Analysis of HER2 expression changes from breast primary to brain metastases and the impact of HER2-low expression on overall survival

Abstract Background There are limited data regarding HER2-low expression dynamics between matched primary tumors and brain metastases (BrMs) in breast cancer. HER2-low expression has emerged as a new therapeutic biomarker for highly active antibody-drug conjugates with emerging intracranial activity. Methods Patients with metastatic breast cancer and BrMs seen at an NCI-designated center between 2003 and 2023 were identified. HER2 expression was defined as HER2-positive (3+, 2+/ISH amplified), HER2-low (1+, 2+/ISH negative), or HER2–0 by ASCO-CAP guidelines. Estrogen receptor (ER) status was defined as ER ≥1%. Multivariate survival analyses by Cox proportional hazard models were determined from the time of BrM resection to death or last follow-up between the 3 subtypes, controlling for ER and age. Results Among 197 matched primary and resected BrMs, 81% exhibited HER2 expression in the brain: 61% HER2-positive, 20% HER2-low, and 19% HER2–0. Concordance was high in HER2-positive primary tumors with 100% retaining HER2 expression (97% retained HER2-positive expression and 2.7% switched to HER2-low). HER2–0 primaries frequently showed HER2 gain in BrMs to HER2-low (35%) or HER2-positive (5.4%) status. Among 48 HER2-low primary tumors, 52% were discordant for HER2 status in the brain with 21% testing HER2-positive and 31% testing HER2–0. In adjusted analyses, patients with HER2-positive BrMs had significantly lower death risk than patients with HER2-low BrMs (HR = 0.41, P = .0006); no difference was observed between HER2–0 and HER2-low. Conclusions In this retrospective analysis, HER2 expression is common in breast cancer BrMs, emphasizing the need for improved, noninvasive diagnostics. Patients with HER2-low and HER2–0 BrMs face inferior survival, presenting an unmet clinical need.