Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches Journal Article


Authors: Drilon, A.; Wang, L.; Arcila, M. E.; Balasubramanian, S.; Greenbowe, J. R.; Ross, J. S.; Stephens, P.; Lipson, D.; Miller, V. A.; Kris, M. G.; Ladanyi, M.; Rizvi, N. A.
Article 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: Purpose: 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. Experimental Design: 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. © 2015 American Association for Cancer Research.
Keywords: protein kinase b; adult; clinical article; controlled study; aged; gene mutation; exon; erlotinib; cancer growth; patient selection; cancer staging; polymerase chain reaction; gene amplification; epidermal growth factor receptor; epidermal growth factor receptor 2; intron; gene frequency; smoking; tumor biopsy; phosphatidylinositol 3 kinase; patient identification; lung adenocarcinoma; gene rearrangement; drug response; reactive oxygen metabolite; egfr gene; oncogene k ras; k ras protein; tumor gene; genetic screening; lobectomy; b raf kinase; protein mdm2; braf gene; anaplastic lymphoma kinase; copy number variation; oncogene n ras; pleura biopsy; wedge resection; crizotinib; microtubule associated protein 2; suppressor of cytokine signaling; genetic damage; tp53 gene; next generation sequencing; cabozantinib; afatinib; cdk4 gene; mdm2 gene; setd2 gene; cd74 gene; human; male; female; priority journal; article; ccdc6 gene; kif5b gene
Journal Title: Clinical Cancer Research
Volume: 21
Issue: 16
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2015-08-15
Start Page: 3631
End Page: 3639
Language: English
DOI: 10.1158/1078-0432.ccr-14-2683
PROVIDER: scopus
PUBMED: 25567908
PMCID: PMC4917003
DOI/URL:
Notes: Export Date: 2 November 2015 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Naiyer A Rizvi
    156 Rizvi
  2. Marc Ladanyi
    863 Ladanyi
  3. Lu Wang
    139 Wang
  4. Maria Eugenia Arcila
    336 Arcila
  5. Mark Kris
    597 Kris
  6. Alexander Edward Drilon
    136 Drilon