Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer
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 understo...
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BMC
2023-07-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-023-01201-7 |
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| author | 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 Ryu Tae 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 |
| author_facet | 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 Ryu Tae 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 |
| author_sort | Yeon Hee Park |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:15:23Z |
| format | Article |
| id | doaj.art-e43bea5e36154033b3975c0ba6d40d38 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-03-12T22:15:23Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-e43bea5e36154033b3975c0ba6d40d382023-07-23T11:21:40ZengBMCGenome Medicine1756-994X2023-07-0115111810.1186/s13073-023-01201-7Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancerYeon Hee Park0Seock-Ah Im1Kyunghee Park2Ji Wen3Kyung-Hun Lee4Yoon-La Choi5Won-Chul Lee6Ahrum Min7Vinicius Bonato8Seri Park9Sripad Ram10Dae-Won Lee11Ji-Yeon Kim12Su Kyeong Lee13Won-Woo Lee14Jisook Lee15Miso Kim16Hyun Seon Kim17Scott L. Weinrich18Han Suk Ryu19Tae Yong Kim20Stephen Dann21Yu-Jin Kim22Diane R. Fernandez23Jiwon Koh24Shuoguo Wang25Song Yi Park26Shibing Deng27Eric Powell28Rupesh Kanchi Ravi29Jadwiga Bienkowska30Paul A. Rejto31Woong-Yang Park32Zhengyan Kan33Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversitySamsung Genome Institute, Samsung Medical CenterOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityBiostatistics, Pfizer IncDepartment of Health Science and Technology, School of Medicine & SAIHST, Sungkyunkwan UniversityDrug Safety R&D, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineResearch Center for Future Medicine, Samsung Medical CenterSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityPfizer OncologyOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversitySeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityOncology Research & Development, Pfizer IncSeoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul National UniversityBiostatistics, Pfizer IncOncology Research & Development, Pfizer IncOncology Research & Development, Pfizer IncOncology Research & Development, Pfizer IncOncology Research & Development, Pfizer IncDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineOncology Research & Development, Pfizer IncAbstract 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.https://doi.org/10.1186/s13073-023-01201-7Advanced breast cancerDrug resistanceGenomic profileGene expression profilingPalbociclibHomologous recombination repair deficiengy (HRD) |
| spellingShingle | 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 Ryu Tae 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 Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer Genome Medicine Advanced breast cancer Drug resistance Genomic profile Gene expression profiling Palbociclib Homologous recombination repair deficiengy (HRD) |
| title | Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer |
| title_full | Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer |
| title_fullStr | Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer |
| title_full_unstemmed | Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer |
| title_short | Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer |
| title_sort | longitudinal multi omics study of palbociclib resistance in hr positive her2 negative metastatic breast cancer |
| topic | Advanced breast cancer Drug resistance Genomic profile Gene expression profiling Palbociclib Homologous recombination repair deficiengy (HRD) |
| url | https://doi.org/10.1186/s13073-023-01201-7 |
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