TY - JOUR
T1 - FGFR1 amplification mediates endocrine resistance but retains torc sensitivity in metastatic hormone receptor-positive (HR+) breast cancer
AU - Drago, Joshua Z.
AU - Formisano, Luigi
AU - Juric, Dejan
AU - Niemierko, Andrzej
AU - Servetto, Alberto
AU - Wander, Seth A.
AU - Spring, Laura M.
AU - Vidula, Neelima
AU - Younger, Jerry
AU - Peppercorn, Jeffrey
AU - Yuen, Megan
AU - Malvarosa, Giuliana
AU - Sgroi, Dennis
AU - Isakoff, Steven J.
AU - Moy, Beverly
AU - Ellisen, Leif W.
AU - Iafrate, A. John
AU - Arteaga, Carlos L.
AU - Bardia, Aditya
N1 - Funding Information:
L. Formisano reports receiving commercial research grants from Lilly. D. Juric is a consultant/advisory board member for Novartis, Genentech, Eisai, and Ipsen, and reports receiving commercial research support from Novartis, Genentech, Eisai, EMD Serono, Takeda, Celgene, and Placon Therapeutics. S.A. Wander is a consultant/advisory board member for Foundation Medicine, InfiniteMD, Eli Lilly, and Puma Biotechnology. A.J. Iafrate has ownership interests (including patents) at ArcherDx and reports receiving commercial research grants from Sanofi. C.L. Arteaga has ownership interests (including patents) in Provista and Y-TRAP; is a consultant/advisory board member for Abbvie, Merck, Lilly, Symphogen, Daiichi Sankyo, Radius, Taiho Oncology, Puma Biotechnology, Novartis, Sanofi, H3Biomedicine, OrigMed, Immunomedics, Petra Pharma, G1 Therapeutics, and Athenex; reports receiving commercial research grants from PUMA, Lilly, Pfizer, Radius, Takeda, and Symphogen; and serves in the Scientific Advisory Board of the Komen Foundation. A. Bardia is a consultant/advisory board member for Novartis. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We thank all the patients who participated in this study. We are grateful to Massachusetts General Hospital nurses for their help with the study. This work was supported by Susan G Komen grant CCR15224703 (to A. Bardia), K12 5K12CA087723 (to A. Bardia), KL2 TR001100 (to L.M. Spring), ASCO Young Investigator Award (to L.M. Spring), and Breast Cancer Research Foundation (to D. Sgroi).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-0138
DO - 10.1158/1078-0432.CCR-19-0138
M3 - Article
C2 - 31371343
AN - SCOPUS:85074445131
SN - 1078-0432
VL - 25
SP - 6443
EP - 6451
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -