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We thank the support received from the Welfare Projects Division of the La Caixa Foundation to the Molecular Therapeutics Research Unit (UITM) . We thank Anna Sunol for her contribution in sample management in VHIO Breast Cancer Unit and Daniel Zingg (Jos Jonker's laboratory, NKI) for helpful discussion. Figures were elaborated using Servier Medical Art. This work was cofunded by the Instituto de Salud Carlos III (ISCIII-FEDER, PI15/00360, to J. Rodon) and Grants4Targets Bayer (2015-08-1441, to C. Hierro) . The 360 degrees FGFR Resistance project was partly funded by the CIBOT program from Novartis. The project has also received funding from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement number 675392 to M. Graupera. V. Serra is supported by the ISCIII (CPII19/00033, PI20/00892) , the Catalan Agency for Management of University and Research Grants (AGAUR, 2017 SGR 540) , a GHD-Pink Grant and the FERO Foundation. C. Saura received support from the Department of Health (Generalitat de Catalunya, SLT006/17/224) . The authors acknowledge the Cellex Foundation for providing research facilities and equipment.

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High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer

Publicated to:Clinical Cancer Research. 28 (1): 137-149 - 2022-01-01 28(1), DOI: 10.1158/1078-0432.ccr-21-1810

Authors: Sánchez-Guixé, M; Hierro, C; Jiménez, J; Viaplana, C; Villacampa, G; Monelli, E; Brasó-Maristany, F; Ogbah, Z; Parés, M; Guzmán, M; Grueso, J; Rodríguez, O; Oliveira, M; Azaro, A; Garralda, E; Tabernero, J; Casanovas, O; Scaltriti, M; Prat, A; Dienstmann, R; Nuciforo, P; Saura, C; Graupera, M; Vivancos, A; Rodon, J; Serra, V

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Abstract

FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (BC) and is associated with resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). Multi-tyrosine kinase inhibitors (MTKI) and selective pan-FGFR inhibitors (FGFRi) are being developed for FGFR1amp BC. High-level FGFR amplification and protein expression by IHC have identified BC responders to FGFRi or MTKI, respectively.Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of seventeen BC patient-derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in ten patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.High FGFR1-4 mRNA levels but not copy number alteration (CNA) associated with FGFRi response. Treatment with MTKI showed higher response rates than with FGFRi (86% vs 53%), regardless of the FGFR1-4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRi or MTKI, and PDXs exclusively sensitive to MTKI exhibited an additional anti-angiogenic response. Consistently, clinical benefit of MTKI was not associated with high FGFR1-4 mRNA levels and it was observed in patients previously treated with anti-angiogenic drugs.Tailored therapy with FGFRi in molecularly-selected metastatic BC based on high FGFR1-4 mRNA levels warrants prospective validation in luminal BC CDK4/6i-resistant patients and in TNBC patients without targeted therapeutic options.Copyright ©2021, American Association for Cancer Research.

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