激素受体阳性（HR）/人表皮生长因子受体2阴性（HER2-）乳腺癌是最常见的乳腺癌类型，其中内分泌治疗耐药和远处复发仍然是未解决的挑战。迫切需要准确的分子分类来指导精准治疗。我们建立了一个由 579 名 HR /HER2- 乳腺癌患者组成的大规模多组学队列，并确定了以下四种分子亚型：典型管腔型、免疫原性型、增殖型和受体酪氨酸激酶 (RTK) 驱动型。这四种亚型的肿瘤表现出不同的生物学和临床特征，表明亚型特异性的治疗策略。 RTK 驱动的亚型的特点是 RTK 通路的激活，并与不良结果相关。免疫原性亚型具有丰富的免疫细胞，可以从免疫检查点治疗中受益。此外，我们开发了卷积神经网络模型来根据数字病理学区分这些亚型，以实现潜在的临床转化。分子分类提供了对分子异质性的见解，并强调了 HR /HER2- 乳腺癌精准治疗的潜力。© 2023。作者获得 Springer Nature America, Inc. 的独家许可。

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR+/HER2- breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR+/HER2- breast cancer.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.