title: Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein.
abstract: BACKGROUND
  Oncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.
  
  
  METHODS
  Genomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).
  
  
  RESULTS
  The histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.
  
  
  CONCLUSIONS
  The patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd,, FC8,3038, Box 0455, Houston, TX 77030, USA. vsubbiah@mdanderson.org.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Westin
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Dejka
authors.initials: D
authors.lastname: Araujo
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Gary A
authors.initials: GA
authors.lastname: Palmer
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics; D010671:Phenylurea Compounds / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018952:Antigens, CD34; C568616:BRAF-KIAA1549 fusion protein, human; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D009418:S100 Proteins; D009536:Niacinamide; D000068258:Bevacizumab; C401859:temsirolimus; D000077157:Sorafenib; C546842:MTOR protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus