Background: Brain metastases (BrM) are a major cause of morbidity and mortality among women with breast cancer (BC). Central nervous system (CNS)-penetrating systemic therapies for patients with HER2-negative BrM are lacking; this is particularly problematic for patients with triple negative disease (TNBC) who have a high likelihood of developing BrM. Given CNS activity of trastuzumab deruxtecan, efficacy for patients with HER2-low BrM is of interest. Methods: A retrospective study of two cohorts of patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre between 1999-2013 and 2008-2018 were identified. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2) status were assessed based on 2018 ASCO/CAP guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH) negative status. HER2-positive was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathological features were recorded. We also assessed the prognostic association between extent of HER2 expression and i) brain-specific progression free survival (bsPFS), as well as ii) overall survival (OS). Results: Out of 137 patients with resected BrM, tissue for HER2 assessment was available in 74.5% (n=102) of cases. In this cohort, the median age at BrM diagnosis was 53.5 (range, 32-85). 18.6% (n=19) had leptomeningeal disease and 68.6% (n=70) had extracranial disease. 53% (n=54) of the BrM were HER2-positive; 29.4% (n=30) were HER2-low and 17.6% (n=18) had HER2-zero status. Among BrM that were triple negative based on ASCO/CAP guidelines, 14 out of 22 cases (63.6%) were re-classified as being HER2-low. 15/25 (60%) BrM that were hormone receptor positive/HER2 negative (HR+/HER2-) based on ASCO/CAP guidelines were re-classified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low and HER2-positive were concordant in 82.3% (n= 42/51) of cases (Cohen’s kappa 0.58, p=0.0719). In 7 cases, the primary breast tissue was HER2-zero whereas the BrM was either HER2-low (n=5) or HER2-positive (n=2). In only one case (2%), expression of HER2 was lower in the BrM (HER2-low) compared to the primary BC (HER2-positive). Median time from primary BC to the development of BrM was 35 months (IQR, 14-69) in the overall cohort; patients with HER2-zero BrM had a numerically longer time to development of BrM (45.8 months), compared to those with HER2-low (35 months) and HER2-positive (35 months) BrM (p=0.948). There was no significant association between HER2-zero, HER2-low and HER2-positive status in BrM and either bsPFS or OS. Conclusions: Among patients with surgically resected BrM, a high proportion of those with metastatic TNBC and HR+/HER2-negative disease have “HER2-low” BrM with potential to benefit from HER2-targeted therapy.