title: Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.
abstract: Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Tex., USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.forename: Kyle
authors.initials: K
authors.lastname: Gowen
authors.forename: Daniel
authors.initials: D
authors.lastname: Spritz
authors.forename: Behrang
authors.initials: B
authors.lastname: Amini
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Sarina
authors.initials: S
authors.lastname: Piha-Paul
authors.forename: Maria
authors.initials: M
authors.lastname: Zarzour
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Erlich
authors.forename: David L
authors.initials: DL
authors.lastname: Stockman
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Vergilio
authors.forename: James H
authors.initials: JH
authors.lastname: Suh
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
mesh_terms: D000293:Adolescent; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary; D000077547:Crizotinib; D005260:Female; D006801:Humans; D007191:Indazoles; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D017599:Neuroectodermal Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D066066:Response Evaluation Criteria in Solid Tumors; D013449:Sulfonamides / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: C574775:EWSR1-CREB1 fusion protein, human; D007191:Indazoles; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D000077547:Crizotinib; C516667:pazopanib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases