Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression

Background: Breast cancer (BC) expressing low levels of human epidermal growth factor receptor 2 (HER2 Low) is an emerging category that needs further refining. This study aims to provide a comprehensive clinicopathological and molecular profile of HER2 Low BC including response to therapy and patient outcome in the adjuvant and neoadjuvant settings.Methods: Two different independent and well-characterised BC cohorts were included. Nottingham cohort (A) (n = 5744) and The Cancer Genome Atlas (TCGA) BC cohort (B) (n = 854). The clinical, molecular, biological and immunological profile of HER2 Low BC was investigated. Transcriptomic and pathway enrichment analyses were performed on the TCGA BC cohort and validated through next-generation sequencing in a subset of Nottingham cases.Results: Ninety percent of HER2 Low tumours were hormone receptor (HR) positive (HR+), enriched with luminal intrinsic molecular subtype, lacking significant expression of HER2 oncogenic signalling genes and of favourable clinical behaviour compared to HER2 negative (HER2-) BC. In HR+ BC, no significant prognostic differences were detected between HER2 Low and HER2- tumours. However, in HR- BC, HER2 Low tumours were less aggressive with longer patient survival. Transcriptomic data showed that the majority of HR- /HER2 Low tumours were of luminal androgen receptor (LAR) intrinsic subtype, enriched with T-helper lymphocytes, activated dendritic cells and tumour associated neutrophils, while most HR-/HER2- tumours were basal-like, enriched with tumour associated macrophages.Conclusion: HER2 Low BC is mainly driven by HR signalling in HR+ tumours. HR-/HER2 Low tumours tend to be enriched with LAR genes with a unique immune profile.