title: Incorporation of Next-Generation Sequencing into Routine Clinical Care to Direct Treatment of Head and Neck Squamous Cell Carcinoma.
abstract: The clinical impact of next-generation sequencing (NGS) in patients with head and neck squamous cell carcinoma (HNSCC) has not been described. We aimed to evaluate the clinical impact of NGS in the routine care of patients with HNSCC and to correlate genomic alterations with clinical outcomes.
  
  
  
  Single-center study examining targeted NGS platform used to sequence tumor DNA obtained from 213 HNSCC patients evaluated in outpatient head and neck oncology clinic between August 2011 and December 2014. We correlated tumor genomic profiling results with clinical outcomes.
  
  
  
  PI3K/RTK pathway activation occurred frequently [activating PIK3CA mutation or amplification (13%), PTEN inactivation (3%), RAS activation (6%), EGFR or ERBB2 activation (9%)]. Alterations in pathways affecting cell-cycle regulation [CCND1 amplification (9%), CDKN2A inactivation (17%), BRCA2 inactivation (2%)] and squamous differentiation [NOTCH1 inactivation (8%) andEP300 inactivation (6%)] were identified. PIK3CA amplification (n = 43), not PIK3CA mutation, was associated with significantly poorer progression-free survival (P = 0.0006). Oncogenic RAS mutations (n = 13) were associated with significantly poorer progression-free survival (P = 0.0001) and lower overall survival (P = 0.003). Eight patients with advanced, treatment-refractory HNSCC enrolled on clinical trials matched to tumor profiling results, and 50% achieved a partial response.
  
  
  
  Incorporation of NGS clinical assays into the routine care of patients with HNSCC is feasible and may readily facilitate enrollment into clinical trials of targeted therapy with a higher likelihood of success. Data can be utilized for discovery of genomic biomarkers of outcome. PIK3CA amplification and RAS mutations were frequently identified and associated with poorer prognosis in this cohort. Clin Cancer Res; 22(12); 2939-49. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Chau
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vickie Y
authors.initials: VY
authors.lastname: Jo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Rabinowits
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Lorch
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roy B
authors.initials: RB
authors.lastname: Tishler
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Danielle N
authors.initials: DN
authors.lastname: Margalit
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schoenfeld
authors.affiliation: Division of Otolaryngology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Annino
authors.affiliation: Division of Otolaryngology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Goguen
authors.affiliation: Division of Otolaryngology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tom
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hailey
authors.initials: H
authors.lastname: Becker
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Peter_Hammerman@dfci.harvard.edu Robert_Haddad@dfci.harvard.edu.
authors.forename: Tyler
authors.initials: T
authors.lastname: Haddad
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Krane
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Haddad
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Peter_Hammerman@dfci.harvard.edu Robert_Haddad@dfci.harvard.edu.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)