Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer

Young Kwang Chae, Pedro Viveiros, Gilberto Lopes, Bhoomika Sukhadia, Muhammad Mubbashir Sheikh, Diana Saravia, Vaia Florou, Ethan S. Sokol, Garrett M. Frampton, Zachary R. Chalmers, Siraj M. Ali, Jeffrey S. Ross, Sangmin Chang, Si Wang, Lauren Chiec, Ashkon Rahbari, Nisha Mohindra, Victoria Villaflor, Sang Ha Shin, Michael OhJonathan Anker, Lee Chun Park, Victor Wang, Jeffrey Chuang, Wungki Park*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Introduction: Presently, programmed death ligand 1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in NSCLC. Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindels) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs. Positive correlation of fsindels with ICI response has been studied in melanoma and renal cell carcinoma. We investigated the implication of fsindels in the clinical outcomes and immune landscape of patients with NSCLC treated with ICIs. Methods: We utilized The Cancer Genome Atlas data set to analyze tumor mutational burden, neoantigen burden, and immune landscape in relation to fsindel status. In addition, utilizing the clinical data from 122 patients treated with ICIs, we evaluated the influence of fsindels on disease response rates and survival outcomes. Results: A positive correlation between fsindel burden and tumor mutational burden and activated CD4/CD8 T-cell infiltration was shown. Presence of fsindels was also associated with significant prolongation of progression-free survival in patients treated with ICIs (median 6.2 versus 2.7 months [p = 0.01]). In addition, significant differences in the overall response rates (26% versus 12% [p = 0.04]) and disease control rates (68% versus 48% [p = 0.02]) were observed in patients with fsindels. Conclusion: Our findings suggest that fsindels may have a predictive role for ICI response in NSCLC.

Original languageEnglish (US)
Pages (from-to)1807-1817
Number of pages11
JournalJournal of Thoracic Oncology
Volume14
Issue number10
DOIs
StatePublished - Oct 2019

    Fingerprint

Keywords

  • Biomarker
  • Frameshift
  • Genetics
  • Immunotherapy
  • Non–small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Chae, Y. K., Viveiros, P., Lopes, G., Sukhadia, B., Sheikh, M. M., Saravia, D., Florou, V., Sokol, E. S., Frampton, G. M., Chalmers, Z. R., Ali, S. M., Ross, J. S., Chang, S., Wang, S., Chiec, L., Rahbari, A., Mohindra, N., Villaflor, V., Shin, S. H., ... Park, W. (2019). Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer. Journal of Thoracic Oncology, 14(10), 1807-1817. https://doi.org/10.1016/j.jtho.2019.06.016