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 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.
Authors
- Eduardo Caleiras (ORCID: https://orcid.org/0000-0001-8768-3630)
- Pablo Tolosa (ORCID: https://orcid.org/0000-0002-3747-4766)
- Miguel Quintela-Fandiño (ORCID: https://orcid.org/0000-0003-1648-1964)
- Begoña Bermejo (ORCID: https://orcid.org/0000-0001-7773-5994)
- Eva Ciruelos
- Sònia Pernas (ORCID: https://orcid.org/0000-0002-1485-5080)
- Silvia Calabuig‐Fariñas (ORCID: https://orcid.org/0000-0001-7749-174X)
- José Á. García-Sáenz (ORCID: https://orcid.org/0000-0001-6880-0301)
- Luís Manso (ORCID: https://orcid.org/0000-0002-1683-550X)
- Silvana Mourón (ORCID: https://orcid.org/0000-0001-6287-8001)
- Rodrigo Sánchez-Bayona (ORCID: https://orcid.org/0000-0002-5255-6620)
- Manuel Alva
- Elena Piñeiro-Yáñez (ORCID: https://orcid.org/0000-0003-2773-2343)
- Laura Muinelo‐Romay (ORCID: https://orcid.org/0000-0002-7456-7531)
- Juan Guerra (ORCID: https://orcid.org/0000-0001-5747-9823)
- María J. Bueno (ORCID: https://orcid.org/0000-0002-3910-0637)
- Noelia Martínez-Jáñez (ORCID: https://orcid.org/0000-0002-0436-0906)
- Serafin M. Morales (ORCID: https://orcid.org/0000-0001-7445-4193)
- Sandra Gallach (ORCID: https://orcid.org/0000-0002-6721-1211)
- Jorge Silva
Institutions
- Universitat de València (ES)
- Universidade de Santiago de Compostela (ES)
- Hospital Universitari Arnau de Vilanova (ES)
- Hospital Clínico San Carlos (ES)
- Spanish National Cancer Research Centre (ES)
- Hospital Clínico Universitario de Valencia (ES)
- Complejo Hospitalario Universitario de Santiago (ES)
- Hospital Universitario 12 De Octubre (ES)
- Centro Nacional de Epidemiología (ES)
- Centro Nacional de Biotecnología (ES)
- Institut Català d'Oncologia (ES)
- Center for Research in Molecular Medicine and Chronic Diseases (ES)
- Hospital General Universitario De Valencia (ES)
- Fundación General (ES)
- Instituto de Investigación Sanitaria de Santiago (ES)
- Hospital Universitario de Fuenlabrada (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Hospital Universitario Ramón y Cajal (ES)
- Centro de Investigacion Principe Felipe (ES)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-11-07
- DOI
- https://doi.org/10.1038/s41698-025-01106-1
- Primary Topic
- Advanced Breast Cancer Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Bayer Canada
- Instituto de Salud Carlos III
- European Regional Development Fund