Clinical Relevance of HER2-Low and HER2-Zero Subgroups in Hormone Receptor-Negative Breast Cancer: A Retrospective Single-Center Cohort Study 2014-2024.

INTRODUCTION: HER2-negative and hormone receptor (HR)-negative breast cancer is typically associated with poor prognosis due to limited treatment options. Recent research has demonstrated efficacy of anti-HER2 antibody-drug conjugates in patients with HER2-low (HER2 1+ and HER2 2+/ISH-negative) breast cancer, suggesting this subgroup as a distinct clinical and biological entity with actionable therapeutic targets. Retrospective analyses of cohorts prior to the introduction of targeted agents in HER2-low patients are essential to establish natural disease course and prognostic relevance of this subgroup independent of targeted therapy. METHODS: We retrospectively analyzed data of HR-negative and either HER2-zero or HER2-low breast cancer patients treated in a single clinical center between 2014 and 2024. Primary endpoints included overall survival (OS) and event-free survival (EFS), secondary endpoints included pathological complete response (pCR) after neoadjuvant chemotherapy and clinicopathological characteristics across the HER2 subgroups. RESULTS: Among 277 patients, 160 (57.8%) had HER2-zero, 75 (27.1%) had HER2 1+ and 42 (15.2%) HER2 2+/ISH-negative tumors. Higher tumor stages (p = 0.053) and lower Ki-67 indices (p = 0.038) were notably more prevalent in HER2 2+/ISH-negative patients. OS was significantly worse in HER2 2+/ISH-negative patients (HR 8.12, 95% CI: 1.98-33.37, p = 0.004), whereas EFS and pCR rates did not differ significantly across the HER2 subgroups. Patients with pCR after neoadjuvant chemotherapy had significantly better OS (p = 0.007) and EFS (p = 0.003) compared to those with non-pCR, without differences observed among the HER2 subgroups. CONCLUSIONS: HER2 2+/ISH-negative status was associated with poorer OS. While EFS and pCR rates also tended to be lower, the differences were not statistically significant. Distinct clinicopathological features associated with lower pCR rates may have contributed to the inferior survival in this group.