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

Authors

• 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.

APA Citation

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; and Northfelt, Donald, "Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial" (2026). GW Authored Works. Paper 8522.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8522

Department

Biochemistry and Molecular Medicine