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

Genome Medicine

Research

Shibing Deng¹  Vinicius Bonato¹  Seri Park²  Ji-Yeon Kim³  Yeon Hee Park⁴  Yoon-La Choi⁴  Woong-Yang Park⁵  Sripad Ram⁶  Ji Wen⁷  Stephen Dann⁷  Zhengyan Kan⁷  Diane R. Fernandez⁷  Eric Powell⁷  Scott L. Weinrich⁷  Rupesh Kanchi Ravi⁷  Jisook Lee⁷  Shuoguo Wang⁷  Paul A. Rejto⁷  Won-Chul Lee⁷  Jadwiga Bienkowska⁷  Hyun Seon Kim⁸  Su Kyeong Lee⁹  Kyunghee Park^1,10  Seock-Ah Im^1,11  Kyung-Hun Lee^1,11  Ahrum Min^1,11  Song Yi Park^1,11  Miso Kim^1,11  Tae Yong Kim^1,11  Han Suk Ryu^1,11  Won-Woo Lee^1,11  Jiwon Koh^1,11  Dae-Won Lee^1,11  Yu-Jin Kim^1,11 

[1] Biostatistics, Pfizer Inc, San Diego, CA, USA;Department of Health Science and Technology, School of Medicine & SAIHST, Sungkyunkwan University, Seoul, Republic of Korea;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;Department of Health Science and Technology, School of Medicine & SAIHST, Sungkyunkwan University, Seoul, Republic of Korea;Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;Department of Health Science and Technology, School of Medicine & SAIHST, Sungkyunkwan University, Seoul, Republic of Korea;Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea;Drug Safety R&D, Pfizer Inc, San Diego, CA, USA;Oncology Research & Development, Pfizer Inc, San Diego, CA, USA;Pfizer Oncology, Seoul, Republic of Korea;Research Center for Future Medicine, Samsung Medical Center, Seoul, Republic of Korea;Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea;Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University, Seoul, Republic of Korea;

关键词: Advanced breast cancer;    Drug resistance;    Genomic profile;    Gene expression profiling;    Palbociclib;    Homologous recombination repair deficiengy (HRD);   

DOI  :  10.1186/s13073-023-01201-7

 received in 2022-10-24, accepted in 2023-06-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCyclin-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.MethodsTissue 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.ResultsNovel 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.ConclusionsWe identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET.Trial registrationClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

【 授权许可】

CC BY   
© The Author(s) 2023

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