Exploring the spectrum of HER2 in non-metastatic triple negative breast cancer: from HER2-Null to HER2-low, including HER2-ultralow status

HER2-low and -ultralow breast cancer have recently emerged as distinct theranostic subcategories within the HER2 spectrum, prompting reassessment of traditional HER2-negative immunohistochemistry scores (0, 1+ , and 2+ without amplification). This study reclassifies, according to this new categorization, a cohort of 367 patients who have never received chemotherapy and have non-metastatic triple-negative breast cancer (TNBC). We evaluated its association with their clinicopathological features and prognosis. HER2 0 tumors were reclassified as HER2-null (no staining) or HER2-ultralow (≤10% faint, incomplete membrane staining). HER2 1+ or 2+ (non-amplified) tumors were defined as HER2-low. Overall, 38.4%, 37.6% and 24.0% of TNBC samples were reclassified as HER2-null, -ultralow and -low, respectively. HER2-ultralow tumors were more frequently associated with the presence of tertiary lymphoid structures ( p = 0.0259) and BRCA1 promoter methylation ( p = 0.0439) than HER2-low tumors. Moreover, compared with HER2-null samples, HER2-ultralow tumors were of smaller size ( p = 0.0167) and lower stage and grade ( p = 0.0066 and p = 0.0364, respectively). Conversely, age, lymph node involvement, histology, molecular apocrine or basal-like phenotypes, PIK3CA and PTEN status, immune infiltrates, assessed using T-cell (CD3), B-cell (CD20) and macrophage (CD163) markers, and PD-L1 expression in tumor or stromal cells were not associated with the HER2-ultralow status. The survival analysis (median follow-up = 10.3 years) showed that relapse-free survival was not influenced by the HER2 status. Despite some significantly different clinicopathological features, there is no solid evidence to support HER2-ultralow, HER2-low and HER2-null cancers as individual TNBC clinical-molecular entities. Particularly, assigning TNBC samples to the HER2-null, -ultralow and -low categories did not bring any additional prognostic value.