Clinical characteristics and prognostic impact of HER2-ultralow breast cancer and tumor-infiltrating lymphocytes (TILs)
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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 the clinical and prognostic characteristics of HER2-ultralow breast cancer . This study aimed to clarify the clinical characteristics, immune microenvironment, treatment response, and prognosis of HER2-ultralow tumors, with HER2-null and HER2-low tumors analyzed as comparators .
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%). Clinicopathological features , tumor-infiltrating lymphocyte (TIL) counts , pathological complete response (pCR) , and prognostic outcomes (disease-free survival [DFS] and overall survival [OS]) were evaluated .
Results
HER2-ultralow tumors showed significantly higher estrogen receptor (ER) positivity compared with HER2-null tumors (51.8% vs. 19.6%, p < 0.001), and also tended to have higher progesterone receptor positivity (p = 0.048). In contrast, HER2-null tumors were associated with younger age (median 50.0 vs. 56.0 years, p = 0.004) and higher TIL density (50.0% vs. 36.8%, p = 0.016). The overall pCR rate was 27.9%. DFS showed no significant differences among the three groups (p = 0.087), but OS was significantly worse in HER2-null compared with Not HER2-null tumors (p = 0.026, HR = 0.454). HER2-ultralow cases demonstrated an intermediate prognosis between HER2-low and HER2-null (OS comparison with HER2-null,>p= 0.101).
Conclusion
HER2-ultralow tumors represent a distinct subgroup characterized by higher hormone receptor positivity , whereas HER2-null tumors were associated with younger age, higher TIL density, and poorer survival. These findings emphasize the clinical significance of refining HER2-negative subclassification to distinguish HER2-ultralow , while acknowledging limitations of sample size and retrospective design .
