TY - JOUR
T1 - Comprehensive genomic profiling identifies a subset of Crizotinib- responsive ALK-rearranged non-small cell lung cancer not detected by fluorescence in situ hybridization
AU - Ali, Siraj M.
AU - Hensing, Thomas
AU - Schrock, Alexa B.
AU - Allen, Justin
AU - Sanford, Eric
AU - Gowen, Kyle
AU - Kulkarni, Atul
AU - He, Jie
AU - Suh, James H.
AU - Lipson, Doron
AU - Elvin, Julia A.
AU - Yelensky, Roman
AU - Chalmers, Zachary
AU - Chmielecki, Juliann
AU - Peled, Nir
AU - Klempner, Samuel J.
AU - Firozvi, Kashif
AU - Frampton, Garrett M.
AU - Molina, Julian R.
AU - Amenon, Smith
AU - Brahmer, Julie R.
AU - MacMahon, Heber
AU - Nowak, Jan
AU - Ignatius Ou, Sai Hong
AU - Zauderer, Marjorie
AU - Ladanyi, Marc
AU - Zakowski, Maureen
AU - Fischbach, Neil
AU - Ross, Jeffrey S.
AU - Stephens, Phil J.
AU - Miller, Vincent A.
AU - Wakelee, Heather
AU - Ganesan, Shridar
AU - Salgia, Ravi
N1 - Publisher Copyright:
© AlphaMed Press 2016.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - ALK
KW - Crizotinib
KW - Fluorescence in situ hybridization
KW - Fusion
KW - Genomic profiling
UR - http://www.scopus.com/inward/record.url?scp=84975257905&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2015-0497
DO - 10.1634/theoncologist.2015-0497
M3 - Article
C2 - 27245569
AN - SCOPUS:84975257905
SN - 1083-7159
VL - 21
SP - 762
EP - 770
JO - Oncologist
JF - Oncologist
IS - 6
ER -