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Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial
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| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , |
| In: | Clinical Cancer Research, 25, 2019, 2, S. 771-783 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Sudhan, Dhivya R. Schwarz, Luis J. Guerrero-Zotano, Angel Formisano, Luigi Nixon, Mellissa J. Croessmann, Sarah González Ericsson, Paula I. Sanders, Melinda Balko, Justin M. Avogadri-Connors, Francesca Cutler, Richard E. Lalani, Alshad S. Bryce, Richard Auerbach, Alan Arteaga, Carlos L. Sudhan, Dhivya R. Schwarz, Luis J. Guerrero-Zotano, Angel Formisano, Luigi Nixon, Mellissa J. Croessmann, Sarah González Ericsson, Paula I. Sanders, Melinda Balko, Justin M. Avogadri-Connors, Francesca Cutler, Richard E. Lalani, Alshad S. Bryce, Richard Auerbach, Alan Arteaga, Carlos L. |
|---|---|
| author |
Sudhan, Dhivya R. Schwarz, Luis J. Guerrero-Zotano, Angel Formisano, Luigi Nixon, Mellissa J. Croessmann, Sarah González Ericsson, Paula I. Sanders, Melinda Balko, Justin M. Avogadri-Connors, Francesca Cutler, Richard E. Lalani, Alshad S. Bryce, Richard Auerbach, Alan Arteaga, Carlos L. |
| spellingShingle |
Sudhan, Dhivya R. Schwarz, Luis J. Guerrero-Zotano, Angel Formisano, Luigi Nixon, Mellissa J. Croessmann, Sarah González Ericsson, Paula I. Sanders, Melinda Balko, Justin M. Avogadri-Connors, Francesca Cutler, Richard E. Lalani, Alshad S. Bryce, Richard Auerbach, Alan Arteaga, Carlos L. Clinical Cancer Research Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial Cancer Research Oncology |
| author_sort |
sudhan, dhivya r. |
| spelling |
Sudhan, Dhivya R. Schwarz, Luis J. Guerrero-Zotano, Angel Formisano, Luigi Nixon, Mellissa J. Croessmann, Sarah González Ericsson, Paula I. Sanders, Melinda Balko, Justin M. Avogadri-Connors, Francesca Cutler, Richard E. Lalani, Alshad S. Bryce, Richard Auerbach, Alan Arteaga, Carlos L. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-18-1131 <jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose:</jats:title><jats:p>The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.</jats:p><jats:p>Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>Mice receiving “extended adjuvant” therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2− MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.</jats:p></jats:sec> Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial Clinical Cancer Research |
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10.1158/1078-0432.ccr-18-1131 |
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American Association for Cancer Research (AACR), 2019 |
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American Association for Cancer Research (AACR), 2019 |
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1557-3265 1078-0432 |
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American Association for Cancer Research (AACR) |
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Clinical Cancer Research |
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| title |
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_unstemmed |
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_full |
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_fullStr |
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_full_unstemmed |
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_short |
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_sort |
extended adjuvant therapy with neratinib plus fulvestrant blocks er/her2 crosstalk and maintains complete responses of er+/her2+ breast cancers: implications to the extenet trial |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-18-1131 |
| publishDate |
2019 |
| physical |
771-783 |
| description |
<jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose:</jats:title><jats:p>The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.</jats:p><jats:p>Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>Mice receiving “extended adjuvant” therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2− MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.</jats:p></jats:sec> |
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| author | Sudhan, Dhivya R., Schwarz, Luis J., Guerrero-Zotano, Angel, Formisano, Luigi, Nixon, Mellissa J., Croessmann, Sarah, González Ericsson, Paula I., Sanders, Melinda, Balko, Justin M., Avogadri-Connors, Francesca, Cutler, Richard E., Lalani, Alshad S., Bryce, Richard, Auerbach, Alan, Arteaga, Carlos L. |
| author_facet | Sudhan, Dhivya R., Schwarz, Luis J., Guerrero-Zotano, Angel, Formisano, Luigi, Nixon, Mellissa J., Croessmann, Sarah, González Ericsson, Paula I., Sanders, Melinda, Balko, Justin M., Avogadri-Connors, Francesca, Cutler, Richard E., Lalani, Alshad S., Bryce, Richard, Auerbach, Alan, Arteaga, Carlos L., Sudhan, Dhivya R., Schwarz, Luis J., Guerrero-Zotano, Angel, Formisano, Luigi, Nixon, Mellissa J., Croessmann, Sarah, González Ericsson, Paula I., Sanders, Melinda, Balko, Justin M., Avogadri-Connors, Francesca, Cutler, Richard E., Lalani, Alshad S., Bryce, Richard, Auerbach, Alan, Arteaga, Carlos L. |
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| description | <jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose:</jats:title><jats:p>The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.</jats:p><jats:p>Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>Mice receiving “extended adjuvant” therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2− MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.</jats:p></jats:sec> |
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| spelling | Sudhan, Dhivya R. Schwarz, Luis J. Guerrero-Zotano, Angel Formisano, Luigi Nixon, Mellissa J. Croessmann, Sarah González Ericsson, Paula I. Sanders, Melinda Balko, Justin M. Avogadri-Connors, Francesca Cutler, Richard E. Lalani, Alshad S. Bryce, Richard Auerbach, Alan Arteaga, Carlos L. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-18-1131 <jats:title>Abstract</jats:title><jats:sec><jats:title>Purpose:</jats:title><jats:p>The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.</jats:p><jats:p>Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.</jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p>Mice receiving “extended adjuvant” therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2− MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.</jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p>These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.</jats:p></jats:sec> Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial Clinical Cancer Research |
| spellingShingle | Sudhan, Dhivya R., Schwarz, Luis J., Guerrero-Zotano, Angel, Formisano, Luigi, Nixon, Mellissa J., Croessmann, Sarah, González Ericsson, Paula I., Sanders, Melinda, Balko, Justin M., Avogadri-Connors, Francesca, Cutler, Richard E., Lalani, Alshad S., Bryce, Richard, Auerbach, Alan, Arteaga, Carlos L., Clinical Cancer Research, Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial, Cancer Research, Oncology |
| title | Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_full | Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_fullStr | Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_full_unstemmed | Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_short | Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| title_sort | extended adjuvant therapy with neratinib plus fulvestrant blocks er/her2 crosstalk and maintains complete responses of er+/her2+ breast cancers: implications to the extenet trial |
| title_unstemmed | Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-18-1131 |