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Clinicopathological response and survival outcomes of HER2-low versus HER2-zero early breast Cancer: A systematic review and Meta-analysis.

Lijuan Liu·Xiaochen Ma·Cun Liu·Guanghui Liu·Minpu Zhang·Tianhua Wang·Changgang Sun
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Abstract

BACKGROUND: Breast cancer is the most common malignant tumor in women. Human epidermal growth factor receptor 2 (HER2) is a key biomarker for classification and treatment. A subgroup with HER2-low expression has been identified, but existing evidence is heterogeneous. This systematic review and meta-analysis compared pathological response and survival outcomes between HER2-low and HER2-zero early-stage breast cancer to clarify prognostic features. METHODS: This study followed PRISMA guidelines and was registered in PROSPERO (CRD420251120506). PubMed, Embase, Web of Science, ClinicalTrials.gov, and major oncology conferences were searched through September 2025. Cohort studies of early-stage breast cancer comparing HER2-low (IHC 1+/2+ and ISH-negative) vs. HER2-zero with extractable pCR, DFS, or OS data were included. Studies involving HER2-positive patients or inconsistent definitions were excluded. Meta-analyses were performed using RevMan 5.3. RESULTS: Twenty-eight studies involving 115,182 patients were included. HER2-low patients showed significantly lower pCR rates (OR = 0.58, 95% CI: 0.52-0.65). DFS favored HER2-low (multivariate HR = 0.75, 95% CI: 0.69-0.83), especially in HR+ tumors, with a weaker effect in HR- cases. OS also favored HER2-low (HR = 0.80, 95% CI: 0.72-0.89), mainly driven by the HR- subgroup; no OS difference was seen in HR+ tumors. Sensitivity analyses and funnel plots indicated robust results with no apparent publication bias. Overall study quality was high (17 high-quality, 11 moderate-quality). CONCLUSION: HER2-low early breast cancer shows lower pCR after neoadjuvant therapy but better long-term survival. These findings support the clinical relevance of HER2-low as a biologically meaningful subgroup within HER2-negative disease, while its status as a stable and independent subtype still requires further validation through prospective studies, standardized testing, and multi-omics investigation.

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HumansErb-b2 Receptor Tyrosine KinasesBreast NeoplasmsFemaleEarly breast cancerHER2-lowMeta-analysisSurvival outcomesJournal ArticleSystematic ReviewMeta-Analysis

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Lijuan Liu, Xiaochen Ma, Cun Liu, Guanghui Liu, Minpu Zhang, Tianhua Wang, Changgang Sun. 2026-06-04. Clinicopathological response and survival outcomes of HER2-low versus HER2-zero early breast Cancer: A systematic review and Meta-analysis.. https://doi.org/10.1016/j.cca.2026.121134

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Breast Neoplasms subjectEarly breast cancer subjectErb-b2 Receptor Tyrosine Kinases subjectFemale subjectHER2-low subjectHumans subjectJournal Article subjectJournal Article; Systematic Review; Meta-Analysis resourceMeta-Analysis subjectSystematic reviews study

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