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Background <p>Adding immunotherapy to chemotherapy can modestly improve the pathological complete response (pCR) rate in triple-negative breast cancer (TNBC), while our previous NeoSAC study demonstrated that combining anti-angiogenic therapy can further enhance pCR. However, research on the mechanisms underlying the efficacy differences and biomarker comparisons across these treatment regimens remains insufficient.</p> Patients and methods <p>Female TNBC patients were consecutively enrolled into three groups: chemotherapy (chemo), chemo-immunotherapy (chemo-ICI), and chemo-immunotherapy-anti-angiogenesis (chemo-ICI-AA, from our NeoSAC study, NCT04722718). Efficacy and safety were compared, with RNA sequencing and immune microenvironment analyses conducted to explore mechanisms of efficacy differences and identify potential biomarkers.</p> Results <p>The total pCR rates in the chemo, chemo-ICI, and chemo-ICI-AA groups were 43.3%, 60.0%, and 72.7%, respectively. Baseline immune profiles were similar across groups, with comparable stromal, immune, and GEP scores. In the chemo-ICI-AA group, higher CD8 + T cells, TH1 cells, and TIL infiltration in pCR patients suggested their potential as biomarkers. Enhanced cytolytic activity, pro-inflammatory pathways, T-cell costimulation, and oxeiptosis correlated with higher pCR rates in the chemo-ICI-AA group. Notably, oxeiptosis has emerged as a potential predictor of treatment response, especially in pCR patients from the chemo-ICI and chemo-ICI-AA groups. Additionally, ALK (<i>p</i> = 0.017) and ATP6V1C2 (<i>p</i> = 0.036) were identified as significant genes in the chemo-ICI-AA pCR group, with predictive value for pCR outcomes.</p> Conclusion <p>Adding immunotherapy and anti-angiogenic therapy to chemotherapy progressively increased the pCR rate. We emphasized the critical role of differentially expressed genes and immune microenvironment changes in predicting treatment outcomes.</p>

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Transcriptomic and microenvironment characteristics of triple-negative breast cancer under three different neoadjuvant treatment regimens

  • 期刊论文

  • 发表日期：

    2025年8月27日

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  • Zhilin Liu,
  • Zhen Liu,
  • Miaozhou Wang,
  • Yaobang Liu,
  • Xiaofeng Zhou,
  • Yongxin Li,
  • Zijun Zhu,
  • Jinming Li,
  • Jingqi Han,
  • Yujin Hou,
  • Bowen Zhao,
  • Weiwei Zhang,
  • Fuxing Zhao,
  • Dengfeng Ren,
  • Zitao Li,
  • Yongzhi Chen,
  • Shifen Huang,
  • Mengting Da,
  • Xiaoyan Ma,
  • Xiaofang Ma,
  • Ronghua Wang,
  • Qiuxia Dong,
  • Liang Cui,
  • Jing Bai,
  • Guoshuang Shen,
  • Jiuda Zhao

摘要

Background

Adding immunotherapy to chemotherapy can modestly improve the pathological complete response (pCR) rate in triple-negative breast cancer (TNBC), while our previous NeoSAC study demonstrated that combining anti-angiogenic therapy can further enhance pCR. However, research on the mechanisms underlying the efficacy differences and biomarker comparisons across these treatment regimens remains insufficient.

Patients and methods

Female TNBC patients were consecutively enrolled into three groups: chemotherapy (chemo), chemo-immunotherapy (chemo-ICI), and chemo-immunotherapy-anti-angiogenesis (chemo-ICI-AA, from our NeoSAC study, NCT04722718). Efficacy and safety were compared, with RNA sequencing and immune microenvironment analyses conducted to explore mechanisms of efficacy differences and identify potential biomarkers.

Results

The total pCR rates in the chemo, chemo-ICI, and chemo-ICI-AA groups were 43.3%, 60.0%, and 72.7%, respectively. Baseline immune profiles were similar across groups, with comparable stromal, immune, and GEP scores. In the chemo-ICI-AA group, higher CD8 + T cells, TH1 cells, and TIL infiltration in pCR patients suggested their potential as biomarkers. Enhanced cytolytic activity, pro-inflammatory pathways, T-cell costimulation, and oxeiptosis correlated with higher pCR rates in the chemo-ICI-AA group. Notably, oxeiptosis has emerged as a potential predictor of treatment response, especially in pCR patients from the chemo-ICI and chemo-ICI-AA groups. Additionally, ALK (p = 0.017) and ATP6V1C2 (p = 0.036) were identified as significant genes in the chemo-ICI-AA pCR group, with predictive value for pCR outcomes.

Conclusion

Adding immunotherapy and anti-angiogenic therapy to chemotherapy progressively increased the pCR rate. We emphasized the critical role of differentially expressed genes and immune microenvironment changes in predicting treatment outcomes.