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

55 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Fingerprint Dive into the research topics of 'Pulmonary Sarcomatoid Carcinomas Commonly Harbor Either Potentially Targetable Genomic Alterations or High Tumor Mutational Burden as Observed by Comprehensive Genomic Profiling'. Together they form a unique fingerprint.

  • Cite this

    Schrock, A. B., Li, S. D., Frampton, G. M., Suh, J., Braun, E., Mehra, R., Buck, S. C., Bufill, J. A., Peled, N., Karim, N. A., Hsieh, K. C., Doria, M., Knost, J., Chen, R., Ou, S. H. I., Ross, J. S., Stephens, P. J., Fishkin, P., Miller, V. A., ... Liu, J. J. (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, 12(6), 932-942. https://doi.org/10.1016/j.jtho.2017.03.005