Qiu X, Tarantino P, Li R, Grinshpun A, Gupta H, Hughes M E, Kirkner G, Scholl L, Johnson B E, Meyerson M, Cherniack A D, Jiang Y, Zhou N, Lin N U, Long H W, Tolaney S M, Jeselsohn R
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA; Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, USA; Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy.
ESMO Open. 2025 Feb;10(2):104111. doi: 10.1016/j.esmoop.2024.104111. Epub 2025 Jan 17.
The approval of trastuzumab deruxtecan has prompted the subgrouping of human epidermal growth factor receptor 2-negative (HER2-) breast cancers (BCs) to HER2 0 and HER2 low on the basis of immunohistochemistry, although the biological significance of these subgroups remains uncertain. This study is aimed to better understand the molecular and genetic differences among HER2- tumors stratified by quantitative levels of HER2.
We analyzed the transcriptomic and genomic data from the Molecular Taxonomy of BC International Consortium (discovery cohort) and The Cancer Genome Atlas (independent validation cohort). HER2- BCs, including hormone receptor positive and triple negative, were divided into three subgroups based on ERBB2 messenger RNA (mRNA) levels: minimal, moderate and enhanced.
We observed significant differences in mutational and transcriptional profiles across the subgroups. Tumors with enhanced ERBB2 mRNA expression had a higher prevalence of PIK3CA mutations and increased estrogen receptor signaling, while tumors with minimal ERBB2 mRNA expression displayed higher expression of proliferation and immune-related genes. We identified a distinct subgroup of BCs characterized by a large deletion of chromosome 17q12 (17q12del) with heterozygous loss of ERBB2, very low ERBB2 mRNA and HER2 protein expression. This subgroup was also enriched for heterozygous losses of TP53 and other tumor suppressor genes. Analysis of two large real-world cohorts of patients with HER2- metastatic BC (Dana-Farber Cancer Institute cohort n = 1063 and Memorial Sloan Kettering MetTropism cohort n = 1018) showed that patients with 17q12del and heterozygous loss of ERBB2 had poorer overall survival (OS).
We identified a biologically and clinically distinct subgroup of BCs characterized by a 17q12del with a heterozygous loss of ERBB2 and low ERBB2 mRNA and HER2 protein expression. In two large real-world cohorts of patients with HER2- metastatic BC, this subgroup was associated with poor OS, highlighting its clinical significance.
曲妥珠单抗德曲妥珠单抗的获批促使基于免疫组织化学将人表皮生长因子受体2阴性（HER2-）乳腺癌（BC）细分为HER2 0和HER2低表达亚型，尽管这些亚型的生物学意义仍不确定。本研究旨在更好地了解根据HER2定量水平分层的HER2-肿瘤之间的分子和基因差异。
我们分析了来自乳腺癌国际分子分类联盟（发现队列）和癌症基因组图谱（独立验证队列）的转录组和基因组数据。HER2- BC，包括激素受体阳性和三阴性，根据ERBB2信使核糖核酸（mRNA）水平分为三个亚组：低、中、高。
我们观察到各亚组之间在突变和转录谱方面存在显著差异。ERBB2 mRNA表达增强的肿瘤PIK3CA突变发生率更高，雌激素受体信号传导增加，而ERBB2 mRNA表达最低的肿瘤增殖和免疫相关基因表达更高。我们鉴定出一个独特的BC亚组，其特征是17号染色体q12区域（17q12）大片段缺失，ERBB2杂合性缺失，ERBB2 mRNA和HER2蛋白表达极低。该亚组还富集了TP53和其他肿瘤抑制基因的杂合性缺失。对两个大型HER2-转移性BC患者真实世界队列（丹娜法伯癌症研究所队列n = 1063和纪念斯隆凯特琳癌症中心MetTropism队列n = 1018）的分析表明，17q12缺失且ERBB2杂合性缺失的患者总生存期（OS）较差。
我们鉴定出一个生物学和临床特征独特的BC亚组，其特征为17q12缺失、ERBB2杂合性缺失以及ERBB2 mRNA和HER2蛋白低表达。在两个大型HER2-转移性BC患者真实世界队列中，该亚组与较差的OS相关，突出了其临床意义。
