HER2 expression heterogeneity (IHC/FISH) in breast cancer: A systematic review and meta-analysis of prognostic implications.

e13023 Background: Human epidermal growth factor receptor 2 (HER2/ERBB2) is a validated predictive and prognostic biomarker in breast cancer that guides the use of HER2-targeted therapies. While current guidelines use a binary IHC/FISH classification, increasing evidence suggests clinically relevant intratumoral HER2 expression heterogeneity. This study reviewed the association between intratumoral HER2 expression heterogeneity and clinical outcomes in patients with HER2-positive breast cancer. Methods: PubMed, Scopus, Embase, Cochrane, and ClinicalTrials.gov were searched from 2018 to December 2026 in accordance with PRISMA guidelines for studies reporting the prognostic implications of HER2 expression heterogeneity (IHC/FISH) in breast cancer. Dichotomous outcomes were pooled using risk ratios (RRs) with 95% confidence intervals (CIs), while continuous outcomes were analyzed using mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. Analyses were conducted using RevMan 5.4.0. Heterogeneity was assessed using I² statistics (I² > 50%). A p-value < 0.05 was considered significant. Results: High intratumor HER2 heterogeneity emerged as a robust negative prognostic indicator across seven studies (n = 2847)of HER2+ breast cancer patients primarily aged 50+. High heterogeneity significantly correlated with diminished clinical outcomes, notably reduced pathological complete response rates (49.6%) and increased treatment resistance (P = 0.007). Meta-analysis confirmed 4.3 fold risk of poorer distant recurrence-free survival (HR: 4.26; 95% CI: 1.69–6.94; P = 0.00062), worse overall survival (HR: 2.02; 95% CI: 1.09–3.74; P = 0.025), all comparing heterogeneous vs. homogeneous HER2 IHC/FISH expression. Conclusions: This systematic review and meta-analysis suggested that intratumoral HER2 IHC/FISH expression heterogeneity is not just a pathological nuance but a clinically important feature that meaningfully influences outcomes in HER2-positive breast cancer. Across seven studies, largely involving patients aged 50 years and older, tumors with greater HER2 IHC/FISH heterogeneity consistently showed poorer responses to HER2-targeted therapy and worse long-term outcomes. Overall, a binary HER2 classification oversimplifies disease biology, and routine IHC/FISH heterogeneity assessment should be integrated into prognostic models and trial design.