Yang Yinlong, Pan Liangwei, Zhou Wenzhe, Shao Zhimin
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Fudan University, Shanghai Medical College, Shanghai, China.
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Fudan University, Shanghai Medical College, Shanghai, China.
Breast. 2025 Sep 21;84:104584. doi: 10.1016/j.breast.2025.104584.
The emergence of novel human epidermal growth factor receptor 2 (HER2)-targeting drugs has provided a new therapeutic option for HER2-low triple-negative breast cancer (TNBC) patients who had limited treatment choices previously. However, the biological implications and prognostic significance of HER2-low status in TNBC are still not fully appreciated.
Utilizing a single-center multi-omics cohort of TNBC patients that includes whole exome sequencing and RNA sequencing data, this study aims to explore the clinical and molecular characteristics between HER2-low and HER2-0 TNBC.
The study comprised 207 patients with HER2-low TNBC and 153 patients with HER2-0 TNBC. Findings revealed that HER2-low tumors exhibited lower tumor grade, more nodal involvement and lower Ki-67 index compared to HER2-0 tumors. Additionally, HER2-low TNBC were associated with more mutations in PIK3CA and its corresponding pathways, a more prominent clock-like mutation signature, along with activation of androgen receptor (AR)-related pathways and fatty acid metabolism. While HER2-low status did not significantly influence recurrence-free survival (RFS) across the entire study population, HER2-low patients showed significant better RFS compared to HER2-0 patients within the luminal androgen receptor (LAR) subtype. This distinction was also evident at molecular level.
HER2-low TNBC demonstrated unique clinical, transcriptomic and genomic characteristics when contrasted with HER2-0 TNBC. In the LAR subtype, a clear molecular and prognostic discrepancy between HER2-0 and HER2-low tumors was identified.
新型人表皮生长因子受体2（HER2）靶向药物的出现为既往治疗选择有限的HER2低表达三阴性乳腺癌（TNBC）患者提供了新的治疗选择。然而，TNBC中HER2低表达状态的生物学意义和预后意义仍未得到充分认识。
本研究利用一个包含全外显子测序和RNA测序数据的TNBC患者单中心多组学队列，旨在探索HER2低表达和HER2零表达TNBC之间的临床和分子特征。
该研究纳入了207例HER2低表达TNBC患者和153例HER2零表达TNBC患者。研究结果显示，与HER2零表达肿瘤相比，HER2低表达肿瘤的肿瘤分级更低、淋巴结受累更多、Ki-67指数更低。此外，HER2低表达TNBC与PIK3CA及其相应通路的更多突变、更显著的时钟样突变特征以及雄激素受体（AR）相关通路和脂肪酸代谢的激活有关。虽然HER2低表达状态在整个研究人群中对无复发生存期（RFS）没有显著影响，但在腔面雄激素受体（LAR）亚型中，HER2低表达患者的RFS明显优于HER2零表达患者。这种差异在分子水平上也很明显。
与HER2零表达TNBC相比，HER2低表达TNBC表现出独特的临床、转录组和基因组特征。在LAR亚型中，HER2零表达和HER2低表达肿瘤之间存在明显的分子和预后差异。
