Clinical relevance of HER2-low and HER2-zero subgroups in hormone receptor-negative breast cancer: A retrospective single-center cohort study 2014-2024

Introduction: Hormone receptor negative breast cancer lacking HER2 overexpression is associated with poor prognosis and limited treatment options. Recent efficacy of anti HER2 antibody drug conjugates in HER2-low (HER2 1+ and HER2 2+/ISH-negative) disease suggests that this subgroup represents a biologically and clinically distinct entity. Analyses of cohorts treated before the availability of HER2 targeted therapies are needed to define the natural disease course and prognostic relevance of HER2 low status. 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. 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 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. Patients with pCR after neoadjuvant chemotherapy had significantly better OS (p = 0.007) and EFS (p = 0.003) than those with non-pCR, with no differences among the HER2 subgroups. Conclusion: HER2 2+/ISH-negative status was associated with poorer OS. Distinct clinicopathological features associated with lower pCR rates may have contributed to the inferior survival in this group.