Nature communications · 2026
Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial.
СтатьяКлиническое исследование II фазыНазвание и аннотация: Перевод в очереди
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Kong Tim, Mabry Alex, Highkin Maureen, Wang Anthony Z, Hoog Jeremy, Guo Zhanfang, Gonzales-Gonzales Adrian, Thomas Shana, Song Yingduo, Gao Feng, Opyrchal Mateusz, Peterson Lindsay, Ademuyiwa Foluso, Margenthaler Julie, Aft Rebecca, Glover-Collins Katherine, Nehring Leslie, Tao Yu, Sanati Souzan, Hagemann Ian S, Boulos Fouad, Holt Matthew, Ding Li, Zhu Wenge, Oh Stephen T, Wang Jianxin, Witkiewicz Agnieszka K, Knudsen Erik S, Bose Ron, Weber Jason D, Goetz Matthew, Northfelt Donald, Luo Jingqin, Ma Cynthia X
Аннотация
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.