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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 NPJ precision oncology
Vol 5
Issue 1
Date 2021 Sep 03
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_A371delinsS indel unknown FGFR2 T370_A371delinsS 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 serine (S) at the same site (UniProt.org). T370_A371delinsS 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 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
FGFR2 T370_A371delinsS 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_A371delinsS (PMID: 34480077). 34480077