Ji Fei, Chen Xianzhe, Yang Ciqiu, Zhang Liulu, Yang Mei, Li Jieqing, Gao Hongfei, Zhu Teng, Cheng Minyi, Chen Yitian, Peng Hao, Wang Jin, Li Weiwei, Huang Zhan, Zhu Changbin, Wang Kun
Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Department of Medicine, Amoy Diagnostics Co., Ltd., Xiamen, 361026, China.
Sci China Life Sci. 2025 Oct;68(10):2934-2949. doi: 10.1007/s11427-024-2809-y. Epub 2025 Jul 24.
Neoadjuvant therapies are essential for managing high-risk early-stage breast cancer, but their effectiveness is limited, necessitating the exploration of the optimal neoadjuvant treatment strategy based on innovative subtypes. Given the heterogeneity inherent in breast cancer, there is growing need for identifying novel molecular subtypes predictive of treatment response through multi-omic analyses. A comprehensive analysis was performed using data from 142 high-risk early breast cancer patients, including genomic, transcriptomic, proteomic, and phosphoproteomic profiles. The molecular subtypes were explored based on the biological characteristics and responses to neoadjuvant treatments. The results were also validated in the TCGA-breast cancer cohort and external dataset. Three molecular subtypes were identified, each associated with different optimal treatment strategies. The immune-activated (IA) subtype displayed a significantly higher pathologic complete response (pCR) rate when treated with platinum-based neoadjuvant regimens, and exhibited heightened immune cell infiltration. The vesicular transport pathway-activated (VT) subtype, characterized by vesicular transport pathway activation, showed a favorable pCR rate to anthracycline-based neoadjuvant chemotherapy. In contrast, the kinase activation (KA) subtype demonstrated limited responsiveness to both platinum and anthracycline-based treatments and featured enrichment in non-canonical TGF-β signaling, MAPK/ATM kinase activation, and angiogenic signatures. A seven-gene classifier linked to non-canonical TGF-β signaling was created to identify the KA subtype, achieving an area under the curve value of 90%. The drug vulnerability of breast cancer cells within the KA subtype indicated potential therapeutic effectiveness of ATR/ATM inhibitors and anti-angiogenic agents. This study defined three novel molecular subtypes in high-risk early-stage breast cancer patients and provided optimal therapeutic treatment strategies based on these subtypes. Therefore, important insights about intrinsic biological properties can form the basis for new cancer treatment strategies.
新辅助治疗对于管理高危早期乳腺癌至关重要，但其有效性有限，因此有必要探索基于创新亚型的最佳新辅助治疗策略。鉴于乳腺癌固有的异质性，越来越需要通过多组学分析来识别预测治疗反应的新型分子亚型。我们使用来自142例高危早期乳腺癌患者的数据进行了综合分析，包括基因组、转录组、蛋白质组和磷酸蛋白质组图谱。基于生物学特征和对新辅助治疗的反应探索分子亚型。结果也在TCGA乳腺癌队列和外部数据集中得到验证。确定了三种分子亚型，每种亚型都与不同的最佳治疗策略相关。免疫激活（IA）亚型在接受铂类新辅助治疗方案时显示出显著更高的病理完全缓解（pCR）率，并表现出免疫细胞浸润增加。以囊泡运输途径激活为特征的囊泡运输途径激活（VT）亚型对基于蒽环类的新辅助化疗显示出良好的pCR率。相比之下，激酶激活（KA）亚型对铂类和基于蒽环类的治疗均显示出有限的反应性，其特征是在非经典TGF-β信号、MAPK/ATM激酶激活和血管生成特征方面富集。创建了一个与非经典TGF-β信号相关的七基因分类器来识别KA亚型，曲线下面积值达到90%。KA亚型内乳腺癌细胞的药物敏感性表明ATR/ATM抑制剂和抗血管生成药物具有潜在的治疗效果。本研究定义了高危早期乳腺癌患者的三种新型分子亚型，并基于这些亚型提供了最佳治疗策略。因此，关于内在生物学特性的重要见解可以为新的癌症治疗策略奠定基础。
