Reference Detail

Ref Type

Journal Article

PMID

(34593528)

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	28	1	2022 01 01	137-149	Clin Cancer Res

URL

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.

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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, Oct 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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