【原】中国HER2低表达乳腺癌分子特征与临床意义

　　过去，传统的HER2靶向治疗药物仅对HER2高表达乳腺癌有效。2022年，乳腺癌命运第四交响曲改变了HER2低表达乳腺癌患者的命运，HER2低表达概念也迅速成为热点。不过，HER2低表达乳腺癌的分子异质性以及独有特征尚不明确，尤其对于中国患者，限制了其精准治疗。如何精准地认识和治疗HER2低表达乳腺癌，成为目前亟待解决的关键问题，尤其对于中国患者。

　　2023年8月22日，英国《自然》旗下《自然通讯》在线发表复旦大学附属肿瘤医院戴磊杰、马丁📧、徐钰铮、李明、李玉为、肖毅、金希、吴松阳、赵雅鑫、王晗、杨文涛📧、江一舟📧、邵志敏📧等学者的研究报告，建立了目前规模最大且具有可靠病理诊断的HER2低表达乳腺癌多组学队列，从基因组、转录组、蛋白组和代谢组等多个角度全面刻画了HER2低表达乳腺癌的分子特征，为这部分患者的分层管理和精准诊疗提供了全新视角，这也是该研究在2022年圣安东尼奥乳腺癌大会入选亮点讨论后的正式见刊。

　　该研究建立了由434例中国HER2低表达乳腺癌患者组成的队列，并且整合了基因组、转录组、蛋白质组和代谢组学分析数据。

　　在激素受体阴性乳腺癌亚组中，HER2低表达肿瘤与HER2零表达肿瘤相比，差异更为明显。对于HER2低表达肿瘤，激素受体阴性亚组也存在显著的患者间异质性：基底样肿瘤大多为HER2零表达，而非基底样肿瘤大多为HER2阳性。这些非基底样HER2低表达肿瘤富含HER2富集亚型和管腔雄激素受体亚型，并具有FGFR4、PTK6、ERBB4过表达、PIK3CA突变和脂质代谢激活的特征。

　　在激素受体阳性乳腺癌亚组中，HER2低表达肿瘤的17号染色体长臂基因丢失或缺失峰少于HER2零表达肿瘤，临床预后较好。

　　因此，该研究结果揭示了中国HER2低表达乳腺癌的异质性，并强调需要对激素受体状态和分子亚型进行更精准的分层。

复旦大学附属肿瘤医院HER2低表达乳腺癌队列设计与分子图谱

HER2低表达与HER2零表达患者无远处转移生存的差异

不同激素受体状态的HER2低表达与HER2零表达乳腺癌分子特征差异

激素受体阴性HER2低表达乳腺癌患者的分子异质性

激素受体阳性HER2低表达乳腺癌分子变化与患者生存的关联

Nat Commun. 2023 Aug 22;14(1):5112. IF: 16.6

Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer.

Lei-Jie Dai, Ding Ma, Yu-Zheng Xu, Ming Li, Yu-Wei Li, Yi Xiao, Xi Jin, Song-Yang Wu, Ya-Xin Zhao, Han Wang, Wen-Tao Yang, Yi-Zhou Jiang, Zhi-Ming Shao.

Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.

The molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management in the era of antibody-drug conjugates. To address this issue, we established a cohort of 434 Chinese patients with HER2-low breast cancer (433 female and one male) and integrated genomic, transcriptomic, proteomic, and metabolomic profiling data. In this cohort, HER2-low tumors are more distinguished from HER2-0 tumors in the hormone receptor-negative subgroup. Within HER2-low tumors, significant interpatient heterogeneity also exists in the hormone receptor-negative subgroup: basal-like tumors resemble HER2-0 disease, and non-basal-like HER2-low tumors mimic HER2-positive disease. These non-basal-like HER2-low tumors are enriched in the HER2-enriched subtype and the luminal androgen receptor subtype and feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression and lipid metabolism activation. Among hormone receptor-positive tumors, HER2-low tumors show less loss/deletion in 17q peaks than HER2-0 tumors. In this work, we reveal the heterogeneity of HER2-low breast cancers and emphasize the need for more precise stratification regarding hormone receptor status and molecular subtype.

DOI: 10.1038/s41467-023-40715-x

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