Comparison of the pathological complete response between immunohistochemistry HER2 (3 + ) and HER2...

Human epidermal growth factor receptor 2 (HER2) overexpression defines a distinct breast cancer (BC) subtype that is highly sensitive to anti-HER2 therapy. However, the predictive and prognostic value of varying HER2 expression levels-specifically immunohistochemistry (IHC) 3 + versus IHC 2+/in situ hybridization (ISH)-positive-tumors remains uncertain. This systematic review and meta-analysis compared pathological complete response (pCR) between these subgroups in early-stage HER2-positive BC treated with anti-HER2-based neoadjuvant chemotherapy (NACT).

Following PRISMA guidelines (PROSPERO: CRD420251066320), PubMed, EMBASE, Cochrane Library, and ClinicalTrials databases were searched up to June 2025. Eligible studies compared HER2 (3 + ) and HER2 (2 + )/ISH + early-stage BC receiving anti-HER2-based NACT. Data extraction was performed independently by two reviewers. Pooled odds ratios (ORs) and hazard ratios (HRs) were calculated using fixed- or random-effects models according to heterogeneity.

Thirteen retrospective studies involving 7,206 patients were included. Among 6,081 HER2-positive cases, 76 % were HER2 (3 + ) and 24 % were HER2 (2 + )/ISH + . The pooled pCR rate was significantly higher in HER2 (3 + ) tumors than in HER2 (2 + )/ISH + tumors (55.1 % vs. 21.6 %; OR = 5.38, 95 % CI: 3.72-7.80; p < 0.00001). The difference persisted in dual-targeted regimens (66.0 % vs. 32.9 %; OR = 4.31, 95 % CI: 2.70-6.88; p < 0.00001). No significant difference was observed in 3-year invasive disease-free survival (HR = 0.71, 95 % CI: 0.32-1.57; p = 0.40).

HER2 IHC 3 + tumors are substantially more likely to achieve pCR following anti-HER2-based NACT than HER2 (2 + )/ISH + tumors, indicating that HER2 expression intensity has predictive relevance. Quantitative HER2 assessment should be integrated into therapeutic planning and trial stratification to optimize outcomes in early-stage HER2-positive BC.