Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial
- 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
2026-01-27
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; Ki67 C1D15 ≤ 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 C1D15 > 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.