Reference Detail

Ref Type

Journal Article

PMID

(23658459)

Authors

André F, Bachelot T, Campone M, Dalenc F, Perez-Garcia JM, Hurvitz SA, Turner N, Rugo H, Smith JW, Deudon S, Shi M, Zhang Y, Kay A, Porta DG, Yovine A, Baselga J

Title

Targeting FGFR with dovitinib (TKI258): preclinical and clinical data in breast cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	19	13	2013 Jul 01	3693-702	Clin Cancer Res

URL

Abstract Text

Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer.Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.

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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
Dovitinib	Dovitinib	100	16

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Dovitinib		TKI258\|CHIR-258	CSF1R Inhibitor 28 FGFR Inhibitor (Pan) 26 FLT3 Inhibitor 69 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 VEGFR Inhibitor (Pan) 36	Dovitinib (TKI258) targets multiple receptor tyrosine kinases including Flt3, c-Kit, CSF1R, FGFR 1-4, VEGFR 1-3, and PDGFR alpha and beta, potentially resulting in decreased tumor growth (PMID: 15598814, PMID: 25219510, PMID: 23658459, PMID: 16033847).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	Her2-receptor positive breast cancer	sensitive	Dovitinib	Phase II	Actionable	In a Phase II trial, Dovitinib (TKI258) promoted 6-month stable disease in Erbb2 (Her2)-positive breast cancer patients with FGFR1 amplification (PMID: 23658459).	23658459
FGFR2 amp	Her2-receptor positive breast cancer	sensitive	Dovitinib	Phase I	Actionable	In a Phase I trial, Dovitinib (TKI258) displayed safety and preliminary efficacy resulting in tumor regression of 28.2% and 18.5% in two patients with FGFR2 amplified Erbb2 (Her2)-receptor positive breast cancer (PMID: 23658459).	23658459
FGFR2 amp	breast cancer	sensitive	Dovitinib	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Dovitinib (TKI258) inhibited cell growth of an FGFR2 amplified breast cancer cell line in culture and prevented tumor growth and induced tumor regression in FGFR2 amplified breast cancer patient derived xenograft (PDX) models (PMID: 23658459).	23658459