Incidence, Clinicopathologic Features, and Follow-Up Results of human epidermal growth factor receptor-2–Ultralow Breast Carcinoma

The preliminary result of DESTINY-Breast06 trial demonstrated the effectiveness of antibody-drug conjugate in patients with human epidermal growth factor receptor-2 (HER2)–ultralow breast carcinoma (BC), defined by the presence of ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining on HER2 immunohistochemistry. In this study, we investigated the pathologic features and clinical outcomes in patients with HER2-ultralow, HER2-null, and HER2-low expression. The incidence of HER2 ultralow was 17.5% (260/1486). The incidence of other groups is as follows: 7.7% for HER2 null, 56.8% for HER2 low, and 18% for HER2 positive. HER2-ultralow cases showed similarity to HER2-low cases but a significant difference from HER2-null cases, including older age (61.1 vs 57.3 years; P = .0099), fewer grade 3 BCs (18.1% vs 53.9%; P < .0001), triple-negative BCs (16.2% vs 42.6%; P < .0001), estrogen receptor (ER)–negative BCs (16.5% vs 47.8%; P < .0001), and progesterone receptor–negative BCs (26.2% vs 54.8%; P < .0001). When cases were stratified based on ER positivity, these differences between HER2-null and HER2-ultralow groups were confined to ER+ but not ER− cases. There were no discernible differences in response to neoadjuvant chemotherapy (n = 125) among HER2-null, HER2-ultralow, and HER2-low BCs. HER2-null/ER−BCs displayed a lower probability of overall survival than HER2-ultralow and HER2-low/ER−BCs, but no statistically significant difference was observed in disease-free survival among the 3 groups. HER2-ultralow BCs exhibit distinct features that align more closely with HER2-low BCs than HER2-null BCs. These findings contribute to the evolving classification of HER2 expression in BC and may have implications for refining treatment strategies in this subgroup.