Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer
Abstract Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-09-01
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| Series: | npj Breast Cancer |
| Online Access: | https://doi.org/10.1038/s41523-023-00578-3 |
| _version_ | 1797451976370290688 |
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| author | Jun Ma Jack Junjie Chan Ching Han Toh Yoon-Sim Yap |
| author_facet | Jun Ma Jack Junjie Chan Ching Han Toh Yoon-Sim Yap |
| author_sort | Jun Ma |
| collection | DOAJ |
| description | Abstract Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression treatment regimens and their sequencing continue to evolve in the rapidly changing treatment landscape. In this review, we summarize the mechanisms of resistance to ET and CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators and activation of alternative signaling pathways. Recent clinical trials have been directed at the targets and pathways implicated, including estrogen and androgen receptors, PI3K/AKT/mTOR and MAPK pathways, tyrosine kinase receptors such as FGFR and HER2, homologous recombination repair pathway, other components of the cell cycle and cell death. We describe the findings from these clinical trials using small molecule inhibitors, antibody–drug conjugates and immunotherapy, providing insights into how these novel strategies may circumvent treatment resistance, and discuss how some have not translated into clinical benefit. The challenges posed by tumor heterogeneity, adaptive rewiring of signaling pathways and dose-limiting toxicities underscore the need to elucidate the latest tumor biology in each patient, and develop treatments with improved therapeutic index in the era of precision medicine. |
| first_indexed | 2024-03-09T15:02:11Z |
| format | Article |
| id | doaj.art-957801ca10c349868fc8d6dcbe7b36e7 |
| institution | Directory Open Access Journal |
| issn | 2374-4677 |
| language | English |
| last_indexed | 2024-03-09T15:02:11Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Breast Cancer |
| spelling | doaj.art-957801ca10c349868fc8d6dcbe7b36e72023-11-26T13:53:00ZengNature Portfolionpj Breast Cancer2374-46772023-09-019111610.1038/s41523-023-00578-3Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancerJun Ma0Jack Junjie Chan1Ching Han Toh2Yoon-Sim Yap3Division of Medical Oncology, National Cancer Centre SingaporeDivision of Medical Oncology, National Cancer Centre SingaporeDivision of Medical Oncology, National Cancer Centre SingaporeDivision of Medical Oncology, National Cancer Centre SingaporeAbstract Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression treatment regimens and their sequencing continue to evolve in the rapidly changing treatment landscape. In this review, we summarize the mechanisms of resistance to ET and CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators and activation of alternative signaling pathways. Recent clinical trials have been directed at the targets and pathways implicated, including estrogen and androgen receptors, PI3K/AKT/mTOR and MAPK pathways, tyrosine kinase receptors such as FGFR and HER2, homologous recombination repair pathway, other components of the cell cycle and cell death. We describe the findings from these clinical trials using small molecule inhibitors, antibody–drug conjugates and immunotherapy, providing insights into how these novel strategies may circumvent treatment resistance, and discuss how some have not translated into clinical benefit. The challenges posed by tumor heterogeneity, adaptive rewiring of signaling pathways and dose-limiting toxicities underscore the need to elucidate the latest tumor biology in each patient, and develop treatments with improved therapeutic index in the era of precision medicine.https://doi.org/10.1038/s41523-023-00578-3 |
| spellingShingle | Jun Ma Jack Junjie Chan Ching Han Toh Yoon-Sim Yap Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer npj Breast Cancer |
| title | Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer |
| title_full | Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer |
| title_fullStr | Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer |
| title_full_unstemmed | Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer |
| title_short | Emerging systemic therapy options beyond CDK4/6 inhibitors for hormone receptor-positive HER2-negative advanced breast cancer |
| title_sort | emerging systemic therapy options beyond cdk4 6 inhibitors for hormone receptor positive her2 negative advanced breast cancer |
| url | https://doi.org/10.1038/s41523-023-00578-3 |
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