Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling

Alexa B. Schrock, Shuyu D. Li, Garrett M. Frampton, James Suh, Eduardo Braun, Ranee Mehra, Steven C. Buck, Jose A. Bufill, Nir Peled, Nagla Abdel Karim, K. Cynthia Hsieh, Manuel Doria, James Knost, Rong Chen, Sai Hong Ignatius Ou, Jeffrey S. Ross, Philip J. Stephens, Paul Fishkin, Vincent A. Miller, Siraj M. AliBalazs Halmos, Jane J. Liu

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Introduction Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. Methods Hybrid capture–based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. Results The median age of the patients with PSC was 67 years (range 32–87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. Conclusion Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.

Original languageEnglish (US)
Pages (from-to)932-942
Number of pages11
JournalJournal of Thoracic Oncology
Volume12
Issue number6
DOIs
StatePublished - Jun 2017
Externally publishedYes

Fingerprint

Tumor Burden
Carcinoma
Lung
TYK2 Kinase
Proto-Oncogene Proteins c-met
erbB-2 Genes
Neoplasms
Mutation
Proto-Oncogenes
Gene Regulatory Networks
DNA
p53 Genes
Genomics
Paraffin
Immunotherapy
Formaldehyde
Genes
Exons
Guidelines
Drug Therapy

Keywords

  • BRAF
  • Genomic profiling
  • Immunotherapy
  • Lung sarcomatoid
  • MET exon 14
  • Tumor mutational burden

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling. / Schrock, Alexa B.; Li, Shuyu D.; Frampton, Garrett M.; Suh, James; Braun, Eduardo; Mehra, Ranee; Buck, Steven C.; Bufill, Jose A.; Peled, Nir; Karim, Nagla Abdel; Hsieh, K. Cynthia; Doria, Manuel; Knost, James; Chen, Rong; Ou, Sai Hong Ignatius; Ross, Jeffrey S.; Stephens, Philip J.; Fishkin, Paul; Miller, Vincent A.; Ali, Siraj M.; Halmos, Balazs; Liu, Jane J.

In: Journal of Thoracic Oncology, Vol. 12, No. 6, 06.2017, p. 932-942.

Research output: Contribution to journalArticle

Schrock, AB, Li, SD, Frampton, GM, Suh, J, Braun, E, Mehra, R, Buck, SC, Bufill, JA, Peled, N, Karim, NA, Hsieh, KC, Doria, M, Knost, J, Chen, R, Ou, SHI, Ross, JS, Stephens, PJ, Fishkin, P, Miller, VA, Ali, SM, Halmos, B & Liu, JJ 2017, 'Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling', Journal of Thoracic Oncology, vol. 12, no. 6, pp. 932-942. https://doi.org/10.1016/j.jtho.2017.03.005
Schrock, Alexa B. ; Li, Shuyu D. ; Frampton, Garrett M. ; Suh, James ; Braun, Eduardo ; Mehra, Ranee ; Buck, Steven C. ; Bufill, Jose A. ; Peled, Nir ; Karim, Nagla Abdel ; Hsieh, K. Cynthia ; Doria, Manuel ; Knost, James ; Chen, Rong ; Ou, Sai Hong Ignatius ; Ross, Jeffrey S. ; Stephens, Philip J. ; Fishkin, Paul ; Miller, Vincent A. ; Ali, Siraj M. ; Halmos, Balazs ; Liu, Jane J. / Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling. In: Journal of Thoracic Oncology. 2017 ; Vol. 12, No. 6. pp. 932-942.
@article{bd45bea48c6c41a8bba0e9f01fe2647c,
title = "Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling",
abstract = "Introduction Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. Methods Hybrid capture–based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8{\%}). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. Results The median age of the patients with PSC was 67 years (range 32–87), 58{\%} were male, and 78{\%} had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74{\%} of cases, which had genomics distinct from TP53 wild-type cases, and 62{\%} featured a GA in KRAS (34{\%}) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6{\%}), EGFR (8.8{\%}), BRAF (7.2{\%}), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6{\%}), and ret proto-oncogene (RET) (0.8{\%}). MET exon 14 alterations were enriched in PSC (12{\%}) compared with non-PSC NSCLCs (∼3{\%}) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20{\%} versus 14{\%}, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. Conclusion Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30{\%}) or intermediate or high TMB (43{\%}, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.",
keywords = "BRAF, Genomic profiling, Immunotherapy, Lung sarcomatoid, MET exon 14, Tumor mutational burden",
author = "Schrock, {Alexa B.} and Li, {Shuyu D.} and Frampton, {Garrett M.} and James Suh and Eduardo Braun and Ranee Mehra and Buck, {Steven C.} and Bufill, {Jose A.} and Nir Peled and Karim, {Nagla Abdel} and Hsieh, {K. Cynthia} and Manuel Doria and James Knost and Rong Chen and Ou, {Sai Hong Ignatius} and Ross, {Jeffrey S.} and Stephens, {Philip J.} and Paul Fishkin and Miller, {Vincent A.} and Ali, {Siraj M.} and Balazs Halmos and Liu, {Jane J.}",
year = "2017",
month = "6",
doi = "10.1016/j.jtho.2017.03.005",
language = "English (US)",
volume = "12",
pages = "932--942",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "6",

