Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer

Abstract

Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer.Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed.Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (≥65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Kim et al. TMB in Advanced Gastric Cancer Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.

DNA-protein biomarkers for immunotherapy in the era of precision oncology

“…However, the TMB cut-off points associated with improved survival varied markedly between cancer types, suggesting that a universal definition of high TMB may not be possible. Similar findings in patients with gastric cancer were observed when the following cut-off points were applied: 11% for the higher mutation group in 330 non-ICI-treated patients [8] and 14.31 mt/mb in 63 ICI-treated patients [6].…”

“…Despite efforts to standardize TMB from multiple genomic profiling cancer panels [4], the cut-off value for TMB remains inconsistent. TMB is generally defined as the number of nonsynonymous somatic mutations per megabase of genome examined, and a detailed description of TMB definitions in recently published papers using targeted sequencing is summarized in Table 1 [6][7][8][9][10][11][12][13][14][15][16][17][18].…”

A Potential Biomarker of Combination of Tumor Mutation Burden and Copy Number Alteration for Efficacy of Immunotherapy in KRAS-Mutant Advanced Lung Adenocarcinoma

“…We divided patients into subgroups based on the cutoff value of TMB (13.27 mut/Mb) and CNA (0.05) from X-tile software. Previous studies have revealed that a cut-off value for TMB of 14.31 mut/Mb was used to predict survival in patients who underwent immunotherapy for advanced gastric cancer (30), while intermediate CNA was found to discriminate for recurrence in a prostate cancer population (31). Therefore, more researches are needed to speculate the optimal cutoff for clinical practices.…”

Prediction of Overall Survival for Early-stage Non-small Cell Lung Cancer via a Novel 7-gene Prognostic Signature and Allele Frequency Deviation (AFD)

“…Recently, molecular biomarkers and gene signatures occupied a great deal of interest from researchers and are used in clinical practice for many aspects of cancer including tumorigenesis, progression and prognosis [52]. Gene signatures [53] as well as TMB and bTMB [54,55] survival of TCGA-LUAD and GSE11969 datasets respectively. On the contrary, the AUC of our 7-gene signature was higher with using 7 genes, this makes it appropriately suitable for clinical application.…”