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

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-11-04 DOI:10.1158/0008-5472.CAN-23-4066
Yu-Wei Li, Lei-Jie Dai, Xiang-Rong Wu, Shen Zhao, Yu-Zheng Xu, Xi Jin, Yi Xiao, Ying Wang, Cai-Jin Lin, Yi-Fan Zhou, Tong Fu, Wen-Tao Yang, Ming Li, Hong Lv, Siyuan Chen, Anita Grigoriadis, Yi-Zhou Jiang, Ding Ma, Zhi-Ming Shao
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Abstract

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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HER2 阳性乳腺癌的分子特征和分类为定制治疗策略提供依据。
HER2阳性乳腺癌是一种侵袭性乳腺癌亚型,占所有乳腺癌的15%-20%。最近的研究表明,HER2 阳性乳腺癌是一组对标准治疗方案敏感性不同的异质性疾病。揭示 HER2 阳性乳腺癌的分子异质性可能有助于制定更精确的治疗策略。在这里,我们对HER2阳性乳腺癌队列进行了多组学分析,发现了四种基于转录组的亚型。经典的HER2(HER2-CLA)亚型占样本的28.3%,显示出高ERBB2活化,并能从抗HER2治疗中显著获益。免疫调节(HER2-IM)亚型(20%)具有免疫激活的微环境,可能适合降级治疗和免疫疗法。管腔样(HER2-LUM)亚型(30.6%)具有与激素受体阳性 HER2 阴性乳腺癌相似的分子特征,建议将内分泌治疗和 CDK4/6 抑制剂作为一种潜在的治疗策略。最后,基底/间质样(HER2-BM)亚型(21.1%)对目前的抗HER2双靶向疗法反应不佳,有可能从酪氨酸激酶抑制剂中获益。研究人员在多个队列中进一步探讨了这些亚型的分子特征和临床特点,并在患者来源的类器官模型和患者来源的肿瘤片段模型中验证了所建议的治疗策略的可行性。这项研究阐明了HER2阳性乳腺癌的分子异质性,为更有针对性的治疗铺平了道路。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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