Tags

Type your tag names separated by a space and hit enter

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.
Oncologist 2016; 21(6):762-70O

Abstract

INTRODUCTION

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.

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 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.

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.

IMPLICATIONS FOR PRACTICE

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+Show Affiliations

Foundation Medicine Inc., Cambridge, Massachusetts, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu.Department of Medicine, North Shore University Health System, Evanston, Illinois, USA Department of Medicine, The University of Chicago, Chicago, Illinois, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Cancer Institute of New Jersey, New Brunswick, New Jersey, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Davidoff Cancer Center, Tiqwa, Israel.Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Orange, California, USA.Maryland Hematology-Oncology, Wheaton, Maryland, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Mayo Clinic, Rochester, Minnesota, USA.Froedtert Cancer Center, Milwaukee, Wisconsin, USA.Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.Department of Radiology, The University of Chicago, Chicago, Illinois, USA.Department of Pathology, North Shore University Health System, Evanston, Illinois, USA.Chao Family Comprehensive Cancer Center, School of Medicine, University of California, Irvine, Orange, California, USA.Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA.Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA.Memorial Sloan Kettering Cancer Center, Manhattan, New York, USA.Bridgeport Oncology, Bridgeport, Connecticut, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA Albany Medical College, Albany, New York, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Foundation Medicine Inc., Cambridge, Massachusetts, USA.Department of Medicine, Division of Oncology, School of Medicine, Stanford University, Stanford, California, USA.Cancer Institute of New Jersey, New Brunswick, New Jersey, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu.Department of Medicine, The University of Chicago, Chicago, Illinois, USA rsalgia@coh.org sali@foundationmedicine.com ganesash@cinj.rutgers.edu.

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

27245569

Citation

Ali, Siraj M., et al. "Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected By Fluorescence in Situ Hybridization." The Oncologist, vol. 21, no. 6, 2016, pp. 762-70.
Ali SM, Hensing T, Schrock AB, et al. Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization. Oncologist. 2016;21(6):762-70.
Ali, S. M., Hensing, T., Schrock, A. B., Allen, J., Sanford, E., Gowen, K., ... Salgia, R. (2016). Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization. The Oncologist, 21(6), pp. 762-70. doi:10.1634/theoncologist.2015-0497.
Ali SM, et al. Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected By Fluorescence in Situ Hybridization. Oncologist. 2016;21(6):762-70. PubMed PMID: 27245569.
* Article titles in AMA citation format should be in sentence-case
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 - Menon,Smitha, AU - Brahmer,Julie R, AU - MacMahon,Heber, AU - Nowak,Jan, AU - Ou,Sai-Hong Ignatius, 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, Y1 - 2016/05/31/ PY - 2015/12/07/received PY - 2016/03/07/accepted PY - 2016/6/2/entrez PY - 2016/6/2/pubmed PY - 2017/11/2/medline KW - ALK KW - Crizotinib KW - Fluorescence in situ hybridization KW - Fusion KW - Genomic profiling SP - 762 EP - 70 JF - The oncologist JO - Oncologist VL - 21 IS - 6 N2 - INTRODUCTION: 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. 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 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. 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. IMPLICATIONS FOR PRACTICE: 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. SN - 1549-490X UR - https://www.unboundmedicine.com/medline/citation/27245569/Comprehensive_Genomic_Profiling_Identifies_a_Subset_of_Crizotinib_Responsive_ALK_Rearranged_Non_Small_Cell_Lung_Cancer_Not_Detected_by_Fluorescence_In_Situ_Hybridization_ L2 - https://doi.org/10.1634/theoncologist.2015-0497 DB - PRIME DP - Unbound Medicine ER -