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Ref Type Journal Article
PMID (34250419)
Authors Varghese AM, Patel J, Janjigian YY, Meng F, Selcuklu SD, Iyer G, Houck-Loomis B, Harding JJ, O'Reilly EM, Abou-Alfa GK, Lowery MA, Berger MF
Title Noninvasive Detection of Polyclonal Acquired Resistance to FGFR Inhibition in Patients With Cholangiocarcinoma Harboring FGFR2 Alterations.
Journal JCO precision oncology
Vol 5
Issue
Date 2021
URL
Abstract Text Fibroblast growth factor receptor (FGFR) 2 alterations, present in 5%-15% of intrahepatic cholangiocarcinomas (IHC), are targets of FGFR-directed therapies. Acquired resistance is common among patients who respond. Biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. We studied circulating tumor DNA (ctDNA) as a less invasive means of potentially identifying genomic mechanisms of resistance to FGFR-targeted therapies.Serial blood samples were collected from eight patients with FGFR-altered cholangiocarcinoma for ctDNA isolation and next-generation sequencing (NGS) throughout treatment and at resistance to anti-FGFR-targeted therapy. ctDNA was sequenced using a custom ultra-deep coverage NGS panel, incorporating dual index primers and unique molecular barcodes to enable high-sensitivity mutation detection.Thirty-one acquired mutations in FGFR2, 30/31 located in the kinase domain, were identified at resistance in six of eight patients with detectable ctDNA. Up to 13 independent FGFR2 mutations were detected per patient, indicative of striking genomic concordance among resistant subclones.ctDNA could be an effective means to longitudinally monitor for acquired resistance in FGFR2-altered IHC. The numerous acquired genetic alterations in FGFR2 suggest frequent polyclonal mechanisms of resistance that cannot be detected from single-site tissue biopsies.

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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 D650Y missense unknown FGFR2 D650Y lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). D650Y has been demonstrated to confer resistance to Fgfr inhibitors as a secondary resistance mutation (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2021).
FGFR2 KIAA1217 FGFR2 - KIAA1217 fusion unknown FGFR2-KIAA1217 results from the fusion of FGFR2 and KIAA1217 (PMID: 30745300). FGFR2-KIAA1217 has been identified in cholangiocarcinoma (PMID: 34250419, PMID: 31109923, PMID: 33218975), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Apr 2022).
FGFR2 WAC FGFR2 - WAC fusion unknown FGFR2-WAC results from the fusion of FGFR2 and WAC (PMID: 32315234). FGFR2-WAC has been identified in cholangiocarcinoma (PMID: 32315234, PMID: 34250419), but has not been biochemically characterized and therefore, the effect on protein function is unknown (PubMed, Nov 2021).
FGFR2 K659Q missense unknown FGFR2 K659Q lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K659Q has been demonstrated to confer resistance to Fgfr inhibitors as a secondary resistance mutation (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2022). Y
FGFR2 L550F missense unknown FGFR2 L550F lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L550F has been demonstrated to confer resistance to Fgfr inhibitors as a secondary resistance mutation (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2022). Y
FGFR2 M538L missense unknown FGFR2 M538L lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). M538L has been identified as a secondary resistance mutation in the context of an FGFR2 fusion (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2021).
