Liu Chao, Sun Lisha, Niu Nan, Hou Pengjie, Chen Guanglei, Wang Hao, Zhang Zhan, Jiang Xiaofan, Xu Qianshi, Zhao Yafei, Wang Yimin, Shi Yuan, Liu Mingxin, Yang Yongliang, Qian Wei, Wang Jiandong, Liu Caigang
Cancer Stem Cell and Translation Medicine Lab, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China.
Signal Transduct Target Ther. 2025 Mar 26;10(1):97. doi: 10.1038/s41392-025-02181-3.
Significant heterogeneity exists in hormone receptor (HR)-positive/HER2-positive (HR/HER2) breast cancer, contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens. Overcoming this challenge requires precise molecular classification, which is pivotal for the development of targeted therapies. We conducted molecular typing on a cohort of 211 patients with HR/HER2 breast cancer and performed a comprehensive analysis of the efficacy of various neoadjuvant treatment regimens. Our findings revealed four distinct molecular subtypes, each exhibiting unique characteristics and therapeutic implications. The HER2-enriched subtype, marked by activation of the HER2 signaling and hypoxia-inducible factor 1 (HIF-1) pathway, may benefit from intensified anti-HER2-targeted therapy. Estrogen receptor (ER)-activated subtype demonstrated potential sensitivity to combined therapeutic strategies targeting both ER and HER2 pathways. Characterized by high immune cell infiltration, the immunomodulatory subtype showed sensitivity to HER2-targeted antibody-drug conjugates (ADCs) and promise for immune checkpoint therapy. The highly heterogeneous subtype requires a multifaceted therapeutic approach. Organoid susceptibility assays suggested phosphoinositide 3-kinase inhibitors may be a potential treatment option. These findings underscore the importance of molecular subtyping in HR/HER2 breast cancer, offering a framework for developing precise and personalized treatment strategies. By addressing the heterogeneity of the disease, these approaches have the potential to optimize therapeutic outcomes and improve patient care.
激素受体（HR）阳性/人表皮生长因子受体2（HER2）阳性（HR/HER2）乳腺癌存在显著异质性，导致传统新辅助治疗方案的病理完全缓解率不理想。克服这一挑战需要精确的分子分类，这对于靶向治疗的发展至关重要。我们对211例HR/HER2乳腺癌患者进行了分子分型，并对各种新辅助治疗方案的疗效进行了综合分析。我们的研究结果揭示了四种不同的分子亚型，每种亚型都具有独特的特征和治疗意义。HER2富集亚型以HER2信号通路和缺氧诱导因子1（HIF-1）通路的激活为特征，可能从强化的抗HER2靶向治疗中获益。雌激素受体（ER）激活亚型对靶向ER和HER2通路的联合治疗策略表现出潜在敏感性。免疫调节亚型以高免疫细胞浸润为特征，对HER2靶向抗体药物偶联物（ADC）敏感，有望进行免疫检查点治疗。高度异质性亚型需要多方面的治疗方法。类器官药敏试验表明，磷酸肌醇3激酶抑制剂可能是一种潜在的治疗选择。这些发现强调了分子分型在HR/HER2乳腺癌中的重要性，为制定精确和个性化的治疗策略提供了一个框架。通过解决疾病的异质性，这些方法有可能优化治疗效果并改善患者护理。
