HER2-low metastatic breast cancers: clinic-pathological characteristics, metastatic sites, and survival impact on biomarker discordance

Trastuzumab Deruxtecan has shown promising results in patients with HER2-low and -ultralow (UL) metastatic breast cancers, attracting extensive research on these tumors. While most studies focus on primary tumors, there is limited data on metastatic disease. Here, we aimed to evaluate the clinicopathological features, metastatic patterns and biomarker discordance in HER2-low/UL metastatic breast cancers. The HER2 status in a large cohort of metastatic breast cancer cases was correlated with different pathological and survival parameters. Data from matched primary tumours were also retrieved for further comparisons. HER2-low metastatic breast cancer is significantly associated with ER positivity (p = 0.033), PR positivity (p = 0.037) and Luminal status (p = 0.047), but no distinct overall survival. These tumors were preferentially found in liver metastases (42.9%), differing significantly from HER2-zero cancers (p < 0.001). Downregulation of HER2-positive primaries to HER2-negative metastasis was found to be the highest in liver (50.0%), and the least in lung (0%). Downregulation of HER2 is associated with poorer OS (Chi-sq = 9.248, p = 0.002). In metastatic settings, features and survival outcomes of HER2-UL are not significantly distinct from HER2-null tumors. HER2-low metastatic cancers largely retain clinicopathological characteristics of their primary origins. Liver is the predominant site of HER2-low metastasis and shows a notable risk of HER2 discordance. Given that discordance, particularly the link of worse outcome to HER2 downregulation, re-evaluation of biomarker status in high-risk sites should be considered to optimise therapeutic strategies.