Noninvasive detection of polyclonal acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations Journal Article


Authors: Varghese, A. M.; Patel, J.; Janjigian, Y. Y.; Meng, F.; Selcuklu, S. D.; Iyer, G.; Houck-Loomis, B.; Harding, J. J.; O'Reilly, E. M.; Abou-Alfa, G. K.; Lowery, M. A.; Berger, M. F.
Article Title: Noninvasive detection of polyclonal acquired resistance to FGFR inhibition in patients with cholangiocarcinoma harboring FGFR2 alterations
Abstract: PURPOSE 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 thera pies. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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. (C) 2021 by American Society of Clinical Oncology
Journal Title: JCO Precision Oncology
Volume: 5
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2021-01-08
Start Page: 44
End Page: 50
Language: English
ACCESSION: WOS:000636553200007
DOI: 10.1200/po.20.00178
PROVIDER: wos
PMCID: PMC8232836
PUBMED: 34250419
Notes: Article -- Source: Wos
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MSK Authors
  1. James Joseph Harding
    162 Harding
  2. Anna Mary Varghese
    108 Varghese
  3. Ghassan Abou-Alfa
    425 Abou-Alfa
  4. Yelena Yuriy Janjigian
    292 Janjigian
  5. Gopakumar Vasudeva Iyer
    235 Iyer
  6. Eileen O'Reilly
    567 O'Reilly
  7. Michael Forman Berger
    603 Berger
  8. Fanli   Meng
    22 Meng
  9. Juber Ahamad Abdul Bari Patel
    18 Patel