Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies
Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER + breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/126730 |
| _version_ | 1826213187125510144 |
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| author | Nayar, Utthara Cohen, Ofir Kapstad, Christian Cuoco, Michael S. Waks, Adrienne G. Wander, Seth A. Painter, Corrie Freeman, Samuel Persky, Nicole S. Marini, Lori Helvie, Karla Oliver, Nelly Rozenblatt-Rosen, Orit Ma, Cynthia X. Regev, Aviv Winer, Eric P. Lin, Nancy U. Wagle, Nikhil |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Nayar, Utthara Cohen, Ofir Kapstad, Christian Cuoco, Michael S. Waks, Adrienne G. Wander, Seth A. Painter, Corrie Freeman, Samuel Persky, Nicole S. Marini, Lori Helvie, Karla Oliver, Nelly Rozenblatt-Rosen, Orit Ma, Cynthia X. Regev, Aviv Winer, Eric P. Lin, Nancy U. Wagle, Nikhil |
| author_sort | Nayar, Utthara |
| collection | MIT |
| description | Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER + breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25–30% of people treated with aromatase inhibitors 1–4 , knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER + metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as—in contrast to ER mutations—resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib. |
| first_indexed | 2024-09-23T15:45:02Z |
| format | Article |
| id | mit-1721.1/126730 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:45:02Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1267302022-09-29T15:55:56Z Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies Nayar, Utthara Cohen, Ofir Kapstad, Christian Cuoco, Michael S. Waks, Adrienne G. Wander, Seth A. Painter, Corrie Freeman, Samuel Persky, Nicole S. Marini, Lori Helvie, Karla Oliver, Nelly Rozenblatt-Rosen, Orit Ma, Cynthia X. Regev, Aviv Winer, Eric P. Lin, Nancy U. Wagle, Nikhil Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER + breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25–30% of people treated with aromatase inhibitors 1–4 , knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER + metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as—in contrast to ER mutations—resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib. 2020-08-21T22:21:59Z 2020-08-21T22:21:59Z 2018-12 2017-10 2020-08-20T17:16:13Z Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 https://hdl.handle.net/1721.1/126730 Nayar, Utthara et al. "Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies." Nature Genetics 51, 2 (December 2018): 207–216 © 2018 The Author(s) en http://dx.doi.org/10.1038/s41588-018-0287-5 Nature Genetics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC Prof. Regev via Courtney Crummett |
| spellingShingle | Nayar, Utthara Cohen, Ofir Kapstad, Christian Cuoco, Michael S. Waks, Adrienne G. Wander, Seth A. Painter, Corrie Freeman, Samuel Persky, Nicole S. Marini, Lori Helvie, Karla Oliver, Nelly Rozenblatt-Rosen, Orit Ma, Cynthia X. Regev, Aviv Winer, Eric P. Lin, Nancy U. Wagle, Nikhil Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies |
| title | Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies |
| title_full | Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies |
| title_fullStr | Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies |
| title_full_unstemmed | Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies |
| title_short | Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor–directed therapies |
| title_sort | acquired her2 mutations in er metastatic breast cancer confer resistance to estrogen receptor directed therapies |
| url | https://hdl.handle.net/1721.1/126730 |
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