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

Tim Kong, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Alex Mabry, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Maureen Highkin, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Anthony Z. Wang, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Jeremy Hoog, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Zhanfang Guo, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Adrian Gonzales-Gonzales, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Shana Thomas, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Yingduo Song, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Feng Gao, Division of Public Health Science, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Mateusz Opyrchal, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Lindsay Peterson, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Foluso Ademuyiwa, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Julie Margenthaler, Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Rebecca Aft, Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Katherine Glover-Collins, Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Leslie Nehring, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Yu Tao, Division of Public Health Science, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Souzan Sanati, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Ian S. Hagemann, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Fouad Boulos, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Matthew Holt, Baylor College of Medicine, Houston, TX, USA.
Li Ding, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Wenge Zhu, Department of Biochemistry and Molecular Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Stephen T. Oh, Divison of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Jianxin Wang, Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Agnieszka K. Witkiewicz, Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Erik S. Knudsen, Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Ron Bose, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Jason D. Weber, Divison of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Matthew Goetz, Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
Donald Northfelt, Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ, USA.

Document Type

Journal Article

Publication Date

1-27-2026

Journal

Nature communications

Volume

17

Issue

1

DOI

10.1038/s41467-026-68570-6

Abstract

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 ≤ 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 > 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.

Department

Biochemistry and Molecular Medicine

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