Clinical presentations and prognostication of HER2-low and HER2-zero early breast cancer in Taiwan

BACKGROUND: Human epidermal growth factor receptor II (HER2)low breast cancer has emerged as a clinically relevant subset of HER2‑negative disease, but its prognostic significance in early‑stage, real‑world populations remains uncertain. We aimed to compare clinicopathological features and outcomes of HER2‑low versus HER2‑zero early breast cancers using a nationwide registry and to clarify the impact of hormone‑receptor (HR) status through stratified analyses. METHODS: We conducted a retrospective cohort study using data from the Taiwan Cancer Registry (2011-2020). Eligible cases were stages 0-III HER2‑negative breast cancers managed with upfront surgery. We compared clinical characteristics and estimated overall survival (OS) and relapse‑free survival (RFS). As HR status is a dominant prognostic factor, all analyses were stratified by HR (positive vs. negative) and by pathological stage. Multivariable models adjusted for clinical covariates were used to estimate hazard ratios. RESULTS: We analyzed 38,773 patients; 65.4% were HER2-low and 34.6% were HER2-zero. HER2-low tumors were diagnosed at a slightly younger age (median 56.3 vs 57.1 years; P<0.001) and were more often HR-positive (ER and PR, both P<0.0001). Across HR- and stage-defined strata, pathological stage and HR status remained the principal determinants of prognosis. Compared with HER2-zero, HER2-low showed modestly higher hazards, with small but consistent separations in OS (91.8%, 93%, 83.3% and 86.2% for HR-positive/HER2-low, HR-positive/HER2-zero, HR-negative/HER2-low, and HR-negative/HER2-zero breast cancers, P<0.0001) and RFS (95.6%, 97.1%, 89.6% and 91.1% for HR-positive/HER2-low, HR-positive/HER2-zero, HR-negative/HER2-low, and HR-negative/HER2-zero breast cancers, P<0.0001) within strata, with the exception of stage 0, where curves largely overlapped. CONCLUSION: In Taiwanese early stage breast cancer, HER2-low is common and associated with greater HR positivity and modestly inferior OS/RFS relative to HER2 zero after HR and stage stratification. These clinicopathological distinctions may influence future eligibility for the novel targeted therapy at metastatic relapse, even when early stage outcome differences are small. Further studies are warranted to understand the biological and therapeutic relevance of this newly established taxonomy.