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

• Published in: Genome medicine 2023-07, Vol.15 (1), p.55-55, Article 55
• Main Authors: Park, Yeon Hee, Im, Seock-Ah, Park, Kyunghee, Wen, Ji, Lee, Kyung-Hun, Choi, Yoon-La, Lee, Won-Chul, Min, Ahrum, Bonato, Vinicius, Park, Seri, Ram, Sripad, Lee, Dae-Won, Kim, Ji-Yeon, Lee, Su Kyeong, Lee, Won-Woo, Lee, Jisook, Kim, Miso, Kim, Hyun Seon, Weinrich, Scott L, Ryu, Han Suk, Kim, Tae Yong, Dann, Stephen, Kim, Yu-Jin, Fernandez, Diane R, Koh, Jiwon, Wang, Shuoguo, Park, Song Yi, Deng, Shibing, Powell, Eric, Ravi, Rupesh Kanchi, Bienkowska, Jadwiga, Rejto, Paul A, Park, Woong-Yang, Kan, Zhengyan
• Format: Article
• Language: English
• Subjects: Advanced breast cancer; Analysis; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Aromatase; Biomarkers; Biopsy; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Care and treatment; Cell cycle; Cloning; Cyclin-dependent kinase 4; Cyclin-dependent kinases; Development and progression; Drug resistance; Endocrine therapy; ErbB-2 protein; Estrogen; Estrogen receptors; Estrogens - therapeutic use; Female; Fulvestrant; Gene expression profiling; Genomes; Genomic profile; Genomics; Growth factors; Homologous recombination repair deficiengy (HRD); Humans; Kinases; Medical centers; Metastases; Metastasis; Molecular modelling; Multiomics; Mutation; Oncology, Experimental; Palbociclib; Pathology; Patients; Prognosis; PTEN protein; Receptor, ErbB-2 - analysis; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - therapeutic use; Receptors, Estrogen - analysis; Receptors, Estrogen - genetics; Receptors, Estrogen - therapeutic use; Retinoblastoma; RNA; RNA sequencing; Transcriptomics; Tumor proteins; Tumors
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-023-01201-7

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