Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer

Yeon Hee Park, Seock Ah Im, Kyunghee Park, Ji Wen, Kyung Hun Lee, Yoon La Choi, Won Chul Lee, Ahrum Min, Vinicius Bonato, Seri Park, Sripad Ram, Dae Won Lee, Ji Yeon Kim, Su Kyeong Lee, Won Woo Lee, Jisook Lee, Miso Kim, Hyun Seon Kim, Scott L. Weinrich, Han Suk RyuTae Yong Kim, Stephen Dann, Yu Jin Kim, Diane R. Fernandez, Jiwon Koh, Shuoguo Wang, Song Yi Park, Shibing Deng, Eric Powell, Rupesh Kanchi Ravi, Jadwiga Bienkowska, Paul A. Rejto, Woong Yang Park, Zhengyan Kan

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14 Scopus citations

Abstract

Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2− MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. Methods: Tissue was collected from 89 patients with HR+/HER2− MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. Results: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. Conclusions: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. Trial registration: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

Original languageEnglish
Article number55
JournalGenome Medicine
Volume15
Issue number1
DOIs
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Keywords

  • Advanced breast cancer
  • Drug resistance
  • Gene expression profiling
  • Genomic profile
  • Homologous recombination repair deficiengy (HRD)
  • Palbociclib

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