ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer
Abstract In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of resea...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-08-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-021-01462-3 |
| _version_ | 1818366728959164416 |
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| author | Jamie O. Brett Laura M. Spring Aditya Bardia Seth A. Wander |
| author_facet | Jamie O. Brett Laura M. Spring Aditya Bardia Seth A. Wander |
| author_sort | Jamie O. Brett |
| collection | DOAJ |
| description | Abstract In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations. |
| first_indexed | 2024-12-13T22:40:47Z |
| format | Article |
| id | doaj.art-2c6f9ef6f6494ce989e2d4f140e20b05 |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-13T22:40:47Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-2c6f9ef6f6494ce989e2d4f140e20b052022-12-21T23:28:51ZengBMCBreast Cancer Research1465-542X2021-08-0123111510.1186/s13058-021-01462-3ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancerJamie O. Brett0Laura M. Spring1Aditya Bardia2Seth A. Wander3Department of Medicine, Massachusetts General HospitalHarvard Medical SchoolHarvard Medical SchoolHarvard Medical SchoolAbstract In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.https://doi.org/10.1186/s13058-021-01462-3Breast cancerHormone receptor/estrogen receptorESR1 mutationResistanceCombinationSERD |
| spellingShingle | Jamie O. Brett Laura M. Spring Aditya Bardia Seth A. Wander ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer Breast Cancer Research Breast cancer Hormone receptor/estrogen receptor ESR1 mutation Resistance Combination SERD |
| title | ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer |
| title_full | ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer |
| title_fullStr | ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer |
| title_full_unstemmed | ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer |
| title_short | ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer |
| title_sort | esr1 mutation as an emerging clinical biomarker in metastatic hormone receptor positive breast cancer |
| topic | Breast cancer Hormone receptor/estrogen receptor ESR1 mutation Resistance Combination SERD |
| url | https://doi.org/10.1186/s13058-021-01462-3 |
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