title: Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of the impact of comprehensive tumor profiling using a targeted next-generation sequencing panel.
abstract: BACKGROUND
  Oncogenic genetic alterations "drive" neoplastic cell proliferation. Small molecule inhibitors and antibodies are being developed that target an increasing number of these altered gene products. Next-generation sequencing (NGS) is a powerful tool to identify tumor-specific genetic changes. To determine the clinical impact of extensive genetic analysis, we reviewed our experience using a targeted NGS platform (FoundationOne) in advanced cancer patients.
  
  
  METHODS
  We retrospectively assessed demographics, NGS results, and therapies received for patients undergoing targeted NGS (exonic sequencing of 236 genes and selective intronic sequencing from 19 genes) between April 2012 and August 2013. Coprimary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage who received genotype-directed therapy.
  
  
  RESULTS
  Samples from 103 patients were tested, most frequently breast carcinoma (26%), head and neck cancers (23%), and melanoma (10%). Most patients (83%) were found to harbor potentially actionable genetic alterations, involving cell-cycle regulation (44%), phosphatidylinositol 3-kinase-AKT (31%), and mitogen-activated protein kinase (19%) pathways. With median follow-up of 4.1 months, 21% received genotype-directed treatments, most in clinical trials (61%), leading to significant benefit in several cases. The most common reasons for not receiving genotype-directed therapy were selection of standard therapy (35%) and clinical deterioration (13%).
  
  
  CONCLUSIONS
  Mutational profiling using a targeted NGS panel identified potentially actionable alterations in a majority of advanced cancer patients. The assay identified additional therapeutic options and facilitated clinical trial enrollment. As time progresses, NGS results will be used to guide therapy in an increasing proportion of patients.
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Dahlman
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Knol
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilbert
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Means-Powell
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Murphy
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Goff
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Crispens
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Leora
authors.initials: L
authors.lastname: Horn
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Keedy
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Nishitha M
authors.initials: NM
authors.lastname: Reddy
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Department of Medicine, Department of Cancer Biology, and Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA william.pao@vanderbilt.edu.
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging
chemical_list: D009363:Neoplasm Proteins
keywords: Cancer; Genotype; Molecular targeted therapy; Mutation; Next-generation sequencing; Precision medicine