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

Noelia Martinez-Jañez1, José Ángel García-Saenz2, Sonia Pernas3

  • 1Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain.

NPJ Precision Oncology
|November 7, 2025
PubMed

Insights

Targeting fibroblast growth factor receptor (FGFR) signaling shows promise for advanced hormone receptor-positive, HER2-negative breast cancer resistant to CDK4/6 inhibitors. Biomarker-driven strategies, specifically in PIK3CA- and ESR1-wild type patients, improve progression-free survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Advanced hormone receptor-positive, HER2-negative breast cancer (HR+/HER2-) progressing on endocrine therapy plus CDK4/6 inhibitors presents a significant clinical challenge.
  • Mutational heterogeneity contributes to treatment resistance, with limited efficacy (4-6 months PFS) for current therapies.
  • Fibroblast growth factor receptor (FGFR) signaling is implicated in resistance, but FGFR inhibitors lack efficacy in unselected populations.

Purpose of the Study:

  • To investigate the efficacy of combining FGFR inhibition with standard therapy in a resistant breast cancer population.
  • To identify predictive biomarkers for response to FGFR-targeted therapies.
  • To leverage co-clinical models and patient-derived organoids (PDOs) for biomarker discovery and therapeutic strategy optimization.

Main Methods:

  • Utilized patient-derived organoids (PDOs) to model FGFR-amplified breast cancer.
  • Conducted a dose-escalation clinical trial pre-screening patients for FGFR1/2 alterations (amplification/overexpression).
  • Assessed the efficacy of fulvestrant, palbociclib, and rogaratinib combination therapy, correlating response with PIK3CA and ESR1 mutational status.

Main Results:

  • FGFR-amplified PDOs responded to combination therapy only when PIK3CA and ESR1 were wild-type.
  • >40% of screened patients harbored FGFR alterations.
  • The combination therapy demonstrated significantly improved progression-free survival (PFS) in PIK3CA- and ESR1-wild type patients (9.1 months vs. 1.9 months; P=.0005).

Conclusions:

  • Biomarker-driven approaches are crucial for optimizing FGFR-targeted strategies in endocrine-resistant HR+/HER2- breast cancer.
  • Identifying PIK3CA and ESR1 wild-type status is essential for patient selection in FGFR-targeted trials.
  • The combination therapy showed manageable toxicity and promising activity in a selected patient subgroup.

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