title: Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers.
abstract: BACKGROUND
  The frequency with which targeted tumor sequencing results will lead to implemented change in care is unclear. Prospective assessment of the feasibility and limitations of using genomic sequencing is critically important.
  
  
  METHODS
  A prospective clinical study was conducted on 100 patients with diverse-histology, rare, or poor-prognosis cancers to evaluate the clinical actionability of a Clinical Laboratory Improvement Amendments (CLIA)-certified, comprehensive genomic profiling assay (FoundationOne), using formalin-fixed, paraffin-embedded tumors. The primary objectives were to assess utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board.
  
  
  RESULTS
  Of the tumors from the 92 patients with sufficient tissue, 88 (96%) had at least one genomic alteration (average 3.6, range 0-10). Commonly altered pathways included p53 (46%), RAS/RAF/MAPK (rat sarcoma; rapidly accelerated fibrosarcoma; mitogen-activated protein kinase) (45%), receptor tyrosine kinases/ligand (44%), PI3K/AKT/mTOR (phosphatidylinositol-4,5-bisphosphate 3-kinase; protein kinase B; mammalian target of rapamycin) (35%), transcription factors/regulators (31%), and cell cycle regulators (30%). Many low frequency but potentially actionable alterations were identified in diverse histologies. Use of comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations, including genomically guided therapy, diagnostic modification, and trigger for germline genetic testing.
  
  
  CONCLUSIONS
  Use of targeted next-generation sequencing in the setting of an institutional molecular tumor board led to implementable clinical action in more than one third of patients with rare and poor-prognosis cancers. Major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access. Early and serial sequencing in the clinical course and expanded access to genomically guided early-phase clinical trials and targeted agents may increase actionability.
  
  
  CONCLUSIONS
  Identification of key factors that facilitate use of genomic tumor testing results and implementation of genomically guided therapy may lead to enhanced benefit for patients with rare or difficult to treat cancers. Clinical use of a targeted next-generation sequencing assay in the setting of an institutional molecular tumor board led to implementable clinical action in over one third of patients with rare and poor prognosis cancers. The major barriers to implementation of genomically guided therapy were clinical status of the patient and drug access both on trial and off label. Approaches to increase actionability include early and serial sequencing in the clinical course and expanded access to genomically guided early phase clinical trials and targeted agents.
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Kim M
authors: KM
authors: Hirshfield
authors: Department of Clinical Informatics, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Denis
authors: D
authors: Tolkunov
authors: Department of Pathology and Laboratory Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Hua
authors: H
authors: Zhong
authors: Foundation Medicine, Cambridge, Massachusetts, USA.
authors: Siraj M
authors: SM
authors: Ali
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Mark N
authors: MN
authors: Stein
authors: Department of Pediatrics, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Susan
authors: S
authors: Murphy
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Hetal
authors: H
authors: Vig
authors: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Alexei
authors: A
authors: Vazquez
authors: Department of Pediatrics, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: John
authors: J
authors: Glod
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Rebecca A
authors: RA
authors: Moss
authors: Department of Clinical Informatics, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Vladimir
authors: V
authors: Belyi
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Chang S
authors: CS
authors: Chan
authors: Department of Chemical Biology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
authors: Suzie
authors: S
authors: Chen
authors: Department of Pathology and Laboratory Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Lauri
authors: L
authors: Goodell
authors: Department of Pathology and Laboratory Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: David
authors: D
authors: Foran
authors: Foundation Medicine, Cambridge, Massachusetts, USA.
authors: Roman
authors: R
authors: Yelensky
authors: Foundation Medicine, Cambridge, Massachusetts, USA.
authors: Norma A
authors: NA
authors: Palma
authors: Foundation Medicine, Cambridge, Massachusetts, USA.
authors: James X
authors: JX
authors: Sun
authors: Foundation Medicine, Cambridge, Massachusetts, USA.
authors: Vincent A
authors: VA
authors: Miller
authors: Foundation Medicine, Cambridge, Massachusetts, USA.
authors: Philip J
authors: PJ
authors: Stephens
authors: Foundation Medicine, Cambridge, Massachusetts, USA.|Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York, USA.
authors: Jeffrey S
authors: JS
authors: Ross
authors: Division of Surgical Oncology, Department of Surgery, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Howard
authors: H
authors: Kaufman
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Elizabeth
authors: E
authors: Poplin
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Janice
authors: J
authors: Mehnert
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Antoinette R
authors: AR
authors: Tan
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Joseph R
authors: JR
authors: Bertino
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Joseph
authors: J
authors: Aisner
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors: Robert S
authors: RS
authors: DiPaola
authors: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA ganesash@cinj.rutgers.edu rodriglo@cinj.rutgers.edu.
authors: Lorna
authors: L
authors: Rodriguez-Rodriguez
authors: Division of Medical Oncology, Department of Medicine, Rutgers Cancer Institute of New Jersey/Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA ganesash@cinj.rutgers.edu rodriglo@cinj.rutgers.edu.
authors: Shridar
authors: S
authors: Ganesan
keywords: Cancer; Molecular sequencing; Molecular targeted therapy; Mutation; Tumor genomics