}

TY - JOUR

T1 - Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling

AU - Schrock, Alexa B.

AU - Li, Shuyu D.

AU - Frampton, Garrett M.

AU - Suh, James

AU - Braun, Eduardo

AU - Mehra, Ranee

AU - Buck, Steven C.

AU - Bufill, Jose A.

AU - Peled, Nir

AU - Karim, Nagla Abdel

AU - Hsieh, K. Cynthia

AU - Doria, Manuel

AU - Knost, James

AU - Chen, Rong

AU - Ou, Sai Hong Ignatius

AU - Ross, Jeffrey S.

AU - Stephens, Philip J.

AU - Fishkin, Paul

AU - Miller, Vincent A.

AU - Ali, Siraj M.

AU - Halmos, Balazs

AU - Liu, Jane J.

PY - 2017/6

Y1 - 2017/6

N2 - Introduction Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. Methods Hybrid capture–based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. Results The median age of the patients with PSC was 67 years (range 32–87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. Conclusion Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.

AB - Introduction Pulmonary sarcomatoid carcinoma (PSC) is a high-grade NSCLC characterized by poor prognosis and resistance to chemotherapy. Development of targeted therapeutic strategies for PSC has been hampered because of limited and inconsistent molecular characterization. Methods Hybrid capture–based comprehensive genomic profiling was performed on DNA from formalin-fixed paraffin-embedded sections of 15,867 NSCLCs, including 125 PSCs (0.8%). Tumor mutational burden (TMB) was calculated from 1.11 megabases (Mb) of sequenced DNA. Results The median age of the patients with PSC was 67 years (range 32–87), 58% were male, and 78% had stage IV disease. Tumor protein p53 gene (TP53) genomic alterations (GAs) were identified in 74% of cases, which had genomics distinct from TP53 wild-type cases, and 62% featured a GA in KRAS (34%) or one of seven genes currently recommended for testing in the National Comprehensive Cancer Network NSCLC guidelines, including the following: hepatocyte growth factor receptor gene (MET) (13.6%), EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%). MET exon 14 alterations were enriched in PSC (12%) compared with non-PSC NSCLCs (∼3%) (p < 0.0001) and were more prevalent in PSC cases with an adenocarcinoma component. The fraction of PSC with a high TMB (>20 mutations per Mb) was notably higher than in non-PSC NSCLC (20% versus 14%, p = 0.056). Of nine patients with PSC treated with targeted or immunotherapies, three had partial responses and three had stable disease. Conclusion Potentially targetable GAs in National Comprehensive Cancer Network NSCLC genes (30%) or intermediate or high TMB (43%, >10 mutations per Mb) were identified in most of the PSC cases. Thus, the use of comprehensive genomic profiling in clinical care may provide important treatment options for a historically poorly characterized and difficult to treat disease.

KW - BRAF

KW - Genomic profiling

KW - Immunotherapy

KW - Lung sarcomatoid

KW - MET exon 14

KW - Tumor mutational burden

UR - http://www.scopus.com/inward/record.url?scp=85018898426&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018898426&partnerID=8YFLogxK

U2 - 10.1016/j.jtho.2017.03.005

DO - 10.1016/j.jtho.2017.03.005

M3 - Article

C2 - 28315738

AN - SCOPUS:85018898426

VL - 12

SP - 932

EP - 942

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 6

ER -