FGFR1 amplification mediates endocrine resistance but retains TORC sensitivity in metastatic hormone receptor-positive (HR(+)) breast cancer Journal Article
| Authors: | Drago, J. Z.; Formisano, L.; Juric, D.; Niemierko, A.; Servetto, A.; Wander, S. A.; Spring, L. M.; Vidula, N.; Younger, J.; Peppercorn, J.; Yuen, M.; Malvarosa, G.; Sgroi, D.; Isakoff, S. J.; Moy, B.; Ellisen, L. W.; Iafrate, A. J.; Arteaga, C. L.; Bardia, A. |
| Article Title: | FGFR1 amplification mediates endocrine resistance but retains TORC sensitivity in metastatic hormone receptor-positive (HR(+)) breast cancer |
| Abstract: | 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. © 2019 American Association for Cancer Research. |
| Keywords: | adult; controlled study; treatment response; unclassified drug; gene mutation; human cell; major clinical study; cancer combination chemotherapy; cancer growth; monotherapy; validation process; paclitaxel; sensitivity and specificity; biological marker; gene targeting; enzyme inhibition; gene amplification; gene expression; protein protein interaction; epidermal growth factor receptor 2; cohort analysis; genotype; gene function; in vitro study; phosphatidylinositol 3 kinase; cancer resistance; tumor suppressor gene; fluorescence in situ hybridization; radiology; disease duration; multivariate analysis; hormonal therapy; letrozole; molecular biology; estrogen receptor; progesterone receptor; hormone receptor; metastatic breast cancer; cyclin dependent kinase inhibitor; drug sensitivity; everolimus; fibroblast growth factor receptor 1; cyclin dependent kinase 4; fulvestrant; genetic identification; cyclin dependent kinase 6; clinical outcome; cancer prognosis; fgfr1 gene; human; female; priority journal; article; endocrine resistance; circulating tumor dna; palbociclib; cyclin dependent kinase inhibitor 4; cyclin dependent kinase inhibitor 6; cama-1 cell line |
| Journal Title: | Clinical Cancer Research |
| Volume: | 25 |
| Issue: | 21 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-11-01 |
| Start Page: | 6443 |
| End Page: | 6451 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-19-0138 |
| PUBMED: | 31371343 |
| PROVIDER: | scopus |
| PMCID: | PMC6825550 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 December 2019 -- Source: Scopus |
