title: Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response.
abstract: OBJECTIVE
  Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer.
  
  
  OBJECTIVE
  To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response.
  
  
  METHODS
  Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response.
  
  
  METHODS
  Feasibility, use of WES for decision making, and identification of novel biomarkers.
  
  
  RESULTS
  A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response.
  
  
  CONCLUSIONS
  The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York2Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York3Department of Medicine, Weill Cornell Medical.
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Eng
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Sigaras
authors.affiliation: Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romanel
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Hanna
authors.initials: H
authors.lastname: Rennert
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Myriam
authors.initials: M
authors.lastname: Kossai
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Chantal
authors.initials: C
authors.lastname: Pauli
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
authors.forename: Bishoy
authors.initials: B
authors.lastname: Faltas
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Fontugne
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Kyung
authors.initials: K
authors.lastname: Park
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Jason
authors.initials: J
authors.lastname: Banfelder
authors.affiliation: Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prandi
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Neel
authors.initials: N
authors.lastname: Madhukar
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Tuo
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Jessica
authors.initials: J
authors.lastname: Padilla
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Noah
authors.initials: N
authors.lastname: Greco
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Terra J
authors.initials: TJ
authors.lastname: McNary
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Erick
authors.initials: E
authors.lastname: Herrscher
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Wilkes
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Theresa Y
authors.initials: TY
authors.lastname: MacDonald
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.affiliation: New York Genome Center, New York, New York.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.affiliation: New York Genome Center, New York, New York.
authors.forename: Anne-Katrin
authors.initials: AK
authors.lastname: Emde
authors.affiliation: New York Genome Center, New York, New York.
authors.forename: Dayna
authors.initials: D
authors.lastname: Oschwald
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Adrian Y
authors.initials: AY
authors.lastname: Tan
authors.affiliation: Department of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, New York.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Colin
authors.initials: C
authors.lastname: Collins
authors.affiliation: Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Dimple
authors.initials: D
authors.lastname: Chakravarty
authors.affiliation: Department of Radiology, Weill Cornell Medical College, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Schiffman
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Robert
authors.initials: R
authors.lastname: Kim
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York11Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York6Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Robinson
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.affiliation: Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Tagawa
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York.
authors.forename: Jenny Z
authors.initials: JZ
authors.lastname: Xiang
authors.affiliation: Rockefeller University, New York, New York.
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York6Centre of Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: David S
authors.initials: DS
authors.lastname: Rickman
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York4Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York5Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
mesh_terms: D000046:Academic Medical Centers; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D019295:Computational Biology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005240:Feasibility Studies; D005260:Female; D018628:Gene Dosage; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor