2. Academic Validation
  3. FGFR1 amplification or overexpression and hormonal resistance in luminal breast cancer: rationale for a triple blockade of ER, CDK4/6, and FGFR1

FGFR1 amplification or overexpression and hormonal resistance in luminal breast cancer: rationale for a triple blockade of ER, CDK4/6, and FGFR1

  • Breast Cancer Res. 2021 Feb 12;23(1):21. doi: 10.1186/s13058-021-01398-8.
Silvana Mouron 1,  Luis Manso 2,  Eduardo Caleiras 3,  Jose L Rodriguez-Peralto 4,  Oscar M Rueda 5,  Carlos Caldas 5,  Ramon Colomer 6 7 8 9,  Miguel Quintela-Fandino  # 10 11 12 13,  Maria J Bueno  # 14
Affiliations

Affiliations

  • 1 Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.
  • 2 Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 3 Histopathology Unit, CNIO, Madrid, Spain.
  • 4 Pathology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
  • 5 Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
  • 6 Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain.
  • 7 Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain.
  • 8 Endowed Chair of Personalized Precision Medicine, Universidad Autonoma de Madrid - Fundación Instituto Roche, Madrid, Spain.
  • 9 Unidad de Investigación Clínica y Ensayos Clínicos (UICEC) of Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain.
  • 10 Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain. mquintela@cnio.es.
  • 11 Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain. mquintela@cnio.es.
  • 12 Medical Oncology Department, Hospital Universitario de Fuenlabrada, Madrid, Spain. mquintela@cnio.es.
  • 13 Medical Oncology Department, Hospital Universitario Quiron Pozuelo, Madrid, Spain. mquintela@cnio.es.
  • 14 Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain. mjbueno@cnio.es.
  • # Contributed equally.
PMID: 33579347 DOI: 10.1186/s13058-021-01398-8
Abstract

Background: FGFR1 amplification, but not overexpression, has been related to adverse prognosis in hormone-positive breast Cancer (HRPBC). Whether FGFR1 overexpression and amplification are correlated, what is their distribution among luminal A or B HRPBC, and if there is a potential different prognostic role for amplification and overexpression are currently unknown features. The role of FGFR1 inhibitors in HRPBC is also unclear.

Methods: FGFR1 amplification (FISH) and overexpression (RNAscope) were investigated in a N = 251 HRPBC patients cohort and the METABRIC cohort; effects on survival and FISH-RNAscope concordance were determined. We generated hormonal deprivation resistant (LTED-R) and FGFR1-overexpressing cell line variants of the ER+ MCF7 and T47-D and the ER+, FGFR1-amplified HCC1428 cell lines. The role of ER, CDK4/6, and/or FGFR1 blockade alone or in combinations in Rb phosphorylation, cell cycle, and survival were studied.

Results: FGFR1 overexpression and amplification was non-concordant in > 20% of the patients, but both were associated to a similar relapse risk (~ 2.5-fold; P < 0.05). FGFR1 amplification or overexpression occurred regardless of the luminal subtype, but the incidence was higher in luminal B (16.3%) than A (6.6%) tumors; P < 0.05. The Kappa index for overexpression and amplification was 0.69 (P < 0.001). Twenty-four per cent of the patients showed either amplification and/or overexpression of FGFR1, what was associated to a hazard ratio for relapse of 2.6 (95% CI 1.44-4.62, P < 0.001). In vitro, hormonal deprivation led to FGFR1 overexpression. Primary FGFR1 amplification, engineered mRNA overexpression, or LTED-R-acquired FGFR1 overexpression led to resistance against hormonotherapy alone or in combination with the CDK4/6 inhibitor palbociclib. Blocking FGFR1 with the kinase-inhibitor rogaratinib led to suppression of Rb phosphorylation, abrogation of the cell cycle, and resistance-reversion in all FGFR1 models.

Conclusions: FGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast Cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade.

Keywords

FGFR1 amplification; FGFR1 overexpression; Luminal breast cancer; Palbociclib; Rogaratinib.

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