title: Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.
abstract: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care.
  
  
  
  Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.
  
  
  
  A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months.
  
  
  
  Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.
  
  
  
  Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Department of Medicine, North Shore University Health System, Evanston, Illinois, USA Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hensing
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Alexa B
authors.initials: AB
authors.lastname: Schrock
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Allen
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Sanford
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Gowen
authors.affiliation: Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: He
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Elvin
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Chalmers
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Davidoff Cancer Center, Tiqwa, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Peled
authors.affiliation: Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Orange, California, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Klempner
authors.affiliation: Maryland Hematology-Oncology, Wheaton, Maryland, USA.
authors.forename: Kashif
authors.initials: K
authors.lastname: Firozvi
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Frampton
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Molina
authors.affiliation: Froedtert Cancer Center, Milwaukee, Wisconsin, USA.
authors.forename: Smitha
authors.initials: S
authors.lastname: Menon
authors.affiliation: Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Brahmer
authors.affiliation: Department of Radiology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Heber
authors.initials: H
authors.lastname: MacMahon
authors.affiliation: Department of Pathology, North Shore University Health System, Evanston, Illinois, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Nowak
authors.affiliation: Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Orange, California, USA.
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Zauderer
authors.affiliation: Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Zakowski
authors.affiliation: Bridgeport Oncology, Bridgeport, Connecticut, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Fischbach
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA Albany Medical College, Albany, New York, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Phil J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine Inc., Cambridge, Massachusetts, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Department of Medicine, Division of Oncology, School of Medicine, Stanford University, Stanford, California, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Wakelee
authors.affiliation: Cancer Institute of New Jersey, New Brunswick, New Jersey, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu.
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu.
authors.forename: Ravi
authors.initials: R
authors.lastname: Salgia
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D000077547:Crizotinib; D005260:Female; D020869:Gene Expression Profiling; D015321:Gene Rearrangement; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Crizotinib; Fluorescence in situ hybridization; Fusion; Genomic profiling