Scholarlink

Background <p>Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor–positive, HER2–negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.</p> Methods <p>Single-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression. BL samples were from CDK4/6i responders (median progression-free survival [mPFS] = 25.5&#xa0;months), while progressors were categorized as early-progressors (EP, mPFS = 3&#xa0;months) and late-progressors (LP, mPFS = 11&#xa0;months). Metastatic sites included liver, pleural effusions, ascites, and bone. InferCNV distinguished tumor cells, and functional analysis utilized the Molecular Signatures Database.</p> Results <p>LP tumors displayed enhanced Myc, EMT, TNF-α, and inflammatory pathways compared to those EP tumors. Samples from BL and LP responders showed increased tumor-infiltrating CD8<sup>+</sup> T cells and natural killer (NK) cells compared to EP non-responders. Notably, despite a high frequency of CD8<sup>+</sup> T cells in responding tumors, a functional analysis revealed significant upregulation of genes associated with stress and apoptosis in proliferative CD4<sup>+</sup> and CD8<sup>+</sup> T cells in BL tumors compared to in EP and LP tumors. These genes, including <i>HSP90</i> and <i>HSPA8</i>, are linked to resistance to PD1/PD-L1 immune checkpoint inhibitors. A ligand-receptor analysis showed enhanced interactions associated with inhibitory T-cell proliferation (SPP1-CD44) and suppression of immune activity (MDK-NCL) in LP tumors. Longitudinal biopsies consistently revealed dynamic NK cell expansion and enhanced cytotoxic T cell activity, alongside upregulation of immune activity inhibition, in LP tumors compared to in BL tumors. Notably, the predictive biomarker panel from BL tumor cells was validated in 2 independent cohorts, where it consistently predicted a significant improvement in mPFS duration in signature-high versus -low groups.</p> Conclusion <p>This study underscores the significance of molecular biomarkers in predicting clinical outcomes to CDK4/6i. Tumor-infiltration CD8<sup>+</sup> T and NK cells may also serve as baseline predictors. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, providing a personalized and effective approach for managing HR+/HER2- mBC and improving patient outcomes.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Single-cell RNA sequencing identifies molecular biomarkers predicting late progression to CDK4/6 inhibition in patients with HR+/HER2- metastatic breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年2月15日

查看全文
  • Linjie Luo,
  • Peng Yang,
  • Sofia Mastoraki,
  • Xiayu Rao,
  • Yan Wang,
  • Nicole M. Kettner,
  • Akshara Singareeka Raghavendra,
  • Debasish Tripathy,
  • Senthil Damodaran,
  • Kelly K. Hunt,
  • Jing Wang,
  • Ziyi Li,
  • Khandan Keyomarsi

摘要

Background

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor–positive, HER2–negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.

Methods

Single-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression. BL samples were from CDK4/6i responders (median progression-free survival [mPFS] = 25.5 months), while progressors were categorized as early-progressors (EP, mPFS = 3 months) and late-progressors (LP, mPFS = 11 months). Metastatic sites included liver, pleural effusions, ascites, and bone. InferCNV distinguished tumor cells, and functional analysis utilized the Molecular Signatures Database.

Results

LP tumors displayed enhanced Myc, EMT, TNF-α, and inflammatory pathways compared to those EP tumors. Samples from BL and LP responders showed increased tumor-infiltrating CD8+ T cells and natural killer (NK) cells compared to EP non-responders. Notably, despite a high frequency of CD8+ T cells in responding tumors, a functional analysis revealed significant upregulation of genes associated with stress and apoptosis in proliferative CD4+ and CD8+ T cells in BL tumors compared to in EP and LP tumors. These genes, including HSP90 and HSPA8, are linked to resistance to PD1/PD-L1 immune checkpoint inhibitors. A ligand-receptor analysis showed enhanced interactions associated with inhibitory T-cell proliferation (SPP1-CD44) and suppression of immune activity (MDK-NCL) in LP tumors. Longitudinal biopsies consistently revealed dynamic NK cell expansion and enhanced cytotoxic T cell activity, alongside upregulation of immune activity inhibition, in LP tumors compared to in BL tumors. Notably, the predictive biomarker panel from BL tumor cells was validated in 2 independent cohorts, where it consistently predicted a significant improvement in mPFS duration in signature-high versus -low groups.

Conclusion

This study underscores the significance of molecular biomarkers in predicting clinical outcomes to CDK4/6i. Tumor-infiltration CD8+ T and NK cells may also serve as baseline predictors. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, providing a personalized and effective approach for managing HR+/HER2- mBC and improving patient outcomes.