Co-clinical trial targeting ER, FGFR and CDK4/6 in resistant hormone-positive breast cancer with FGFR alterations PMID: 41203797

ADC Targets in Oncology

2026-04-10

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

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].

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.