Comprehensive genomic profiling identifies a subset of Crizotinib- responsive ALK-rearranged non-small cell lung cancer not detected by fluorescence in situ hybridization

Siraj M. Ali, Thomas Hensing, Alexa B. Schrock, Justin Allen, Eric Sanford, Kyle Gowen, Atul Kulkarni, Jie He, James H. Suh, Doron Lipson, Julia A. Elvin, Roman Yelensky, Zachary Chalmers, Juliann Chmielecki, Nir Peled, Samuel J. Klempner, Kashif Firozvi, Garrett M. Frampton, Julian R. Molina, Smith AmenonJulie R. Brahmer, Heber MacMahon, Jan Nowak, Sai Hong Ignatius Ou, Marjorie Zauderer, Marc Ladanyi, Maureen Zakowski, Neil Fischbach, Jeffrey S. Ross, Phil J. Stephens, Vincent A. Miller, Heather Wakelee, Shridar Ganesan, Ravi Salgia

Research output: Contribution to journalArticlepeer-review

102 Scopus citations


Introduction. For patientswith non-small cell lung cancer (NSCLC) to benefit from ALK in hibitors,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 othermethods 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. Materials and Methods. 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. Results. 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 PRKAR1AALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20were 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. Conclusion. 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.

Original languageEnglish
Pages (from-to)762-770
Number of pages9
Issue number6
StatePublished - Jun 2016
Externally publishedYes


  • ALK
  • Crizotinib
  • Fluorescence in situ hybridization
  • Fusion
  • Genomic profiling


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