Analysis of HER2 expression changes from breast primary to brain metastases and the impact of HER2-low expression on overall survival
Alyssa Pereslete, Melissa E. Hughes, Alyssa R. Martin, Janet Files, Kyleen Nguyen, Lauren Buckley, Ashka Patel, Abigail Moore, Eric P. Winer, Deborah Dillon, Tianyu Li, Sara M. Tolaney, Nancy U. Lin, Sarah Sammons
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.