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 ¼ 0.01]). In addition, significant differences in the overall response rates (26% versus 12% [p ¼ 0.04]) and disease control rates (68% versus 48% [p ¼ 0.02]) were observed in patients with fsindels. Conclusion: Our findings suggest that fsindels may have a predictive role for ICI response in NSCLC.

Combined Model of Frameshift Mutations and Tumor Mutation Burden in Predicting Preliminary Response to Immune Checkpoint Inhibitors in NSCLC

“…In summary, our real-world study supported the findings of Chae et al 1 that fsindel might serve as a synergistic biomarker which could predict the efficacy of ICI therapy for patients with NSCLC. More importantly, the results from a combined model of frameshift mutations and TMB indicated that the presence of fsindel enhanced the predictive ability of TMB in ICI therapy.…”

“…To the Editor: In this Journal, Chae et al 1 described the predictive role of frameshift mutation by insertion or deletion (fsindel) in a cohort of 122 patients with NSCLC who were treated with immune checkpoint inhibitors (ICIs). The results of this study show a positive correlation between fsindel (detected by the Foundatio-nOne CDx) and favorable clinical benefit (objective response rate [ORR] and progression-free survival [PFS]) in ICI-treated patients with NSCLC.…”

Challenges in bioinformatics approaches to tumor mutation burden analysis

“…In another recent paper, an increased progression-free survival was associated with the presence of frameshift InDel burden in patients treated with ICIs (40). In addition, significantly different overall response rates and disease control rates were observed between patients with and without frameshift InDels (40). However, the data available on the role of InDels and the different possible impact on response to ICI are limited and further evaluation is required.…”

Beyond Tumor Mutation Burden: Tumor Neoantigen Burden as a Biomarker for Immunotherapy and Other Types of Therapy

“…Primarily, TNB analysis was performed on SNV ( 47 ). However, other genetic aberrations may produce comparable or even more immunogenic neoantigens ( 23 ). For example, neoantigens were found from a data set of gene fusion-positive tumors ( 48 ).…”

“…A positive correlation has been noted between TMB and TNB. However, TNB is directly used for neoantigen evaluation and may be considered an improved biomarker for immunotherapy compared with TMB ( 23 – 25 ). High TNB was associated with durable progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) treated with programmed death 1 (PD-1) inhibitors ( 26 ).…”