Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations

Alexa B. Schrock; Garrett M. Frampton; James Suh; Zachary R. Chalmers; Mark Rosenzweig; Rachel L. Erlich; Balazs Halmos; Jonathan Goldman; Patrick Forde; Kurt Leuenberger; Nir Peled; Gregory P. Kalemkerian; Jeffrey S. Ross; Philip J. Stephens; Vincent A. Miller; Siraj M. Ali; Sai Hong Ignatius Ou

doi:10.1016/j.jtho.2016.06.004

Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations

Alexa B. Schrock, Garrett M. Frampton, James Suh, Zachary R. Chalmers, Mark Rosenzweig, Rachel L. Erlich, Balazs Halmos, Jonathan Goldman, Patrick Forde, Kurt Leuenberger, Nir Peled, Gregory P. Kalemkerian, Jeffrey S. Ross, Philip J. Stephens, Vincent A. Miller, Siraj M. Ali, Sai Hong Ignatius Ou

School of Medicine

Research output: Contribution to journal › Article › peer-review

146 Scopus citations

Abstract

Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-To-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians. Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclindependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14. Conclusion: Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.

Original language	English (US)
Pages (from-to)	1493-1502
Number of pages	10
Journal	Journal of Thoracic Oncology
Volume	11
Issue number	9
DOIs	https://doi.org/10.1016/j.jtho.2016.06.004
State	Published - 2016

Keywords

Genomic profiling
Lung cancer
Met exon 14 alterations
Met exon 14 skipping
Met y1003 mutation
Splice site mutations

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

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10.1016/j.jtho.2016.06.004

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Schrock, A. B., Frampton, G. M., Suh, J., Chalmers, Z. R., Rosenzweig, M., Erlich, R. L., Halmos, B., Goldman, J., Forde, P., Leuenberger, K., Peled, N., Kalemkerian, G. P., Ross, J. S., Stephens, P. J., Miller, V. A., Ali, S. M., & Ou, S. H. I. (2016). Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations. Journal of Thoracic Oncology, 11(9), 1493-1502. https://doi.org/10.1016/j.jtho.2016.06.004

Schrock, AB, Frampton, GM, Suh, J, Chalmers, ZR, Rosenzweig, M, Erlich, RL, Halmos, B, Goldman, J, Forde, P, Leuenberger, K, Peled, N, Kalemkerian, GP, Ross, JS, Stephens, PJ, Miller, VA, Ali, SM & Ou, SHI 2016, 'Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations', Journal of Thoracic Oncology, vol. 11, no. 9, pp. 1493-1502. https://doi.org/10.1016/j.jtho.2016.06.004

@article{1f6c574ed6a24dd8a94ba0f2f8f165f4,

title = "Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations",

abstract = "Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-To-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians. Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclindependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14. Conclusion: Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.",

keywords = "Genomic profiling, Lung cancer, Met exon 14 alterations, Met exon 14 skipping, Met y1003 mutation, Splice site mutations",

author = "Schrock, {Alexa B.} and Frampton, {Garrett M.} and James Suh and Chalmers, {Zachary R.} and Mark Rosenzweig and Erlich, {Rachel L.} and Balazs Halmos and Jonathan Goldman and Patrick Forde and Kurt Leuenberger and Nir Peled and Kalemkerian, {Gregory P.} and Ross, {Jeffrey S.} and Stephens, {Philip J.} and Miller, {Vincent A.} and Ali, {Siraj M.} and Ou, {Sai Hong Ignatius}",

year = "2016",

doi = "10.1016/j.jtho.2016.06.004",

language = "English (US)",

volume = "11",

pages = "1493--1502",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

number = "9",

}

TY - JOUR

T1 - Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations

AU - Schrock, Alexa B.

AU - Frampton, Garrett M.

AU - Suh, James

AU - Chalmers, Zachary R.

AU - Rosenzweig, Mark

AU - Erlich, Rachel L.

AU - Halmos, Balazs

AU - Goldman, Jonathan

AU - Forde, Patrick

AU - Leuenberger, Kurt

AU - Peled, Nir

AU - Kalemkerian, Gregory P.

AU - Ross, Jeffrey S.

AU - Stephens, Philip J.

AU - Miller, Vincent A.

AU - Ali, Siraj M.

AU - Ou, Sai Hong Ignatius

PY - 2016

Y1 - 2016

N2 - Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-To-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians. Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclindependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14. Conclusion: Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.

AB - Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-To-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs). Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians. Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtype not otherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell (2.1%), large cell (0.8%), and SCLC (0.2%). Acinar features were present in 24% of the METex14 samples. Six cases (2%) harbored MET Y1003X mutations affecting binding of the MET-negative regulator, E3 ubiquitin protein ligase. The median age of all patients with METex14 was 73 years (range 43-95) and 60% were female. Concurrent, murine double minute gene (MDM2) amplification, cyclindependent kinase 4 gene (CDK4) amplification, and EGFR amplification were observed in 35%, 21%, and 6.4% of patients with METex14, respectively. KRAS mutation was observed in 3% of cases. Concurrent MET amplification (METamp) (median copy number 10) was identified in 15% of METex14 samples. Significant differences in tumor mutational burden and type of the METex14 alterations were observed between the METamp and non-METamp samples. Response to MET TKI was observed in both in patients with METamp and in patients without METamp METex14. Conclusion: Diverse targetable METex14 alterations were identified in patients with NSCLC across age groups, including elderly patients, and in all major NSCLC histologic subtypes with an overall frequency of 2.7%. These findings support the use of hybrid capture-based molecular profiling across NSCLC subtypes to identify patients who will potentially benefit from MET TKIs.

KW - Genomic profiling

KW - Lung cancer

KW - Met exon 14 alterations

KW - Met exon 14 skipping

KW - Met y1003 mutation

KW - Splice site mutations

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JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

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Characterization of 298 patients with lung cancer harboring MET Exon 14 skipping alterations

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