionally classified as HER2-neg exhibit HER2-low expression (IHC 1+ or 2+ and ISH neg.). We recently described a high instability of HER2-low expression from primary breast cancer (BC) to relapse (Miglietta F et al., ESMO Breast Cancer 2021). Aim of this study is to track the evolution of HER2-low expression from primary BC to residual disease (RD) after neoadjuvant treatment. Patients undergoing neoadjuvant treatment with available baseline tumor tissue and matched samples of RD (in case of no pCR) were included. HER2 expression was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. Cases diagnosed between 2007 and 2013 were reviewed to comply with the 10% cutoff of IHC for HER2-positivity. HER2-neg cases were further classified as HER2-0 or HER2-low (IHC 1+ or 2+ and ISH neg.). 447 patients were included. Primary BC phenotype was: HR-pos/HER2-neg 23%, triple-negative (TN) 35%, HER2-pos 42%. HER2-low cases were 56% of the HER2-neg cohort and were significantly enriched in the HR-pos/HER2-neg vs TN subgroup (69% vs 47%, p=0.001). In patients failing to achieve pCR after neoadjuvant treatment (n=292), the overall rate of HER2 expression discordance was 27%, mostly driven by cases converting either from HER2-0 primary BC to HER2-low RD (9%) or from HER2-low primary BC to HER2-0 RD (15%; Table). Overall, 36% of non-pCR patients had a HER2-low expression on RD, including 12% of patients with TN and 24% of patients with HR-pos/HER2-neg disease. Among HR-pos/HER2-neg patients with HER2-low expression on RD, 23% had an estimated high risk of relapse according to the residual proliferative cancer burden (RPCB class 3).Table: 212PPrimary tumorResidual diseaseHER2-0HER2-lowHER2-posTotaln%n%n%n%HER2-05117269007726HER2-low431570241<111439HER2-pos0083933210135Total9432104369432292100 Open table in a new tab HER2-low expression showed high instability from primary BC to RD after neoadjuvant treatment. HER2-low expression on RD may guide personalized adjuvant treatment for high-risk patients in the context of clinical trials with novel anti-HER2 antibody-drug conjugates.