Clinicopathological characteristics across the HER2 expression spectrum in invasive breast carcinoma of no special type: a single-centre retrospective study.

backgroundThe efficacy of trastuzumab deruxtecan in HER2-low metastatic breast cancer has shifted HER2 classification from a binary framework toward a continuous expression spectrum that now includes HER2-low and HER2-ultralow categories. Accurate characterization of these subgroups is essential for therapeutic stratification, yet their clinicopathological profiles remain incompletely defined, particularly in the Indian population. This study compared the clinicopathological features and short-term outcomes of invasive breast carcinoma of no special type across four HER2-defined subgroups.

methodsThree hundred cases of invasive breast carcinoma of no special type diagnosed on core needle biopsy at a tertiary centre in southern India (2022-2023) were classified into HER2-positive, HER2-low, HER2-ultralow, and HER2-negative subgroups using immunohistochemistry with fluorescence in situ hybridisation confirmation. Associations were evaluated using chi-square tests, Kruskal-Wallis tests, binary logistic regression, correspondence analysis, and Kaplan-Meier survival analysis.

resultsHER2-low constituted the largest subgroup at 51.7%, followed by HER2-positive (32.3%), HER2-ultralow (9.0%), and HER2-negative (7.0%). HER2-low tumours demonstrated significantly higher oestrogen receptor (74.8%) and progesterone receptor (61.3%) positivity, lower Nottingham grade, and a greater proportion of low Ki-67 proliferation index compared to the other subgroups. Age, menopausal status, clinical stage, tumour size, lymphovascular invasion, perineural invasion, and stromal tumour-infiltrating lymphocyte density did not differ significantly across the four subgroups. On multivariate logistic regression, progesterone receptor positivity was the sole independent predictor of HER2-low status (odds ratio 1.92, 95% confidence interval 1.05-3.50, p = 0.034). The triple-negative phenotype increased progressively from HER2-low (25.2%) through HER2-ultralow (40.7%) to HER2-negative (57.1%). Correspondence analysis placed HER2-ultralow in an intermediate position between HER2-low and HER2-negative. No significant survival differences were observed over a median follow-up of 23 months.

conclusionsHER2-low tumours represent the majority of invasive breast carcinomas in this Indian cohort and exhibit a distinct profile defined by hormone receptor enrichment, lower grade, and reduced proliferative activity. The intermediate phenotype of HER2-ultralow supports its recognition as a biologically separate category. These findings highlight the importance of standardised HER2 reporting across the full expression spectrum to guide antibody-drug conjugate therapy eligibility.