Co-clinical trial targeting ER, FGFR and CDK4/6 in resistant hormone-positive breast cancer with FGFR alterations

Management of advanced hormone receptor-positive, HER2-negative breast cancer after progression on endocrine therapy plus CDK4/6 inhibitors is challenging due to mutational heterogeneity. Current therapies yield limited efficacy, achieving 4-6 months PFS. FGFR signaling is implicated in resistance t...

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Detalhes bibliográficos
Autores: Martínez Jañez, Noelia, García Sáenz, José Ángel, Pernas, Sònia, Bermejo, Begoña, Morales, Serafín, Guerra, Juan Antonio, Silva, Jorge, Manso, Luis, Ciruelos, Eva, Tolosa, Pablo, Sánchez Bayona, Rodrigo, Alva, Manuel, Calabuig Fariñas, Silvia, Gallach, Sandra, Muinelo Romay, Laura, Piñeiro Yáñez, Elena, Caleiras, Eduardo, Bueno, Maria J., Mourón, Silvana, Quintela Fandino, Miguel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/224911
Acesso em linha:https://hdl.handle.net/2445/224911
Access Level:acceso abierto
Palavra-chave:Hormonoteràpia
Assaigs clínics
Oncologia
Hormone therapy
Clinical trials
Oncology
Descrição
Resumo:Management of advanced hormone receptor-positive, HER2-negative breast cancer after progression on endocrine therapy plus CDK4/6 inhibitors is challenging due to mutational heterogeneity. Current therapies yield limited efficacy, achieving 4-6 months PFS. FGFR signaling is implicated in resistance to endocrine plus CDK4/6 inhibitors, but FGFR inhibitors have shown limited activity in unselected populations. Co-clinical trials bridge preclinical and clinical findings, optimize resources, and enable biomarker identification. Using patient-derived organoids (PDOs), we demonstrated that FGFR-amplified PDOs respond to fulvestrant, palbociclib, and rogaratinib only when PIK3CA and ESR1 are wild-type. In a dose-escalation trial pre-screening 66 patients with FGFR1/2-amplification (FISH) and/or overexpression (RNAScope) patients, >40% harbored FGFR alterations. Nine patients were enrolled; the combination showed activity specifically in PIK3CA- and ESR1-wild type patients (9.1 vs. 1.9 months PFS; P = 0.0005). Toxicity was manageable and consistent with prior data. Our findings highlight biomarker-driven approaches as essential for refining FGFR-targeted strategies in this resistant population.

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