Re-evaluation of HER2 status and prognostic implications of ultra-low and low HER2 expression in estrogen receptor–positive breast cancer.

e12546 Background: Recent studies have shown antibody-drug conjugates' efficacy in HER2-low breast cancer, but the classification and clinical significance of HER2 expression levels (ultra-low and low) remain debated, particularly regarding HER2 immunohistochemistry (IHC) score reproducibility and whether low HER2 expression represents a distinct breast cancer subtype. Methods: We retrospectively analyzed 849 early-stage ER-positive, HER2-negative breast cancer patients who underwent Oncotype DX testing post-surgery. HER2 IHC slides were re-evaluated using a classification including ultra-low expression. Relationships between HER2 status and clinico-pathological features, multigene assay prognostic scores, and survival outcomes were investigated. Results: A total of 129 cases (15.2%) were reclassified as HER2-null, 241 cases (28.4%) as HER2-ultralow, 386 cases (45.5%) as HER2-1+, and 93 cases (11.0%) as HER2-2+. Among the initially HER2-0 cases, 162 cases (45.5%) were reclassified as HER2-ultralow. Re-evaluated HER2 IHC scores significantly correlated with HER2 gene scores via qRT-PCR (p<0.001). HER2-low cases showed significantly higher proportions of strong ER expression, wild-type p53 expression, and low Ki-67 compared to HER2-null (p=0.038, 0.015, 0.002, respectively). HER2-ultralow showed no significant differences. Using ODx score threshold of 26, high-risk patient proportions were 20.9% for HER2-null, 13.3% for HER2-ultralow (p=0.057), and 12.7% for HER2-low (p=0.020). During 44-month median follow-up, HER2-low showed better disease-free survival in univariable analysis (HR 0.33, 95% CI 0.12-0.90, p=0.029) compared to HER2-null, while HER2-ultralow showed no significance. However, multivariable analysis showed neither HER2-low nor ultralow had significant differences in ODx high-risk proportions or survival outcomes. Conclusions: There appears to be a potential need for re-examination of existing HER2 interpretations to define candidates for T-DXd (Trastuzumab deruxtecan) treatment. In ER-positive early breast cancer, HER2-low expression is associated with better prognosis compared to HER2-null, while HER2 ultra-low shows no significant difference. This difference is attributable to variations in clinicopathological features observed in HER2-low cases, and neither HER2 ultra-low nor HER2-low demonstrated independent prognostic significance when compared to HER2-null. Logistic regression analysis of clinico-pathological factors associated with Oncotype DX high-risk(≥26). Proportion of ODx high-risk Univariable analysis Multivariable analysis OR 95% CI p OR 95% CI p HER2 status Null 20.9% ref ref Ultra-low 13.3% 0.58 0.33-1.02 0.057 0.65 0.34-1.24 0.652 Low 12.7% 0.55 0.33-0.91 0.020 0.83 0.47-1.48 0.527