Ou-Yang Yang, Lin Caijin, Xie Yifan, Song Xiaoqing, Jiang Yi-Zhou
Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Chin J Cancer Res. 2025 Jun 30;37(3):316-336. doi: 10.21147/j.issn.1000-9604.2025.03.03.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype that lacks targeted therapies, leading to a poorer prognosis. However, some patients achieve long-term recurrence-free survival (RFS), offering valuable insights into tumor biology and potential treatment strategies.
We conducted a comprehensive multi-omics analysis of 132 patients with American Joint Committee on Cancer (AJCC) stage III TNBC, comprising 36 long-term survivors (RFS≥8 years), 62 moderate-term survivors (RFS: 3-8 years), and 34 short-term survivors (RFS<3 years). Analyses investigated clinicopathological factors, whole-exome sequencing, germline mutations, copy number alterations (CNAs), RNA sequences, and metabolomic profiles.
Long-term survivors exhibited fewer metastatic regional lymph nodes, along with tumors showing reduced stromal fibrosis and lower Ki67 index. Molecularly, these tumors exhibited multiple alterations in genes related to homologous recombination repair, with higher frequencies of germline mutations and somatic CNAs. Additionally, tumors from long-term survivors demonstrated significant downregulation of the RTK-RAS signaling pathway. Metabolomic profiling revealed decreased levels of lipids and carbohydrate, particularly those involved in glycerophospholipid, fructose, and mannose metabolism, in long-term survival group. Multivariate Cox analysis identified fibrosis [hazard ratio (HR): 12.70, 95% confidence interval (95% CI): 2.19-73.54, P=0.005] and copy number loss/deletion (HR: 0.22, 95% CI: 0.06-0.83, P=0.026) as independent predictors of RFS. Higher fructose/mannose metabolism was associated with worse overall survival (HR: 1.30, 95% CI: 1.01-1.68, P=0.045). Our findings emphasize the association between biological determinants and prolonged survival in patients with TNBC.
Our study systematically identified the key molecular and metabolic features associated with prolonged survival in AJCC stage III TNBC, suggesting potential therapeutic targets to improve patient outcomes.
三阴性乳腺癌（TNBC）是一种侵袭性很强的亚型，缺乏靶向治疗方法，预后较差。然而，一些患者实现了长期无复发生存（RFS），这为肿瘤生物学和潜在治疗策略提供了有价值的见解。
我们对132例美国癌症联合委员会（AJCC）III期TNBC患者进行了全面的多组学分析，其中包括36例长期生存者（RFS≥8年）、62例中期生存者（RFS：3 - 8年）和34例短期生存者（RFS<3年）。分析调查了临床病理因素、全外显子测序、种系突变、拷贝数改变（CNA）、RNA序列和代谢组学谱。
长期生存者的转移性区域淋巴结较少，肿瘤的间质纤维化减少，Ki67指数较低。在分子水平上，这些肿瘤在与同源重组修复相关的基因中表现出多种改变，种系突变和体细胞CNA的频率较高。此外，长期生存者的肿瘤显示RTK - RAS信号通路显著下调。代谢组学分析显示，长期生存组中脂质和碳水化合物水平降低，特别是那些参与甘油磷脂、果糖和甘露糖代谢的物质。多变量Cox分析确定纤维化[风险比（HR）：12.70，95%置信区间（95%CI）：2.19 - 73.54，P = 0.005]和拷贝数丢失/缺失（HR：0.22，95%CI：0.06 - 0.83，P = 0.026）是RFS的独立预测因素。较高的果糖/甘露糖代谢与较差的总生存相关（HR：1.30，95%CI：1.01 - 1.68，P = 0.045）。我们的研究结果强调了TNBC患者生物学决定因素与延长生存之间的关联。
我们的研究系统地确定了与AJCC III期TNBC延长生存相关的关键分子和代谢特征，提示了改善患者预后的潜在治疗靶点。