FGFR2 N652S missense unknown FGFR2 N652S lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N652S has been demonstrated to confer resistance to Fgfr inhibitors as a secondary resistance mutation (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2022). Y
FGFR2 Q746L missense unknown FGFR2 Q746L lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). Q746L has been demonstrated to confer resistance to Fgfr inhibitors as a secondary resistance mutation (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2022). Y
FGFR2 Y779C missense unknown FGFR2 Y779C lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). Y779C has been demonstrated to confer resistance to Fgfr inhibitors as a secondary resistance mutation (PMID: 34250419), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Apr 2022). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - WAC FGFR2 M537I FGFR2 M538L FGFR2 N549H FGFR2 N549K FGFR2 N549T FGFR2 L550F FGFR2 V564F FGFR2 V564I FGFR2 E565A FGFR2 D650Y FGFR2 N652S FGFR2 K659Q cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-WAC fusion experienced disease progression after 5.6 months of treatment with Truseltiq (infigratinib) and was found to have acquired additional FGFR2 mutations, M537I, M538L, N549H, N549T, N549K, L550F, V564F, V564I, E565A, D650Y, N652S, K659Q (PMID: 34250419). 34250419
FGFR2 - NRAP cholangiocarcinoma predicted - sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, treatment with Truseltiq (infigratinib) resulted in stable disease for seven months in a patient with cholangiocarcinoma harboring an FGFR2-NRAP fusion (PMID: 34250419). 34250419
FGFR2 - KIAA1217 FGFR2 N549D FGFR2 N549H FGFR2 N549K FGFR2 V564F FGFR2 V564I FGFR2 V564L FGFR2 E565A FGFR2 L617F FGFR2 L617V FGFR2 K659M FGFR2 Q746L cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-KIAA1217 fusion experienced disease progression after 10.6 months of treatment with Truseltiq (infigratinib) and was found to have acquired additional FGFR2 mutations, N549K, N549D, N549H, V564F, V564I, V564L, E565A, L617V, L617F, K659M, Q746L (PMID: 34250419). 34250419
FGFR2 - WAC cholangiocarcinoma predicted - sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, treatment with Truseltiq (infigratinib) resulted in a partial response in a patient with cholangiocarcinoma harboring an FGFR2-WAC fusion (PMID: 34250419). 34250419
FGFR2 - KIAA1217 cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, treatment with Truseltiq (infigratinib) resulted in stable disease for 6.6 months in a patient with cholangiocarcinoma harboring an FGFR2-KIAA1217 fusion (PMID: 34250419). 34250419
FGFR2 - DDX21 FGFR2 K659M FGFR2 Y779C cholangiocarcinoma predicted - resistant Debio 1347 Case Reports/Case Series Actionable In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-DDX21 fusion experienced disease progression after 5.5 months of treatment with Debio 1347 and was found to have acquired additional FGFR2 mutations, K659M and Y779C (PMID: 34250419). 34250419
FGFR2 M537I FGFR2 V564L FGFR2 amp cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with cholangiocarcinoma with amplification of FGFR2 experienced disease progression after 3.9 months of treatment with Truseltiq (infigratinib) and was found to have acquired additional FGFR2 mutations, M537I and V564L (PMID: 34250419). 34250419
FGFR2 - KIAA1217 cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, treatment with Truseltiq (infigratinib) resulted in stable disease for 10.6 months in a patient with cholangiocarcinoma harboring an FGFR2-KIAA1217 fusion (PMID: 34250419). 34250419
FGFR2 - NRAP FGFR2 N549K FGFR2 V564L cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-NRAP fusion experienced disease progression after seven months of treatment with Truseltiq (infigratinib) and was found to have acquired additional FGFR2 mutations, N549K and V564L (PMID: 34250419). 34250419
FGFR2 - DDX21 cholangiocarcinoma sensitive Debio 1347 Case Reports/Case Series Actionable In a clinical case study, treatment with Debio 1347 resulted in stable disease for 5.5 months in a patient with cholangiocarcinoma harboring an FGFR2-DDX21 fusion (PMID: 34250419). 34250419
FGFR2 amp cholangiocarcinoma sensitive Infigratinib Case Reports/Case Series Actionable In a clinical case study, treatment with Truseltiq (infigratinib) resulted in stable disease for 3.9 months in a patient with cholangiocarcinoma with amplification of FGFR2 (PMID: 34250419). 34250419
FGFR2 - KIAA1217 FGFR2 L550F cholangiocarcinoma predicted - resistant Infigratinib Case Reports/Case Series Actionable In a clinical case study, a patient with cholangiocarcinoma harboring an FGFR2-KIAA1217 fusion experienced disease progression after 6.6 months of treatment with Truseltiq (infigratinib) and was found to have acquired an FGFR2 L550F mutation (PMID: 34250419). 34250419