Abstract：
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.
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.
摘要：
背景：表达低水平人表皮生长因子受体2（HER2Low）的乳腺癌（BC）是一个新兴的类别，需要进一步完善。本研究旨在提供HER2低BC的全面临床病理和分子特征，包括对辅助和新辅助治疗的反应和患者预后。
方法：包括两个不同的独立且充分表征的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)。临床，分子，研究了HER2低BC的生物学和免疫学特征。在TCGABC队列上进行转录组学和途径富集分析，并在诺丁汉病例亚组中通过下一代测序进行验证。
结果：90%的低HER2肿瘤为激素受体（HR）阳性（HR+），富含腔内在分子亚型，与HER2阴性（HER2-）BC相比，缺乏HER2致癌信号基因的显着表达和良好的临床行为。在HR+BC中，在HER2Low和HER2肿瘤之间没有检测到显著的预后差异.然而,在HR-BC，HER2低肿瘤的侵袭性较差，患者生存期更长。转录组数据显示，大多数HR-/HER2低肿瘤是腔内雄激素受体（LAR）固有亚型，富含T辅助淋巴细胞，激活的树突状细胞和肿瘤相关的中性粒细胞，虽然大多数HR-/HER2-肿瘤是基底样的，富含肿瘤相关巨噬细胞。
结论：HER2低BC主要由HR+肿瘤中的HR信号驱动。HR-/HER2低肿瘤往往富含具有独特免疫谱的LAR基因。
方法：包括两个不同的独立且充分表征的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)。临床，分子，研究了HER2低BC的生物学和免疫学特征。在TCGABC队列上进行转录组学和途径富集分析，并在诺丁汉病例亚组中通过下一代测序进行验证。
结果：90%的低HER2肿瘤为激素受体（HR）阳性（HR+），富含腔内在分子亚型，与HER2阴性（HER2-）BC相比，缺乏HER2致癌信号基因的显着表达和良好的临床行为。在HR+BC中，在HER2Low和HER2肿瘤之间没有检测到显著的预后差异.然而,在HR-BC，HER2低肿瘤的侵袭性较差，患者生存期更长。转录组数据显示，大多数HR-/HER2低肿瘤是腔内雄激素受体（LAR）固有亚型，富含T辅助淋巴细胞，激活的树突状细胞和肿瘤相关的中性粒细胞，虽然大多数HR-/HER2-肿瘤是基底样的，富含肿瘤相关巨噬细胞。
结论：HER2低BC主要由HR+肿瘤中的HR信号驱动。HR-/HER2低肿瘤往往富含具有独特免疫谱的LAR基因。
