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

Alyssa M 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 L Sammons

doi:10.1093/neuonc/noae163

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

Neuro Oncol. 2024 Aug 30:noae163. doi: 10.1093/neuonc/noae163. Online ahead of print.

Authors

Alyssa M Pereslete^{1

2

3}, Melissa E Hughes^{1

2}, Alyssa R Martin^{1

2}, Janet Files^{1

2}, Kyleen Nguyen^{1

2}, Lauren Buckley^{1

2}, Ashka Patel^{1

2}, Abigail Moore^{1

2}, Eric P Winer^{1

2

4}, Deborah Dillon^{5

4}, Tianyu Li⁶, Sara M Tolaney^{1

2

4}, Nancy U Lin^{1

2

4}, Sarah L Sammons^{1

2

4}

Affiliations

¹ Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
² Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA.
³ Herbert Wertheim College of Medicine, Florida International University, Miami, FL.
⁴ Harvard Medical School, Boston, MA.
⁵ Department of Pathology, Brigham and Women's Hospital, Boston, MA.
⁶ Data Science, Dana-Farber Cancer Institute, Boston, MA.

PMID: 39211994
DOI: 10.1093/neuonc/noae163

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 (MBC) and BrMs seen at an NCI-designated center between 2003-2023 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 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+ 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=0.0006); 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, non-invasive diagnostics. Patients with HER2-low and HER2-0 BrMs face inferior survival, presenting an unmet clinical need.

Keywords: HER2 low; brain metastases; breast cancer; overall survival.