Reference Detail

Ref Type

Journal Article

PMID

(34480077)

Authors

Bitzer M, Spahn S, Babaei S, Horger M, Singer S, Schulze-Osthoff K, Missios P, Gatidis S, Nann D, Mattern S, Scheble V, Nikolaou K, Armeanu-Ebinger S, Schulze M, Schroeder C, Biskup S, Beha J, Claassen M, Ruhm K, Poso A, Malek NP

Title

Targeting extracellular and juxtamembrane FGFR2 mutations in chemotherapy-refractory cholangiocarcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
NPJ precision oncology	5	1	2021 Sep 03	80	NPJ Precis Oncol

URL

Abstract Text

Intrahepatic cholangiocarcinoma (iCCA) has emerged as a promising candidate for precision medicine, especially in the case of activating FGFR2 gene fusions. In addition to fusions, a considerable fraction of iCCA patients reveals FGFR2 mutations, which might lead to uncontrolled activation of the FGFR2 pathway but are mostly of unknown functional significance. A current challenge for molecular tumor boards (MTB) is to predict the functional consequences of such FGFR2 alterations to guide potential treatment decisions. We report two iCCA patients with extracellular and juxtamembrane FGFR2 mutations. After in silico investigation of the alterations and identification of activated FGFR2 downstream targets in tumor specimens by immunohistochemistry and transcriptome analysis, the MTB recommended treatment with an FGFR-inhibiting tyrosine kinase inhibitor. Both patients developed a rapidly detectable and prolonged partial response to treatment. These two cases suggest an approach to characterize further detected FGFR2 mutations in iCCA to enable patients´ selection for a successful application of the FGFR -inhibiting drugs.

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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
FGFR2	T370_A371delinsC	indel	unknown	FGFR2 T370_A371delinsC results in a deletion of a threonine (T) and an alanine (A) from aa 370 to aa 371 within the extracellular domain of the Fgfr2 protein, combined with the insertion of a cysteine (C) at the same site (UniProt.org). T370_A371delinsC has been identified in the scientific literature (PMID: 34480077), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Jul 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 T370_A371delinsC	intrahepatic cholangiocarcinoma	predicted - sensitive	Lenvatinib	Case Reports/Case Series	Actionable	In a clinical case study, Lenvima (lenvatinib) treatment resulted in a reduction in tumor burden and ongoing response at 11.6 months in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 T370_A371delinsC (PMID: 34480077).	34480077
FGFR2 F276C	intrahepatic cholangiocarcinoma	predicted - sensitive	Pazopanib	Case Reports/Case Series	Actionable	In a clinical case study, Votrient (pazopanib) treatment resulted in a partial response that continued for 11 months after starting treatment in a patient with intrahepatic cholangiocarcinoma harboring FGFR2 F276C (PMID: 34480077).	34480077