Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial
Abstract
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 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.
Article Details
Authors (34)
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