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

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

  • NPJ Precis Oncol. 2025 Nov 7;9(1):343. doi: 10.1038/s41698-025-01106-1.
Noelia Martinez-Jañez 1,  José Ángel García-Saenz 2,  Sonia Pernas 3,  Begoña Bermejo 4,  Serafín Morales 5,  Juan Guerra 6,  Jorge Silva 7,  Luis Manso 8,  Eva Ciruelos 8,  Pablo Tolosa 8,  Rodrigo Sánchez-Bayona 8,  Manuel Alva 8,  Silvia Calabuig-Fariñas 9 10 11 12,  Sandra Gallach 10 11 12,  Laura Muinelo-Romay 10 13,  Elena Piñeiro-Yáñez 14,  Eduardo Caleiras 15,  Maria J Bueno 7,  Silvana Mouron 7,  Miguel Quintela-Fandino 16 17
Affiliations

Affiliations

  • 1 Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain.
  • 2 Medical Oncology, Hospital Universitario Clinico San Carlos, Madrid, Spain.
  • 3 Medical Oncology, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
  • 4 Medical Oncology, Hospital Clinico Universitario. INCLIVA, Medicine department, Universidad de Valencia, Valencia, Spain.
  • 5 Medical Oncology, Hospital Universitario Arnau de Vilanova, Lleida, Spain.
  • 6 Medical Oncology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain.
  • 7 Breast Cancer Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
  • 8 Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 9 Department of Pathology, Universitat de Valencia, Valencia, Spain.
  • 10 Centro de Investigación Biomédica en Red Cáncer-CIBERONC, Madrid, Spain.
  • 11 Molecular Oncology Laboratory, Fundación Investigación Hospital General Universitario de Valencia, Valencia, Spain.
  • 12 TRIAL Mixed Unit Centro Investigación Príncipe Felipe-Fundación Investigación Hospital General Universitario de Valencia, Valencia, Spain.
  • 13 Liquid Biopsy Analysis Unit - Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain.
  • 14 Bioinformatics Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
  • 15 Histopathology Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
  • 16 Breast Cancer Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain. [email protected].
  • 17 Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain. [email protected].
PMID: 41203797 DOI: 10.1038/s41698-025-01106-1
Abstract

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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