HER2 status change in residual breast carcinoma after neoadjuvant HER2-targeted therapy in patients with HER2-positive breast cancer

Assessment of HER2 status change in HER2-positive breast carcinoma (BC) prior to and after HER2-targeted neoadjuvant therapy (NAT) may potentially impact adjuvant HER2-targeted therapy. Reported rates of HER2 status change vary widely (< 10–56%), underscoring the need for further study. This study evaluated the frequency of HER2 status change and its clinicopathologic correlations in HER2-positive BC cases. Residual breast carcinomas were retrospectively assessed at a single institution after HER2-targeted NAT. HER2 status on residual tumor was evaluated by immunohistochemistry (IHC) and, for IHC 2 + cases, confirmed by fluorescence in situ hybridization (FISH). Tumors were categorized as HER2-retained (IHC 3 + or 2+/FISH amplified) or HER2-change (IHC 0/1 + or 2+/FISH non-amplified). Clinicopathologic features were correlated with post-treatment HER2 status. Among 161 HER2-positive BC patients treated with HER2-targeted NAT between 2016 and 2025, 65 had adequate residual invasive tumor for HER2 assessment. Invasive ductal carcinoma was the predominant histologic type. Retained HER2 overexpression was observed in 28/65 (43%) cases, while 37/65 (57%) showed HER2 status change. Pre-NAT hormone receptor positivity was present in 23 (82.1%) HER2-retained and 33 (89.2%) HER2- status changed cases. Clinicopathologic parameters were comparable between the groups. HER2 status change from HER2 overexpression to loss of overexpression occurred in more than half of residual breast carcinomas following HER2-targeted NAT. The current national and international guidelines recommend adjuvant HER2-targeted therapy regardless of post-treatment HER2. Prospective randomized phase II/III trials are needed to determine the benefit of adjuvant HER2-targeted therapy in this subgroup of patients with HER2-positive BC.