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<p>CDK4/6 inhibitors (CDK4/6i) improve outcomes for estrogen receptor (ER) positive/HER2-negative breast cancers (BCs), yet intrinsic and acquired resistance exist. Here, we evaluated anastrozole in combination with palbociclib (ANA/PAL) in the NeoPalAna Endocrine-Resistant cohort (NCT01723774). Thirty-four patients with clinical stage II/III ER + /HER2– BCs resistant to standard neoadjuvant endocrine therapy (on-treatment Ki67 &gt; 10%) received neoadjuvant ANA/PAL, with serial biopsies analyzed. The primary endpoint, complete cell cycle arrest (CCCA; Ki67<sub>C1D15</sub> ≤ 2.7% at cycle 1, day 15), was achieved in 57.6% of patients (95%CI: 39.2–74.5%). Resistance to ANA/PAL (Ki67<sub>C1D15</sub> &gt; 10%) was associated with higher pre-treatment tumor grade, Ki67, and specific PAM50 subtypes. Resistant tumors demonstrated reduced ER signaling and upregulation of cell cycle, mTOR, interferon, JAK/STAT, and immune checkpoints. Additionally, a 33-gene signature that predicted neoadjuvant Ki67 response to ANA/PAL was prognostic in a metastatic validation cohort. These findings underscore dysregulated oncogenic pathways as potential resistance mechanisms and biomarkers of response to CDK4/6i.</p>

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Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月27日

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  • Tim Kong,
  • Alex Mabry,
  • Maureen Highkin,
  • Anthony Z. Wang,
  • Jeremy Hoog,
  • Zhanfang Guo,
  • Adrian Gonzales-Gonzales,
  • Shana Thomas,
  • Yingduo Song,
  • Feng Gao,
  • Mateusz Opyrchal,
  • Lindsay Peterson,
  • Foluso Ademuyiwa,
  • Julie Margenthaler,
  • Rebecca Aft,
  • Katherine Glover-Collins,
  • Leslie Nehring,
  • Yu Tao,
  • Souzan Sanati,
  • Ian S. Hagemann,
  • Fouad Boulos,
  • Matthew Holt,
  • Li Ding,
  • Wenge Zhu,
  • Stephen T. Oh,
  • Jianxin Wang,
  • Agnieszka K. Witkiewicz,
  • Erik S. Knudsen,
  • Ron Bose,
  • Jason D. Weber,
  • Matthew Goetz,
  • Donald Northfelt,
  • Jingqin Luo,
  • Cynthia X. Ma

摘要

CDK4/6 inhibitors (CDK4/6i) improve outcomes for estrogen receptor (ER) positive/HER2-negative breast cancers (BCs), yet intrinsic and acquired resistance exist. Here, we evaluated anastrozole in combination with palbociclib (ANA/PAL) in the NeoPalAna Endocrine-Resistant cohort (NCT01723774). Thirty-four patients with clinical stage II/III ER + /HER2– BCs resistant to standard neoadjuvant endocrine therapy (on-treatment Ki67 > 10%) received neoadjuvant ANA/PAL, with serial biopsies analyzed. The primary endpoint, complete cell cycle arrest (CCCA; Ki67C1D15 ≤ 2.7% at cycle 1, day 15), was achieved in 57.6% of patients (95%CI: 39.2–74.5%). Resistance to ANA/PAL (Ki67C1D15 > 10%) was associated with higher pre-treatment tumor grade, Ki67, and specific PAM50 subtypes. Resistant tumors demonstrated reduced ER signaling and upregulation of cell cycle, mTOR, interferon, JAK/STAT, and immune checkpoints. Additionally, a 33-gene signature that predicted neoadjuvant Ki67 response to ANA/PAL was prognostic in a metastatic validation cohort. These findings underscore dysregulated oncogenic pathways as potential resistance mechanisms and biomarkers of response to CDK4/6i.