title: Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions.
abstract: Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evaluated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.
  
  
  CONCLUSIONS
  Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no "standard-of-care" therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee. christine.lovly@vanderbilt.edu.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Abha
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Geoff
authors.initials: G
authors.lastname: Otto
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Tina
authors.initials: T
authors.lastname: Brennan
authors.affiliation: Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Chung
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Borinstein
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts. Albany Medical College, Albany, New York.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Coffin
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D000077547:Crizotinib; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009379:Neoplasms, Muscle Tissue / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta