FGFR1 gene amplification mediates endocrine resistance but retains TORC sensitivity in metastatic hormone receptor positive (HR+) breast cancer
| Autor: | Megan Yuen, Carlos L. Arteaga, Andrzej Niemierko, Luigi Formisano, Neelima Vidula, Jerry Younger, Steven J. Isakoff, Alberto Servetto, Dennis C. Sgroi, Jeffrey Peppercorn, Laura Spring, Joshua Z. Drago, Aditya Bardia, Seth A. Wander, Leif W. Ellisen, Dejan Juric, Beverly Moy, A. John Iafrate, Giuliana Malvarosa |
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| Přispěvatelé: | Formisano, L, Drago, Jz, Juric, D, Niemierko, A, Servetto, A, Wander, Sa, Spring, Lm, Vidula, N, Younger, J, Peppercorn, J, Yuen, M, Malvarosa, G, Sgroi, D, Isakoff, Sj, Moy, B, Ellisen, Lw, Iafrate, Aj, Arteaga, Cl, Bardia, A |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.drug_class medicine.medical_treatment Palbociclib Article 03 medical and health sciences 0302 clinical medicine Breast cancer Progesterone receptor medicine biological marker circulating tumor DNA cyclin dependent kinase 4 cyclin dependent kinase 6cyclin dependent kinase inhibitor cyclin dependent kinase inhibitor 4cyclin dependent kinase inhibitor 6epidermal growth factor receptor 2estrogen receptor everolimus fibroblast growth factor receptor 1fulvestranthormone receptor letrozole paclitaxel palbociclib phosphatidylinositol 3 kinase progesterone receptor unclassified drug skin and connective tissue diseases Everolimus Fulvestrant business.industry medicine.disease Metastatic breast cancer stomatognathic diseases 030104 developmental biology Oncology Estrogen 030220 oncology & carcinogenesis Cancer research Hormone therapy business medicine.drug |
| Zdroj: | Clin Cancer Res |
| Popis: | Purpose: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic breast cancer (MBC) remains undefined. Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor–positive (HR+)/HER2− MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro. Results: In the clinical cohort (N = 110), we identified that patients with FGFR1+ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P = 0.005), coexisting TP53 mutations (41% vs. 21%; P = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1+ HR+/HER2− MBC. In preclinical models, estrogen receptor–positive (ER+)/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER+ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition. Conclusions: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER+/FGFR1+ MBC. |
| Databáze: | OpenAIRE |
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