Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial
Palbociclib plus anastrozole achieves a complete cell‑cycle arrest (CCCA) rate of 57.6 % (95 % CI 39.2‑74.5 %) as a neoadjuvant therapy for endocrine‑resistant ER +/HER2‑ breast cancer, with distinct molecular signatures that predict response and resistance.
CDK4/6 inhibitors improve outcomes for estrogen receptor (ER) positive/HER2‑negative breast cancers (BCs), yet intrinsic and acquired resistance exist. This phase 2 NeoPalAna Endocrine‑Resistant cohort trial enrolled 34 patients with clinical stage II/III ER+/HER2‑ BCs resistant to standard neoadjuvant endocrine therapy. Patients received neoadjuvant anastrozole plus palbociclib with serial biopsies. The primary endpoint (complete cell‑cycle arrest, Ki67_C1D15 ≤ 2.7 %) was achieved in 57.6 % of evaluable patients. Resistant tumors displayed higher pre‑treatment tumor grade, Ki67, and specific PAM50 subtypes. Molecular profiling revealed that resistant tumors had reduced ER signaling and up‑regulation of cell‑cycle, mTOR, interferon, JAK/STAT, and immune‑checkpoint pathways. A 33‑gene signature predictive of Ki67 response was prognostic in a metastatic validation cohort, underscoring dysregulated oncogenic pathways as potential resistance mechanisms and biomarkers of response to CDK4/6 inhibitors.
These findings identify actionable biomarkers that can guide personalized neoadjuvant therapy for endocrine‑resistant ER+/HER2‑ breast cancer, potentially improving clinical outcomes by predicting which patients will benefit from CDK4/6 inhibition.
Evidence level: Megerősített klinikai bizonyíték. Több vagy erősebb humán vizsgálat támogatja.
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