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

Jinchul Kim,Jeeyun Lee,Won Ki Kang,Seung Tae Kim,You Jeong Heo,Kyoung-Mee Kim,Binnari Kim,Se Hoon Park,So Young Kang

doi:10.3389/fonc.2020.00314

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).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.

Highlights

Immunotherapy has emerged as an innovative treatment for several types of cancer [1,2,3,4,5,6]
Cancer cells can escape immune surveillance by upregulating immune-checkpoint proteins, such as programmed death ligand 1 (PD-L1) [7]. This escape can be counteracted by using immune-checkpoint blockade (ICB), such as pembrolizumab and nivolumab, which interrupt the interaction between programmed cell death-1 (PD-1) and PDL1
Clinical data of 63 patients with advanced gastric cancer treated with ICB and quantifiable Tumor mutational burden (TMB) were evaluated

Summary

Introduction

Immunotherapy has emerged as an innovative treatment for several types of cancer [1,2,3,4,5,6]. Cancer cells can escape immune surveillance by upregulating immune-checkpoint proteins, such as programmed death ligand 1 (PD-L1) [7]. This escape can be counteracted by using immune-checkpoint blockade (ICB), such as pembrolizumab and nivolumab, which interrupt the interaction between programmed cell death-1 (PD-1) and PDL1. ICB have durable antitumor activity and improve survival in a subset of patients with PD-L1-expressing, MSI, and EBV-positive tumors [11, 12], there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential nonresponders [13]

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Results

Conclusion