Translational Medical Science, School of Medicine, the University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK; Department of Pathology, Faculty of Medicine, Menoufia University, Egypt.
School of Veterinary Medicine and Sciences, University of Nottingham, Sutton Bonington, UK.
Eur J Cancer. 2023 Dec;195:113371. doi: 10.1016/j.ejca.2023.113371. Epub 2023 Oct 7.
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 clinico-pathological and molecular profile of HER2 Low BC including response to therapy and patient outcome in the adjuvant and neoadjuvant settings.
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.
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.
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.
人表皮生长因子受体 2（HER2）低表达的乳腺癌（BC）是一个新兴的类别，需要进一步细化。本研究旨在提供 HER2 低表达 BC 的全面临床病理和分子特征，包括辅助和新辅助治疗的反应和患者结局。
纳入了两个不同的独立且特征明确的 BC 队列。诺丁汉队列（A）（n=5744）和癌症基因组图谱（TCGA）BC 队列（B）（n=854）。研究了 HER2 低表达 BC 的临床、分子、生物学和免疫学特征。对 TCGA BC 队列进行了转录组和通路富集分析，并在诺丁汉的一组病例中通过下一代测序进行了验证。
90%的 HER2 低表达肿瘤为激素受体（HR）阳性（HR+），富含管腔内在分子亚型，缺乏 HER2 致癌信号基因的显著表达，与 HER2 阴性（HER2-）BC 相比具有良好的临床行为。在 HR+ BC 中，HER2 低表达和 HER2-肿瘤之间没有发现显著的预后差异。然而，在 HR- BC 中，HER2 低表达肿瘤侵袭性较低，患者生存时间较长。转录组数据显示，大多数 HR- /HER2 低表达肿瘤为管腔雄激素受体（LAR）内在亚型，富含 T 辅助淋巴细胞、激活的树突状细胞和肿瘤相关中性粒细胞，而大多数 HR- /HER2-肿瘤为基底样，富含肿瘤相关巨噬细胞。
HR+肿瘤中 HER2 低表达 BC 主要由 HR 信号驱动。HR-/HER2 低表达肿瘤倾向于富含具有独特免疫特征的 LAR 基因。
