TY - JOUR
T1 - Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer
T2 - a phase 2 trial
AU - Kong, Tim
AU - Mabry, Alex
AU - Highkin, Maureen
AU - Wang, Anthony Z.
AU - Hoog, Jeremy
AU - Guo, Zhanfang
AU - Gonzales-Gonzales, Adrian
AU - Thomas, Shana
AU - Song, Yingduo
AU - Gao, Feng
AU - Opyrchal, Mateusz
AU - Peterson, Lindsay
AU - Ademuyiwa, Foluso
AU - Margenthaler, Julie
AU - Aft, Rebecca
AU - Glover-Collins, Katherine
AU - Nehring, Leslie
AU - Tao, Yu
AU - Sanati, Souzan
AU - Hagemann, Ian S.
AU - Boulos, Fouad
AU - Holt, Matthew
AU - Ding, Li
AU - Zhu, Wenge
AU - Oh, Stephen T.
AU - Wang, Jianxin
AU - Witkiewicz, Agnieszka K.
AU - Knudsen, Erik S.
AU - Bose, Ron
AU - Weber, Jason D.
AU - Goetz, Matthew
AU - Northfelt, Donald
AU - Luo, Jingqin
AU - Ma, Cynthia X.
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/12
Y1 - 2026/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105028703227
U2 - 10.1038/s41467-026-68570-6
DO - 10.1038/s41467-026-68570-6
M3 - Article
C2 - 41593097
AN - SCOPUS:105028703227
SN - 2041-1723
VL - 17
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 949
ER -