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 Oh; Jonathan Anker; Lee Chun Park; Victor Wang; Jeffrey Chuang; Wungki Park

doi:10.1016/j.jtho.2019.06.016

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

Medicine, Hematology Oncology Division

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

35 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 language	English (US)
Pages (from-to)	1807-1817
Number of pages	11
Journal	Journal of Thoracic Oncology
Volume	14
Issue number	10
DOIs	https://doi.org/10.1016/j.jtho.2019.06.016
State	Published - Oct 2019

Funding

Disclosure: Dr. Chae reports research funding from AbbVie, BMS, Biodesix, Lexent Bio, and Freenome and honoraria for service on advisory boards from Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, Neogenomics, Guardant Health, Boehringher Ingelheim, Biodesix, Immuneoncia, Lilly Oncology, Merck, and Takeda Pharmaceuticals. Dr. Sokol, Dr. Frampton, Dr. Ali, and Dr. Ross are Foundation Medicine employees with an equity stake in Roche. Dr. Wungki Park reports research funding from the National Institutes of Health K12, Parker Institute for Cancer Immunotherapy, Society of Immunotherapy for Cancer-Sparkathon, Merck, and Astellas and provision of consultancy services to Ipsen. Dr. Lopes reports research funding from AstraZeneca, EMD Serono, and Merck. The remaining authors declare no conflict of interest.

Keywords

Biomarker
Frameshift
Genetics
Immunotherapy
Non–small cell lung cancer

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtho.2019.06.016

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

@article{8cd526bbab08404ba6c03403e4483f41,

title = "Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer",

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",

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

note = "Publisher Copyright: {\textcopyright} 2019 International Association for the Study of Lung Cancer",

year = "2019",

month = oct,

doi = "10.1016/j.jtho.2019.06.016",

language = "English (US)",

volume = "14",

pages = "1807--1817",

journal = "Journal of Thoracic Oncology",

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Chae, YK , Viveiros, P, Lopes, G, Sukhadia, B, Sheikh, MM, Saravia, D, Florou, V, Sokol, ES, Frampton, GM, Chalmers, ZR, Ali, SM, Ross, JS, Chang, S, Wang, S, Chiec, L, Rahbari, A, Mohindra, N, Villaflor, V, Shin, SH, Oh, M, Anker, J, Park, LC, Wang, V, Chuang, J & Park, W 2019, 'Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer', Journal of Thoracic Oncology, vol. 14, no. 10, pp. 1807-1817. https://doi.org/10.1016/j.jtho.2019.06.016

TY - JOUR

T1 - Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer

AU - Chae, Young Kwang

AU - Viveiros, Pedro

AU - Lopes, Gilberto

AU - Sukhadia, Bhoomika

AU - Sheikh, Muhammad Mubbashir

AU - Saravia, Diana

AU - Florou, Vaia

AU - Sokol, Ethan S.

AU - Frampton, Garrett M.

AU - Chalmers, Zachary R.

AU - Ali, Siraj M.

AU - Ross, Jeffrey S.

AU - Chang, Sangmin

AU - Wang, Si

AU - Chiec, Lauren

AU - Rahbari, Ashkon

AU - Mohindra, Nisha

AU - Villaflor, Victoria

AU - Shin, Sang Ha

AU - Oh, Michael

AU - Anker, Jonathan

AU - Park, Lee Chun

AU - Wang, Victor

AU - Chuang, Jeffrey

AU - Park, Wungki

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

KW - Biomarker

KW - Frameshift

KW - Genetics

KW - Immunotherapy

KW - Non–small cell lung cancer

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DO - 10.1016/j.jtho.2019.06.016

M3 - Article

C2 - 31238177

AN - SCOPUS:85071398876

SN - 1556-0864

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JF - Journal of Thoracic Oncology

IS - 10

ER -

Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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