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<p>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, &gt;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; <i>P</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月7日

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  • Noelia Martinez-Jañez,
  • José Ángel García-Saenz,
  • Sonia Pernas,
  • Begoña Bermejo,
  • Serafín Morales,
  • Juan Guerra,
  • Jorge Silva,
  • Luis Manso,
  • Eva Ciruelos,
  • Pablo Tolosa,
  • Rodrigo Sánchez-Bayona,
  • Manuel Alva,
  • Silvia Calabuig-Fariñas,
  • Sandra Gallach,
  • Laura Muinelo-Romay,
  • Elena Piñeiro-Yáñez,
  • Eduardo Caleiras,
  • Maria J. Bueno,
  • Silvana Mouron,
  • Miguel Quintela-Fandino

摘要

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.