HER2 阳性乳腺癌是一种侵袭性亚型，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具有不同敏感性的异质性疾病。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，并确定了四种基于转录组的亚型。经典 HER2 (HER2-CLA) 亚型占样本的 28.3%，显示出高 ERBB2 激活性，并能从抗 HER2 治疗中获益显着。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，表明内分泌治疗和 CDK4/6 抑制剂是一种潜在的治疗策略。最后，基底/间质样 (HER2-BM) 亚型 (21.1%) 对当前抗 HER2 双靶向疗法反应较差，可能会受益于酪氨酸激酶抑制剂。在多个队列中进一步探讨了亚型的分子特征和临床特征，并在患者来源的类器官和患者来源的肿瘤碎片模型中验证了所提出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，并为更有针对性的治疗铺平了道路。

HER2-positive breast cancer is an aggressive subtype that accounts for 15-20% 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. Here, 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 anti-HER2 dual-targeted therapies 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.