title: Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches.
abstract: OBJECTIVE
  Broad, hybrid capture-based next-generation sequencing (NGS), as a clinical test, uses less tissue to identify more clinically relevant genomic alterations compared with profiling with multiple non-NGS tests. We set out to determine the frequency of such genomic alterations via this approach in tumors in which previous extensive non-NGS testing had not yielded a targetable driver alteration.
  
  
  METHODS
  We enrolled patients with lung adenocarcinoma with a ≤ 15 pack-year smoking history whose tumors previously tested "negative" for alterations in 11 genes (mutations in EGFR, ERBB2, KRAS, NRAS, BRAF, MAP2K1, PIK3CA, and AKT1 and fusions involving ALK, ROS1, and RET) via multiple non-NGS methods. We performed hybridization capture of the coding exons of 287 cancer-related genes and 47 introns of 19 frequently rearranged genes and sequenced these to deep, uniform coverage.
  
  
  RESULTS
  Actionable genomic alterations with a targeted agent based on NCCN guidelines were identified in 26% [8 of 31: EGFR G719A, BRAF V600E, SOCS5-ALK, HIP1-ALK, CD74-ROS1, KIF5B-RET (n = 2), CCDC6-RET]. Seven of these patients either received or are candidates for targeted therapy. Comprehensive genomic profiling using this method also identified a genomic alteration with a targeted agent available on a clinical trial in an additional 39% (12 of 31).
  
  
  CONCLUSIONS
  Broad, hybrid capture-based NGS identified actionable genomic alterations in 65% [95% confidence interval (CI), 48%-82%] of tumors from never or light smokers with lung cancers deemed without targetable genomic alterations by earlier extensive non-NGS testing. These findings support first-line profiling of lung adenocarcinomas using this approach as a more comprehensive and efficient strategy compared with non-NGS testing. See related commentary by McCutcheon and Giaccone, p. 3584.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. drilona@mskcc.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Sohail
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Greenbowe
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Phil
authors.initials: P
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Doron
authors.initials: D
authors.lastname: Lipson
authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D015894:Genome, Human; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D009363:Neoplasm Proteins