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|Ref Type||Journal Article|
|Authors||Sánchez-Guixé M, Hierro C, Jiménez J, Viaplana C, Villacampa G, Monelli E, Brasó-Maristany F, Ogbah Z, Parés M, Guzmán M, Grueso J, Rodríguez O, Oliveira M, Azaro A, Garralda E, Tabernero J, Casanovas O, Scaltriti M, Prat A, Dienstmann R, Nuciforo P, Saura C, Graupera M, Vivancos A, Rodon J, Serra V|
|Title||High FGFR1-4 mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2022 01 01|
|Abstract Text||FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient-derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.High FGFR1-4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1-4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1-4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1-4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FGFR1||W4C||missense||unknown||FGFR1 W4C does not lie within any known functional domains of the Fgfr1 protein (UniProt.org). W4C has been identified in the scientific literature (PMID: 34593528), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Feb 2022).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR1 amp||triple-receptor negative breast cancer||predicted - sensitive||Lucitanib||Preclinical - Pdx||Actionable||In a preclinical study, Lucitanib (E-3810) treatment resulted in reduced tumor volume in FGFR1-amplified triple-negative breast cancer patient-derived xenograft (PDX) models (PMID: 34593528).||34593528|
|FGFR1 W4C FGFR1 amp||estrogen-receptor positive breast cancer||no benefit||Rogaratinib||Preclinical - Pdx||Actionable||In a preclinical study, Rogaratinib (BAY 1163877) treatment did not inhibit tumor growth in an ER-positive breast cancer patient-derived xenograft (PDX) model with FGFR1 W4C and FGFR1 amplification (PMID: 34593528).||34593528|
|FGFR1 amp||triple-receptor negative breast cancer||no benefit||Rogaratinib||Preclinical - Pdx||Actionable||In a preclinical study, Rogaratinib (BAY 1163877) treatment did not inhibit tumor growth in a patient-derived xenograft (PDX) model of triple-negative breast cancer with FGFR1 amplification (PMID: 34593528).||34593528|
|FGFR1 W4C FGFR1 amp||estrogen-receptor positive breast cancer||predicted - sensitive||Lucitanib||Preclinical - Pdx||Actionable||In a preclinical study, Lucitanib (E-3810) treatment resulted in reduced tumor volume in an ER-positive breast cancer patient-derived xenograft (PDX) model harboring FGFR1 W4C and FGFR1 amplification (PMID: 34593528).||34593528|