title: Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib.
abstract: Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy.
  
  
  
  We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib.
  
  
  
  The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3-ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR.
  
  
  
  In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations.
authors.affiliation: Division of Medical Oncology, Department of Oncology.
authors.forename: A S
authors.initials: AS
authors.lastname: Mansfield
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Department of Molecular Medicine.
authors.forename: S J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Department of Molecular Medicine.
authors.forename: F R
authors.initials: FR
authors.lastname: Harris
authors.affiliation: Division of Medical Oncology, Department of Oncology.
authors.forename: S I
authors.initials: SI
authors.lastname: Robinson
authors.affiliation: Division of Medical Oncology, Department of Oncology.
authors.forename: R S
authors.initials: RS
authors.lastname: Marks
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Department of Molecular Medicine.
authors.forename: S H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Department of Molecular Medicine.
authors.forename: J B
authors.initials: JB
authors.lastname: Smadbeck
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Department of Molecular Medicine.
authors.forename: G C
authors.initials: GC
authors.lastname: Halling
authors.affiliation: Department of Laboratory Medicine and Pathology.
authors.forename: E S
authors.initials: ES
authors.lastname: Yi
authors.affiliation: Department of Surgery.
authors.forename: D
authors.initials: D
authors.lastname: Wigle
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Department of Molecular Medicine vasmatszis.george@mayo.edu.
authors.forename: G
authors.initials: G
authors.lastname: Vasmatzis
authors.affiliation: Division of Experimental Pathology and Laboratory Medicine, Department of Laboratory Medicine and Pathology.|Medical Genome Facility.|Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mayo Clinic, Rochester, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jen
mesh_terms: D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D058628:Myofibroblasts / Q000187:drug effects / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059039:Standard of Care; D013450:Sulfones / Q000008:administration & dosage; D014335:Tropomyosin / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; C498783:TPM3 protein, human; D014335:Tropomyosin; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C000605860:PDGFRB protein, human; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; C586847:ceritinib
keywords: ALK; IMT; ceritinib; chromoplexy; resistance