Molecular Characterization and Classification of HER2-Positive Breast Cancer Inform Tailored Therapeutic Strategies

乳腺癌 医学 肿瘤科 癌症 内科学 靶向治疗 肿瘤微环境 曲妥珠单抗 免疫疗法 癌症研究
作者
Yu-Wei Li,Lei-Jie Dai,Xiangrong Wu,Shen Zhao,Yu-Zheng Xu,Xi Jin,Yi Xiao,Ying Wang,Cai-Jin Lin,Yi-Fan Zhou,Tong Fu,Wentao Yang,Ming Li,Hong Lv,Siyuan Chen,Anita Grigoriadis,Yi‐Zhou Jiang,Ding Ma,Zhi‐Ming Shao
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:84 (21): 3669-3683 被引量:10
标识
DOI:10.1158/0008-5472.can-23-4066
摘要

HER2-positive breast cancer is an aggressive subtype that accounts for 15% to 20% of all breast cancers. Recent studies have suggested that HER2-positive breast cancer is a group of heterogeneous diseases with different sensitivities to standard treatment regimens. Revealing the molecular heterogeneity of HER2-positive breast cancer could potentially enable more precise treatment strategies. In this study, we performed multiomics profiling on a HER2-positive breast cancer cohort and identified four transcriptome-based subtypes. The classical HER2 (HER2-CLA) subtype comprised 28.3% of the samples and displayed high ERBB2 activation and significant benefit from anti-HER2 therapy. The immunomodulatory (HER2-IM) subtype (20%) featured an immune-activated microenvironment, potentially suitable for de-escalated treatment and immunotherapy. The luminal-like (HER2-LUM) subtype (30.6%) possessed similar molecular features of hormone receptor-positive HER2-negative breast cancer, suggesting endocrine therapy and CDK4/6 inhibitors as a potential therapeutic strategy. Lastly, the basal/mesenchymal-like (HER2-BM) subtype (21.1%) had a poor response to current dual HER2-targeted therapy and could potentially benefit from tyrosine kinase inhibitors. The molecular characteristics and clinical features of the subtypes were further explored across multiple cohorts, and the feasibility of the proposed treatment strategies was validated in patient-derived organoid and patient-derived tumor fragment models. This study elucidates the molecular heterogeneity of HER2-positive breast cancer and paves the way for a more tailored treatment. Significance: Illumination of the inherent heterogeneity within HER2-positive breast cancers through the delineation of distinct molecular subtypes lays the groundwork for developing more personalized treatment strategies based on specific patient characteristics.
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