Clinical Characteristics and Prognostic Impact of HER2-Ultralow Breast Cancer and Tumor-Infiltrating Lymphocytes (TILs)

Purpose: HER2 expression is crucial in breast cancer classification and treatment. Traditionally, tumors were categorized as HER2-positive or HER2-negative, but HER2-low (IHC 1+ or 2+ without ISH amplification) has emerged as a new classification. Among HER2-negative cases, HER2-ultralow (≤10% faint HER2 staining) and HER2-null (completely HER2-negative) have been proposed. While differences between HER2-low and HER2-zero tumors are studied, little is known about HER2-ultralow breast cancer. This study evaluates the clinical characteristics, immune microenvironment, treatment response, and prognosis of HER2-ultralow tumors compared to HER2-null and HER2-low cases. Methods: A retrospective analysis of 244 HER2-negative breast cancer patients treated with neoadjuvant chemotherapy (NAC) at Osaka Metropolitan University Hospital (2007–2018) classified tumors into HER2-low (41.0%), HER2-ultralow (36.1%), and HER2-null (23.0%). Prognostic outcomes, including disease-free survival (DFS) and overall survival (OS), were analyzed. Results: HER2-null tumors were linked to younger age (median 50.0 vs. 56.0 years, p=0.004), lower ER positivity (19.6% vs. 51.8%, p<0.001), and higher TIL density (50.0% vs. 36.8%, p=0.016). DFS showed no significant differences (p=0.087), but HER2-null tumors had worse OS (p=0.026, HR=0.454). Conclusion: HER2-ultralow tumors showed higher hormone receptor positivity, whereas HER2-null tumors had poorer survival. These findings highlight the clinical relevance of HER2-negative subclassification and suggest HER2-ultralow breast cancer may benefit from targeted therapies. Standardized HER2 assessment is needed.