title: The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform.
abstract: OBJECTIVE
  Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies.
  
  
  OBJECTIVE
  To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease.
  
  
  METHODS
  After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis.
  
  
  METHODS
  Next-generation sequencing of tumors and matched normal DNA.
  
  
  METHODS
  Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease.
  
  
  RESULTS
  Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV)-positive tumors, many recurrent and metastatic HPV-positive tumors exhibited a molecular profile more similar to HPV-negative tumors, including enriched frequencies of TP53 mutation (3 of 20 tumors [15%]), whole genome duplication (5 of 20 tumors [25%]), and 3p deletion (11 of 20 tumors [55%]). There were high rates of TERT promoter mutation in recurrent and metastatic HPV-negative HNSCC (13 of 30 tumors [43%]), cutaneous SCC (11 of 21 tumors [52%]), basal cell carcinoma (3 of 4 tumors [75%]), and ACC (5 of 36 tumors [14%]). Activating NOTCH1 mutations were enriched in metastatic ACCs (8 of 36 tumors [22%]).
  
  
  CONCLUSIONS
  These findings reveal the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology. To understand the repertoire of targetable alterations in advanced cancers, it is necessary to sequence recurrent and metastatic tumors. These data are important first steps toward implementation of precision head and neck oncology.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York2Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Luc G T
authors.initials: LGT
authors.lastname: Morris
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Raghu
authors.initials: R
authors.lastname: Chandramohan
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lyndsay
authors.initials: L
authors.lastname: West
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York4Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Zehir
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Debyani
authors.initials: D
authors.lastname: Chakravarty
authors.affiliation: Head and Neck Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David G
authors.initials: DG
authors.lastname: Pfister
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wong
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Lee
authors.affiliation: Head and Neck Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sherman
authors.affiliation: Head and Neck Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shrujal S
authors.initials: SS
authors.lastname: Baxi
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jatin P
authors.initials: JP
authors.lastname: Shah
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Shaha
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jay O
authors.initials: JO
authors.lastname: Boyle
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Snehal G
authors.initials: SG
authors.lastname: Patel
authors.affiliation: Head and Neck Surgical Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Roman
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Barker
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sean M
authors.initials: SM
authors.lastname: McBride
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York6Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Dogan
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York4Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Riaz
authors.affiliation: Head and Neck Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Ho