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J Thorac Oncol. 2019 Oct;14(10):1807-1817. doi: 10.1016/j.jtho.2019.06.016. Epub 2019 Jun 22.

Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer.

Author information

1
Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
2
Leonard M. Miller School of Medicine, University of Miami, Miami, Florida.
3
Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
4
Foundation Medicine, Cambridge, Massachusetts.
5
Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois; Foundation Medicine, Cambridge, Massachusetts.
6
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
7
Leonard M. Miller School of Medicine, University of Miami, Miami, Florida; Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical College, New York, New York. Electronic address: parkw1@mskcc.org.

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.

KEYWORDS:

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

PMID:
31238177
DOI:
10.1016/j.jtho.2019.06.016

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