Determinants of response to CDK4/6 inhibitors in the real-world setting
Abstract Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combi...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00438-0 |
| _version_ | 1827724916144734208 |
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| author | Agnieszka K. Witkiewicz Emily Schultz Jianxin Wang Deanna Hamilton Ellis Levine Tracey O’Connor Erik S. Knudsen |
| author_facet | Agnieszka K. Witkiewicz Emily Schultz Jianxin Wang Deanna Hamilton Ellis Levine Tracey O’Connor Erik S. Knudsen |
| author_sort | Agnieszka K. Witkiewicz |
| collection | DOAJ |
| description | Abstract Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). Most of these patients had modified Scarff–Bloom–Richardson (SBR) scores, and ER, HER2, and PR immunohistochemistry. Both the SBR score and lack of PR expression were associated with shorter PFS in patients treated with AI combinations and remained significant in multivariate analyses (HR = 3.86, p = 0.008). Gene expression analyses indicated substantial changes in cell cycle and estrogen receptor signaling during the course of treatment. Furthermore, gene expression-based subtyping indicated that predominant subtypes changed with treatment and progression. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations when assessed in the pretreatment biopsies; however, they were not associated with OS. Using unbiased approaches, cell cycle-associated gene sets were strongly associated with shorter PFS in pretreatment biopsies irrespective of endocrine therapy. Estrogen receptor signaling gene sets were associated with longer PFS particularly in the AI-treated cohort. Together, these data suggest that there are distinct pathological and biological features of HR+/HER2− breast cancer associated with response to CDK4/6 inhibitors. Clinical trial registration number: NCT04526587. |
| first_indexed | 2024-03-10T22:22:13Z |
| format | Article |
| id | doaj.art-5de605e33d5e4dbfb69355f793daa911 |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-10T22:22:13Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-5de605e33d5e4dbfb69355f793daa9112023-11-19T12:14:14ZengNature Portfolionpj Precision Oncology2397-768X2023-09-017111710.1038/s41698-023-00438-0Determinants of response to CDK4/6 inhibitors in the real-world settingAgnieszka K. Witkiewicz0Emily Schultz1Jianxin Wang2Deanna Hamilton3Ellis Levine4Tracey O’Connor5Erik S. Knudsen6Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterDepartment of Medicine, Roswell Park Comprehensive Cancer CenterDepartment of Medicine, Roswell Park Comprehensive Cancer CenterDepartment of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer CenterAbstract Despite widespread use and a known mechanism of action for CDK4/6 inhibitors in combination with endocrine therapy, features of disease evolution and determinants of therapeutic response in the real-world setting remain unclear. Here, a cohort of patients treated with standard-of-care combination regimens was utilized to explore features of disease and determinants of progression-free survival (PFS) and overall survival (OS). In this cohort of 280 patients, >90% of patients were treated with palbociclib in combination with either an aromatase inhibitor (AI) or fulvestrant (FUL). Most of these patients had modified Scarff–Bloom–Richardson (SBR) scores, and ER, HER2, and PR immunohistochemistry. Both the SBR score and lack of PR expression were associated with shorter PFS in patients treated with AI combinations and remained significant in multivariate analyses (HR = 3.86, p = 0.008). Gene expression analyses indicated substantial changes in cell cycle and estrogen receptor signaling during the course of treatment. Furthermore, gene expression-based subtyping indicated that predominant subtypes changed with treatment and progression. The luminal B, HER2, and basal subtypes exhibited shorter PFS in CDK4/6 inhibitor combinations when assessed in the pretreatment biopsies; however, they were not associated with OS. Using unbiased approaches, cell cycle-associated gene sets were strongly associated with shorter PFS in pretreatment biopsies irrespective of endocrine therapy. Estrogen receptor signaling gene sets were associated with longer PFS particularly in the AI-treated cohort. Together, these data suggest that there are distinct pathological and biological features of HR+/HER2− breast cancer associated with response to CDK4/6 inhibitors. Clinical trial registration number: NCT04526587.https://doi.org/10.1038/s41698-023-00438-0 |
| spellingShingle | Agnieszka K. Witkiewicz Emily Schultz Jianxin Wang Deanna Hamilton Ellis Levine Tracey O’Connor Erik S. Knudsen Determinants of response to CDK4/6 inhibitors in the real-world setting npj Precision Oncology |
| title | Determinants of response to CDK4/6 inhibitors in the real-world setting |
| title_full | Determinants of response to CDK4/6 inhibitors in the real-world setting |
| title_fullStr | Determinants of response to CDK4/6 inhibitors in the real-world setting |
| title_full_unstemmed | Determinants of response to CDK4/6 inhibitors in the real-world setting |
| title_short | Determinants of response to CDK4/6 inhibitors in the real-world setting |
| title_sort | determinants of response to cdk4 6 inhibitors in the real world setting |
| url | https://doi.org/10.1038/s41698-023-00438-0 |
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