Abstract PS11-06: Analysis of HER2 expression changes from breast primary to brain metastases including HER2 Low and impact on overall survival

Abstract Background: Previous studies have shown that breast cancer receptor subtype switching between matched primary and metastatic brain metastases (BrM) is common. HER2 expression at low levels, termed “HER2 Low”, has emerged as a new therapeutic biomarker for highly active antibody drug conjugates with potential intracranial activity. Trastuzumab deruxtecan is FDA approved for the treatment of HER2 Low and HER2 positive breast cancer with emerging evidence of CNS responses and clinical benefit in patients with BrM. This study aimed to investigate the relationship between HER2 expression including HER2-Low between matched breast cancer primary tumors and brain metastases. We also sought to evaluate the impact of low HER2 expression on overall survival in breast cancer brain metastases. Methods: We identified pts with MBC seen at least once at a single, NCI-designated center and had a diagnosis of BrM between 2003 and 2023. Of 1252 MBC pts with a diagnosis of BrM, 265 pts underwent resection/biopsy for BrM with available ER/PR/HER2 status. Only pts with available matched primary and BrM tissue were analyzed. HER2 expression was defined as: HER2+ (3+ or 2+/ISH amplified), HER2-Low (1+, 2+/ISH neg) or HER2-0 by ASCO-CAP guidelines. Estrogen receptor (ER) status was defined as ER≥1%. Multivariate overall survival (OS) analyses by Cox proportional hazard models were determined from time of BrM resection to death or last follow-up between HER2+, HER2-Low and HER2-0 patients controlling for ER and age. Results: 197 matched breast cancer primary and BrMs with available ER, PR, and HER2 testing were evaluated. Median age at BrM resection was 51 yrs. ER was positive in 48% (N=95) of BrMs. Of 265 resected BrMs, HER2 expression was found in 72%: 49.8% HER2+ (N=132), 22.2% HER2-Low (N=59), and 27.9% HER2-0 (N=74). HER2 expression by 197 primary tumors was: 57% HER2+ (N=112), 24% HER2-Low (N=48), 19% HER2 0 (N=37). Amongst 112 HER2+ primary tumors, 97% (N=109) had concordant HER2+ BrMs, 3 (2.6%) switched to HER2-Low, with 100% retaining some HER2 expression. Of 37 HER2-0 primaries, 35% (13/37) gained HER2-Low expression and 5.4% (2/37) gained HER2+ expression in the BrM. Amongst 48 HER2-Low primary tumors, half (52%) changed expression to either HER2+ (21%) or HER2-0 (31.2%) in the brain. 66 tumors had extracranial tissue biopsied prior to BrM resection available for HER2 analysis. Of 15 HER2-0 extracranial tumors, 47% gained HER2-Low and 13% gained HER2+ at time of BrMs. After adjusting for age and ER status at the time of BrMs, patients with HER2+ BrM had a statistically significant lower risk of death at time of follow up than those with HER2-Low BrM (HR=0.41, P=0.0006). The risk of death between patients with HER2-0 BrM did not differ from HER2-Low BrM after adjustment for ER and age (HR=0.96, p =0.9). Median survival from BrM resection was 12.4m, 16.1m, 47.6m for HER2-Low, HER2-0 and HER2+ respectively (p = .0004). Conclusions: HER2 expression amongst primary, extracranial and brain metastases is dynamic with frequent change. Over 40% of HER2-0 primary or extracranial tumors gain HER2 expression in the brain. These changes have therapeutic implications given HER2 targeting antibody drug conjugates with improved OS and emerging evidence of CNS activity, highlighting the need for better diagnostics, including those that do not require invasive tissue sampling, to determine HER2 status in the brain. Patients with HER2-Low and HER2-0 BrMs have inferior survival and are a clinical unmet need. Citation Format: Alyssa Pereslete, Melissa Hughes, Alyssa Patterson, Janet Files, Kyleen Nguyen, Lauren Buckley, Ashka Patel, Abigail Moore, Eric Winer, Tianyu Li, Sara Tolaney, Nancy Lin, Sarah Sammons. Analysis of HER2 expression changes from breast primary to brain metastases including HER2 Low and impact on overall survival abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS11-06.