Refining HER2-Negative breast cancer: distinct survival profiles of HER2-Low and HER2-Ultralow tumors.

Purpose: To evaluate the clinical, pathological, and prognostic significance of HER2-low and HER2-ultralow expression in breast cancer.

Methods: In this retrospective study, 171 HER2-negative breast cancer cases were reclassified by immunohistochemistry as HER2-low, HER2-ultralow, or HER2 IHC 0. Clinicopathological variables, Ki-67 index, hormone receptor (HR) status, and treatment data were analyzed. Welch's ANOVA, Kaplan-Meier survival with a 60-month landmark, and Cox regression were applied.

Results: The cohort included 49.1 % HER2-low, 27.5 % HER2-ultralow, and 23.4 % HER2 IHC 0 cases. No significant differences were found in clinical stage, histologic grade, or treatment distribution. Ki-67 index was lower in HER2 IHC 0 tumors (p = 0.047). Overall survival (OS) differed significantly: HER2-ultralow patients had the best outcomes (median OS: 47.5 months), followed by HER2 IHC 0 (37.5) and HER2-low (33.0) (log-rank p < 0.05). In multivariable Cox analysis, HER2-low status was independently associated with worse OS versus HER2-ultralow (HR = 1.86; p = 0.006), while HER2 IHC 0 showed no significant difference (HR = 1.42; p = 0.212). Higher Ki-67 and negative ER status were also linked to worse prognosis. Subgroup analysis revealed the poorest outcomes in HER2-low/HR-negative tumors.

Conclusion: HER2-ultralow tumors were associated with better survival than HER2-low, suggesting clinical relevance in further subclassifying HER2-negative breast cancers. Although the retrospective design and minor proportional hazard violations warrant caution, these findings may guide treatment for more individualized approaches. Future multicenter studies, supported by molecular profiling and AI-assisted HER2 scoring, are essential to validate these findings and improve reproducibility in low-level HER2 assessment.